ESC Guidelines on Diabetes, Pre-Diabetes, and CVD
ESC Guidelines on Diabetes, Pre-Diabetes, and CVD
A joint scientific statement from the ADA and EASD advocates lifestyle management (including healthy eating, physical activity and cessation of smoking) as a first measure for the prevention and/or management of T2DM, with targets of weight loss and reduction of cardiovascular risk. An individualized approach to T2DM is also recommended by other organizations. A recent Cochrane review concluded that data on the efficacy of dietary intervention in T2DM are scarce and of relatively poor quality. The ADA position statement, Nutrition Recommendations and Interventions for Diabetes provides a further review of these issues.
Most European people with T2DM are obese, and weight control has been considered a central component of lifestyle intervention. 'Look AHEAD (Action for Health in Diabetes)' was a large clinical trial of the effects of long-term weight loss on glycaemia and prevention of CVD events in T2DM. One-year results of the intensive lifestyle intervention showed an average 8.6% weight loss, a significant reduction in HbA1c and a reduction in several CVD risk factors—benefits that were sustained after four years. The trial was, however, stopped for reasons of futility in 2012, since no difference in CVD events was detected between groups. Weight reduction—or at least stabilization in overweight or moderately obese people—will still be an important component in a lifestyle programme and may have pleiotropic effects. In very obese individuals, bariatric surgery causes long-term weight loss and reduces the rate of incident T2DM and mortality.
6.1.1 Diet. Dietary interventions recommended by the EASD Diabetes and Nutrition Study Group are less prescriptive than many earlier sets of dietary advice. They acknowledge that several dietary patterns can be adopted and emphasize that an appropriate intake of total energy and a diet in which fruits, vegetables, wholegrain cereals and low-fat protein sources predominate are more important than the precise proportions of total energy provided by the major macronutrients. It is also considered that salt intake should be restricted.
It has been suggested that there is no benefit in a high-protein- over a high-carbohydrate diet in T2DM. Specific dietary recommendations include limiting saturated and trans fats and alcohol intake, monitoring carbohydrate consumption and increasing dietary fibre. Routine supplementation with antioxidants, such as vitamins E and C and carotene, is not advised because of lack of efficacy and concern related to long-term safety. For those who prefer a higher intake of fat, a Mediterranean-type diet is acceptable, provided that fat sources are derived primarily from monounsaturated oils—as shown by the Primary Prevention of Cardiovascular Disease with a Mediterranean Diet (PREDIMED) study using virgin olive oil.
Recommended Distributions of Macronutrients:
Proteins: 10–20% of total energy in patients without nephropathy (if nephropathy, less protein).
Saturated and transunsaturated fatty acids: combined <10% of the total daily energy. A lower intake, <8%, may be beneficial if LDL-C is elevated.
Oils rich in monounsaturated fatty acids are useful fat sources and may provide 10–20% total energy, provided that total fat intake does not exceed 35% of total energy.
Polyunsaturated fatty acids: up to 10% total daily energy.
Total fat intake should not exceed 35% of total energy. For those who are overweight, fat intake <30% may facilitate weight loss. Consumption of two to three servings of—preferably—oily fish each week and plant sources of n-3 fatty acids (e.g. rapeseed oil, soybean oil, nuts and some green leafy vegetables) are recommended to ensure an adequate intake of n-3 fatty acids. Cholesterol intake should be <300 mg/day and be further reduced if LDL-C is elevated. The intake of trans fatty acids should be as small as possible, preferably none from industrial origin and limited to <1% of total energy intake from natural origin.
Carbohydrate may range from 45–60% of total energy. Metabolic characteristics suggest that the most appropriate intakes for individuals with DM are within this range. There is no justification for the recommendation of very low carbohydrate diets in DM. Carbohydrate quantities, sources and distribution should be selected to facilitate near-normal long-term glycaemic control. In those treated with insulin or oral hypoglycaemic agents, timing and dosage of the medication should match quantity and nature of carbohydrate. When carbohydrate intake is at the upper end of the recommended range, it is important to emphasize foods rich in dietary fibre and with a low glycaemic index.
Vegetables, legumes, fruits and wholegrain cereals should be part of the diet.
Dietary fibre intake should be >40 g/day (or 20 g/1000 Kcal/day), about half of which should be soluble. Daily consumption of ≥5 servings of fibre-rich vegetables or fruit and ≥4 servings of legumes per week can provide minimum requirements for fibre intake. Cereal-based foods should be wholegrain and high in fibre.
Alcohol drinking in moderate amounts, not exceeding two glasses or 20 g/day for men and one glass or 10 g/day for women, is associated with a lower risk of CVD, compared with teetotallers and heavy alcohol drinkers, both in individuals with and without DM. Excessive intake is associated with hypertriglyceridaemia and hypertension.
Coffee drinking: >4 cups/day is associated with a lower risk of CVD in people with T2DM, but it should be noted that boiled coffee without filtering raises LDL-C and should be avoided.
6.1.2 Physical Activity. Physical activity is important in the prevention of the development of T2DM in people with IGT and and for the control of glycaemia and related CVD complications. Aerobic and resistance training improve insulin action and PG, lipids, blood pressure and cardiovascular risk. Regular exercise is necessary for continuing benefit.
Little is known about the best way to promote physical activity; however, data from a number of RCTs support the need for reinforcement by healthcare workers. Systematic reviews found that structured aerobic exercise or resistance exercise reduced HbA1c by about 0.6% in T2DM. Since a decrease in HbA1c is associated with a long-term decrease in CVD events and a reduction in microvascular complications, long-term exercise regimens that lead to an improvement in glycaemic control may ameliorate the appearance of vascular complications. Combined aerobic and resistance training has a more favourable impact on HbA1c than aerobic or resistance training alone. In a recent meta-analysis of 23 studies, structured exercise training was associated with a 0.7% fall in HbA1c, compared with controls. Structured exercise of >150 min/week was associated with a fall in HbA1c of 0.9% <150 min/week with a fall of 0.4%. Overall, interventions of physical activity advice were associated with lower HbA1c levels only when combined with dietary advice.
6.1.3 Smoking. Smoking increases the risk of T2DM, CVD and premature death, and should be avoided. Stopping smoking decreases risk of CVD. People with DM who are current smokers should be offered a structured smoking cessation programme including pharmacological support with, for example, buproprion and varenicline if needed. Detailed instruction on smoking cessation should be given according to the five A principles ( Table 7 ) as is further elaborated in the 2012 Joint European Prevention guidelines.
6.1.4 Gaps in Knowledge.
6.1.5 Recommendations on Life Style Modifications in Diabetes.
Randomized controlled trials provide compelling evidence that the microvascular complications of DM are reduced by tight glycaemic control, which also exerts a favourable, although smaller, influence on CVD that becomes apparent after many years. However, intensive glucose control, combined with effective blood pressure control and lipid lowering, appear to markedly shorten the time needed to make improvements in the rate of cardiovascular events.
6.2.1 Microvascular Disease (Retinopathy, Nephropathy and Neuropathy). Intensified glucose lowering, targeting an HbA1c of 6.0–7.0%, (42–53 mmol/mol), has consistently been associated with a decreased frequency and severity of microvascular complications. This applies to both T1DM and T2DM, although the outcomes are less apparent in T2DM with established complications, for which the number needed to treat (NNT) is high. Analyses from the Diabetes Control and Complications Trial (DCCT) and the UKPDS demonstrated a continuous relationship between increasing HbA1c and microvascular complications, without an apparent threshold. In the DCCT, a decrease in HbA1c of 2% (21.9 mmol/mol) significantly lowered the risk of the development and progression of retinopathy and nephropathy, although the absolute reduction was low at HbA1c <7.5% (58 mmol/mol). The UKPDS reported a similar relationship in people with T2DM.
6.2.2 Macrovascular Disease (Cerebral, Coronary and Peripheral Artery Disease). Although there is a strong relationship between glycaemia and microvascular disease, the situation regarding macrovascular disorders is less clear. Hyperglycaemia in the high normal range, with minor elevations in HbA1c, has been associated with increased cardiovascular risk in a dose-dependent fashion. However, the effects of improving glycaemia on cardiovascular risk remain uncertain and recent RCTs have not provided clear evidence in this area. The reasons, of which there are several, include the presence of multiple co-morbidities in long-standing T2DM and the complex risk phenotype generated in the presence of IR (for further details see Section 4).
6.2.3 Medium-term Effects of Glycaemic Control. Action to Control Cardiovascular Risk in Diabetes (ACCORD): A total of 10 251 T2DM participants at high cardiovascular risk were randomized to intensive glucose control achieving an HbA1c of 6.4% (46 mmol/mol), or to standard treatment achieving an HbA1c of 7.5% (58 mmol/mol). After a mean follow-up of 3.5 years the study was terminated due to higher mortality in the intensive arm (14/1000 vs. 11/1000 patient deaths/year), which was pronounced in those with multiple cardiovascular risk factors and driven mainly by cardiovascular mortality. As expected, the rate of hypoglycaemia was higher under intensive treatment and in patients with poorer glycaemic control, although the role of hypoglycaemia in the CVD outcomes is not entirely clear. Further analysis revealed that the higher mortality may have been due to fluctuations in glucose, in combination with an inability to control glucose according to target, despite aggressive glucose lowering treatment. A recent extended follow-up of ACCORD did not support the hypothesis that severe symptomatic hypoglycaemia was related to the higher mortality.
Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE): A total of 11 140 T2DM participants at high cardiovascular risk were randomized to intensive or conventional glucose-lowering therapy. The intensive arm achieved an HbA1c of 6.5% (48 mmol/mol), compared with 7.3% (56 mmol/mol) in the standard arm. The primary endpoint (major macrovascular or microvascular complications) was reduced in the intensive arm (HR 0.90; 95% CI 0.82–0.98) due to a reduction in nephropathy. Intensive glycaemic control failed to influence the macrovascular component of the primary endpoint (HR 0.94; 95% CI 0.84–1.06). In contrast to ACCORD, there was no increase in mortality (HR 0.93; 95% CI 0.83–1.06) despite a similar decrease in HbA1c. Severe hypoglycaemia was reduced by two thirds in the intensive arm of ADVANCE, compared with ACCORD, and HbA1c lowering to target was achieved at a slower rate than in ACCORD. In addition, the studies had a different baseline CVD risk, with a higher rate of events in the control group of ADVANCE.
Veterans Administration Diabetes Trial (VADT): In this trial, 1791 T2DM patients were randomized to intensive or standard glucose control, achieving an HbA1c of 6.9% (52 mmol/mol) in the intensive therapy group, compared with 8.4% (68 mmol/mol) in the standard therapy group. There was no significant reduction of the primary composite cardiovascular endpoint in the intensive therapy group (HR 0.88; 95% CI 0.74–1.05).
Outcome Reduction With an Initial Glargine Intervention Trial (ORIGIN): This study randomized 12 537 people (mean age, 63.5 years) at high CVD risk plus IFG, IGT or T2DM to receive insulin glargine (with a target fasting blood glucose level of 5.3 mmol/L (≤95 mg/dL) or to standard care. After a median follow-up of 6.2 years, the rates of incident CV outcomes were similar in the insulin glargine and standard care groups. Rates of severe hypoglycaemia were 1.00 vs. 0.31 per 100 person-years. Median weight increased by 1.6 kg in the insulin glargine group and fell by 0.5 kg in the standard care group. There was no indication that insulin glargine was associated with cancer.
Conclusion: A meta-analysis of cardiovascular outcomes based on VADT, ACCORD and ADVANCE suggested that an HbA1c reduction of ~1% was associated with a 15% relative risk reduction (RRR) in non-fatal MI but without benefits on stroke or all-cause mortality. However, patients with a short duration of T2DM, lower baseline HbA1c at randomization, and without a history of CVD seemed to benefit from more-intensive glucose-lowering strategies. This interpretation is supported by ORIGIN, which did not demonstrate benefit or detriment on cardiovascular end-points by early institution of insulin-based treatment, even though insulin glargine was associated with increased hypoglycaemia. This suggests that intensive glycaemic control should be appropriately applied in an individualized manner, taking into account age, duration of T2DM and history of CVD.
6.2.4 Long-term Effects of Glycaemic Control. Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC): In DCCT, the rate of cardiovascular events was not significantly altered in the intensive-treatment group. After termination of the study, 93% of the cohort were followed for an additional 11 years under EDIC, during which the differences in HbA1c disappeared. During the combined 17-year follow-up, the risk of any cardiovascular event was reduced in the intensive group by 42% (9–63%; P < 0.01).
United Kingdom Prospective Diabetes Study (UKPDS): Although a clear reduction in microvascular complications was evident, the reduction in MI was only 16% (P = 0.052). In the extension phase of the study, a risk reduction in MI remained at 15%, which became significant as the number of cases increased. Furthermore, the beneficial effects persisted for any DM-related end point; MI and death from any cause was reduced by 13%. It should be noted that this study was performed when lipid lowering and blood pressure were less effectively managed, partially due to the lack of availability of potent, currently available drugs. Thus UKPDS was performed when other important parts of a multifactorial management were less efficient. One may speculate that it may have been easier to verify a beneficial effect of glucose-lowering agents at that time, than in subsequently performed trials.
Conclusion: DCCT and UKPDS showed that, in T1DM and T2DM: (i) glycaemic control is important for reducing long-term macrovascular complications; (ii) a very long follow-up period is required to demonstrate an effect and (iii) early glucose control is important (metabolic memory).
6.2.5 Glycaemic Targets. An HbA1c target of <7.0% (<53 mmol/mol) to reduce microvascular disease is a generally accepted level. The evidence for an HbA1c target in relation to macrovascular risk is less compelling, in part due to the complexities surrounding the chronic, progressive nature of DM and the effects of metabolic memory. Consensus indicates that an HbA1c of ≤7% should be targeted, but with acknowledgement of the need to pay attention to the individual requirements of the patient. Ideally, tight control should be instigated early in the course of the disorder in younger people and without attendant co-morbidities. Fasting plasma glucose (FPG) should be <7.2 mmol/L (<120 mg/dL) and post-prandial <9–10 mmol/L (<160–180 mg/dL) on an individualized basis. Successful glucose-lowering therapy is assisted by self-monitoring of blood glucose, most notably in patients with insulin-treated DM. When near-normoglycaemia is the objective, post-prandial glycaemia needs to be taken into account in addition to fasting glycaemia. However, although post-prandial hyperglycaemia is associated with an increased incidence of CVD events (see section 3:4) it remains controversial as to whether treatment targets addressing post-prandial hyperglycaemia are of added benefit to CVD outcomes.
More stringent targets (e.g. HbA1c 6.0–6.5% (42–48 mmol/mol]) might be considered in selected patients with short disease duration, long life expectancy and no significant CVD, if it can be achieved without hypoglycaemia or other adverse effects. As discussed above, the accumulated results from T2DM cardiovascular trials suggest that not everyone benefits from aggressive glucose management. It follows that it is important to individualize treatment targets.
6.2.6 Glucose-lowering Agents. The choice of pharmacological agent, the combinations employed and the potential side-effects are related to the mode of action of the drug. The choice of agent, the conditions of their use and the role of combination therapy is beyond the scope of this document and has been extensively reviewed in the joint ADA/EASD guidelines. In brief, therapeutic agents for managing hyperglycaemia can be broadly characterized as belonging to one of three groups: (i) insulin providers [insulin, sulphonylureas, meglitinides, glucagon-like peptide-1(GLP-1) receptor agonists, dipeptidylpeptidase-4 (DPP-4) inhibitors]; (ii) insulin sensitizers (metformin, pioglitazone) and (iii) glucose absorption inhibitors [alpha-glucosidase inhibitors, sodium-glucose co-transporter-2 (SGLT2) inhibitors]. The sulphonylureas, meglitinides and incretin mimetics (GLP-1 receptor agonists and DPP-4 inhibitors) all act by stimulating the pancreatic beta-cell to increase endogenous insulin secretion. The GLP-1 receptor agonists and the DPP-4 inhibitors have additional actions on the gastro-intestinal tract and brain, which have a beneficial effect on satiety (weight neutral for DPP-4 inhibitors, weight loss-associated with GLP-1 receptor agonists), although transient nausea occurring in about 20% of those treated may persist for 4–6 weeks after initiation of therapy. Pioglitazone is a PPARγ agonist with partial peroxisome proliferator-activated receptor alpha (PPARα) effects, which lowers glucose by ameliorating insulin resistance, while metformin is a biguanide that exerts similar effects through AMP kinase activation. Both agents tend to reduce insulin requirements in insulin-treated T2DM and, in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROActive) study, pioglitazone use was associated with prolonged reductions in insulin requirements. Acarbose reduces glucose absorption from the gastro-intestinal tract, whilst the SGLT2 inhibitors act on the proximal renal tubule to reduce glucose absorption. The expected decrease in HbA1c with each of the oral treatments, or with subcutaneous administration of GLP-1 agonists as monotherapy, is generally about 0.5–1.0%, although this can vary between individuals, depending on the duration of DM and other factors. Triple therapy—metformin plus two from pioglitazone, sulphonylurea, incretin mimetics, meglitinides and glucose absorption inhibitors—is commonly required as the disorder progresses.
In T1DM, intensive glucose-lowering therapy using a basal-bolus regimen, delivered either by multiple insulin injections or using an insulin pump, is the 'gold standard'. In T2DM, metformin is the first-line drug treatment, especially in overweight patients. A concern over the use of metformin has been the risk of lactic acidosis, especially in patients with impaired renal function and hepatic disease. In systematic reviews of trial data with selected patients, lactic acidosis is not over-represented. Despite this, metformin is not recommended if the estimated eGFR is <50 mL/min. There is an ongoing debate as to whether these thresholds are too restrictive. The UK National Institute for Health and Clinical Excellence (NICE) guidelines are more flexible, allowing use down to a eGFR of 30 mL/min, with dose reduction advised at 45 mL/min.
To attain glucose targets, a combination of glucose-lowering drugs is often required soon after diagnosis. Early aggressive therapy seems to have a role in reducing cardiovascular complications, but has not been formally tested in prospective trials.
Cardiovascular Safety of Glucose-lowering Agents ( Table 8 ): Concerns initiated by possible adverse cardiovascular effects of rosiglitazone raised questions as to the cardiovascular safety of glucose-lowering drugs, particularly when used in combination. A 10-year post-trial follow-up of UKPDS revealed that patients treated with sulphonylurea-insulin had a risk reduction (RR) for MI of 0.85 (95% CI 0.74–0.97; P = 0.01) and for death of 0.87 (95% CI 0.79–0.96; P < 0.007). The corresponding RRs for metformin in overweight patients were 0.67 (95% CI 0.51–0.89; P = 0.005) and 0.73 (95% CI 0.59–0.89; P = 0.002). Although UKPDS indicated that metformin has a beneficial effect on CVD outcomes—which led to metformin being adopted as first line treatment in overweight T2DM—it is important to underline that, overall, there is no clear evidence to support this view and there is a suggestion that, in combination with sulphonylurea, there may be detrimental effects related to both morbidity and mortality. However, the results of this meta-analysis also suggest a benefit after a long duration of treatment in younger patients. Pioglitazone reduced a secondary composite of all-cause mortality, fatal MI and stroke in the PROactive study (HR 0.84; 95% CI 0.72–0.98; P = 0.027) in T2DM patients at high risk of macrovascular disease. However, because the primary outcome in PROactive did not achieve statistical significance, the interpretation of these results remains contentious. The use of pioglitazone is associated with fluid retention secondary to renal effects, and this is associated with peripheral oedoma and worsening of established heart failure in susceptible individuals. Diuretic therapy can be initiated to ameliorate these side-effects. In the STOP-NIDDM trial, acarbose, when given to patients with IGT, reduced the number of CVD events, including cardiovascular mortality. Meglitinides have not been formally tested in T2DM but, in high-risk patients with IGT nateglinide, did not reduce either fatal or non-fatal cardiovascular events. No outcome data from RCTs have so far been published for glucagon-like peptide 1 agonists, DPP-4 inhibitors or SGLT-2 inhibitors, but large prospective trials with cardiovascular outcomes are in progress for GLP-1 receptor agonists and DPP-4 inhibitors and for SGLT2 inhibitors.
6.2.7 Special Considerations. Hypoglycaemia: Intensive glucose lowering increases the incidence of severe hypoglycaemia three- to four-fold in both T1DM and T2DM. Impaired hypoglycaemic awareness increases with duration of DM and is a significant risk factor for hypoglycaemia, which must be taken into account when glucose-lowering therapy is considered. In addition to the short-term risks of cardiac arrhythmia and cardiovascular events, longer-term risks include dementia and cognitive dysfunction. The outcome of glucose-lowering studies has raised the question as to whether hypoglycaemia is an important risk factor for MI in patients with DM. Frier et al. have extensively reviewed this topic, providing evidence for a number of adverse effects of hypoglycaemia on the CV system, particularly in the presence of autonomic neuropathy. Insulin, meglitinides and sulphonylureas are particularly associated with hypoglycaemia, which is a common occurrence in both T1 and T2DM. Attention should be paid to avoidance of hypoglycaemia, whilst achieving glycaemic goals in an individualized manner.
Glucose Lowering Agents in Chronic Kidney Disease: Around 25% of people with T2DM have chronic kidney disease (CKD) stages 3–4 (eGFR <50 mL/min). Aside from the increased CV risk associated with this condition, the use of glucose-lowering agents may need to be modified, either because a particular agent is contra-indicated in CKD or because the dosage needs to be altered. Metformin, acarbose and most sulphonylureas should be avoided in stage 3–4 CKD, whilst insulin therapy and pioglitazone can be used in their place as required. The DPP-4 inhibitors require dose adjustment with progressive CKD with the exception of linagliptin, which is well tolerated in these circumstances. The SGLT2 inhibitors have not been evaluated in CKD.
Elderly People: Older people have a higher atherosclerotic disease burden, reduced renal function and greater co-morbidity. Life expectancy is reduced, especially in the presence of long-term complications. Glycaemic targets for elderly people with long-standing or more complicated disease should be less ambitious than for younger, healthier individuals. If lower targets cannot be achieved with simple interventions, an HbA1c of <7.5–8.0% (<58–64 mmol/mol) may be acceptable, transitioning upwards as age increases and capacity for self-care, cognitive, psychological and economic status and support systems decline.
Individualized Care: The influences on quality of life, adverse effects of polypharmacy and inconvenience of intensified glucose-lowering regimens have to be carefully evaluated for each individual with DM (for further information see Section 9). From a public health perspective, even minor decreases in mean glycaemia may prove advantageous. On the other hand, the intensified glucose-lowering treatment may impose a considerable burden and possible harm on the individual. Each individual should be encouraged to achieve the best compromise between glucose control and vascular risk and, if intensified therapy is instituted, the patients must be informed and understand the benefits and risks.
6.2.8 Gaps in Knowledge.
6.2.9 Recommendations for GLycaemic Control in Diabetes.
The prevalence of hypertension is higher in patients with T1DM than in the general population (up to 49% in DCCT/EDIC) and more than 60% of patients diagnosed with T2DM have arterial hypertension. According to current pathophysiological considerations, this is related to: (i) hyperinsulinaemia linked to increased renal reabsorption of sodium; (ii) increased sympathetic tone and (iii) increased renin-angiotensin-aldosterone system activity. Obesity, aging and the appearance of renal disease further increase the prevalence of hypertension. DM and hypertension are additive risk factors for CVD. While the development of T2DM doubles the cardiovascular risk in men and more than triples the risk in women, hypertension causes a four-fold increase in cardiovascular risk in people with DM. Although treatment targets are presented, it should be recognised that blood pressure management needs to be implemented on an individualized basis. For example, multiple co-morbidities, increasing age, drug interactions and the pattern of vascular disease may all influence the therapeutic approach and individual target.
6.3.1 Treatment Targets. In DM, the recommended level of blood pressure has been debated. In general, measures to lower elevated blood pressure should be applied in all patients with DM, due to the substantially enhanced cardiovascular risk associated with increased blood pressure levels in such patients. RCTs in T2DM have shown the positive effects on cardiovascular outcomes of lowering blood pressure at least below 140 mm Hg systolic and 85 mm Hg diastolic. The Hypertension Optimal Treatment (HOT) trial demonstrated that risk decreased when the diastolic target was below 80 mm Hg. However, the mean diastolic blood pressure in this group was still above 80 and the systolic pressure was as high as 144 mm Hg. The UKPDS showed that 'tight' (mean 144/82), compared with 'less tight' (154/87) control reduced macrovascular events by 24%. In a post-hoc observational analysis of the UKPDS trial, DM-related mortality decreased 15% with each 10 mm Hg drop, down to a systolic blood pressure of 120 mm Hg, with no indication of a threshold. In the more recent ACCORD trial, more than 4700 patients were assigned to intensive- (achieved mean systolic blood pressure 119 mm Hg) or standard treatment [mean systolic blood pressure (BP) 134 mm Hg] over a mean follow-up of 4.7 years. The relative reduction of the composite endpoint (non-fatal MI, non-fatal stroke, or CVD death) by the intensive treatment did not reach statistical significance. The average number of blood pressure-reducing drugs was 3.5 in the intensive group, against 2.1 in the standard group. The proportion of patients with serious side-effect—such as hypotension and declining renal function—increased from 1.3 to 3.3% with aggressive treatment. Since the risk–benefit ratio tipped towards harm, this study does not support a reduction of systolic blood pressure below 130 mm Hg. Bangalore et al. reported a meta-analysis of 13 RCTs with 37 736 patients with DM, IFG or IGT who, in the intensive group, had a systolic pressure ≤135 mm Hg and, in the standard group, ≤140 mm Hg. The more intensive control related to a 10% reduction in all-cause mortality (95% CI 0.83–0.98), a 17% reduction in stroke but a 20% increase in serious adverse events. Systolic BP ≤130 mm Hg was related to a greater reduction in stroke but did not affect other cardiovascular events.
In summary, present evidence makes it reasonable to reduce blood pressure in patients with DM to <140/85 mm Hg. It should be noted that further reduction might be associated with an increased risk of serious adverse events, especially in patients of advanced age and with longer duration of T2DM. Thus the risks and benefits of more intensive blood pressure management need to be carefully considered on an individual basis.
6.3.2 Managing Blood Pressure-lowering. Lifestyle Intervention including salt restriction and weight loss is the therapeutic basis for all patients with hypertension; however, it is usually insufficient for adequate blood pressure control (for details see Section 6.1).
Pharmacological treatment has only been tested in a few RCTs comparing cardiovascular outcomes with blood pressure-lowering agents and specifically targeting patients with DM. However, several RCTs with sizeable DM subgroups reported specifically on the outcome in this subgroup. It appears that blockade of the renin-angiotensin-aldosterone system (RAAS), by means of an angiotensin converting enzyme inhibitor (ACE-I ) or an angiotensin-receptor-blocker (ARB), is of particular value, especially when treating hypertension in patients with DM at high cardiovascular risk. Evidence also supports the efficacy of an ACE-I, rather than a calcium channel blocker, as initial therapy when the intention is to prevent or retard the occurrence of microalbuminuria in hypertensive patients with DM. Dual RAAS blockade combining an ACE-I with an ARB did not show any further benefit in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), but was associated with more adverse events. In the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial, the addition of aliskiren to RAAS blockade in patients with T2DM at high risk for cardiovascular and renal events did not result in a decrease in cardiovascular events and may even have been harmful. Since DM patients tend to have high blood pressure during the night, administration of antihypertensive drugs at bedtime should be considered —ideally after evaluation of the 24-ambulatory blood pressure profile of the patient.
A matter that has been intensively discussed over the past decades is whether the metabolic actions of various blood pressure-lowering drugs are important for long-term cardiovascular outcome. It is well established that the use of thiazides and beta-blockers is associated with an increased risk of developing T2DM, compared with treatment with calcium channel blockers and inhibitors of the RAAS. It is not known whether treatment with beta-blockers and/or thiazides or thiazide-like diuretics in patients with established T2DM has any metabolic adverse events of clinical importance. The observation from UKPDS, that control of hyperglycaemia—in contrast to an effective blood pressure control—had a relatively minor influence on cardiovascular outcome, indicates that negative metabolic effects may be less important when treating hypertension in patients with DM, at least as regards macrovascular complications. Thus, while drugs with negative metabolic effects—especially the combination of a diuretic and a beta-blocker—should be avoided as first-line treatment in hypertensive patients with metabolic syndrome, the objective of lowering blood pressure seems more important than minor alterations in metabolic status in patients with established DM. A recent meta-analysis emphasized the priority of blood pressure lowering over choice of drug class. In the absence of cardiac co-morbidity, beta-blockers are not the first choice for the treatment of hypertension. Appropriate blood pressure control does often require combined therapy with a RAAS inhibitor and a calcium channel blocker or a diuretic. The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial indicated that the calcium channel antagonist amlodipine is superior to hydrochlorothiazide in combination treatment with an ACE-I. In 6946 patients with DM, the number of primary events was 307 in the group treated with amlodipine and 383 in the group treated with hydrochlorothiazide as the add-on to benazepril (P = 0.003), despite a similar reduction of blood pressure in both groups.
6.3.3 Conclusion. The main aim when treating hypertension in patients with DM should be to lower blood pressure to <140/85 mm Hg. To achieve this goal, a combination of blood pressure-lowering drugs is needed in most patients. In patients with hypertension and nephropathy with overt proteinuria, an even lower BP (SBP <130 mm Hg) may be considered if tolerated by the patient (see Section 8). All available blood pressure-lowering drugs can be used, but evidence strongly supports the inclusion of an inhibitor of the RAAS (ACE-I/ARB) in the presence of proteinuria. It should be borne in mind that many DM patients do not reach the recommended BP target. It is also noteworthy that, in contrast to that reported with glycaemic control and statins, there is no hypertensive legacy or memory effect. As a consequence, sustained control and monitoring and consistent medical adjustment are recommended.
These main conclusions regarding treatment of patients with DM and hypertension are consistent with the Re-appraisal of the European Guidelines on Hypertension (2009) and the updated European Guidelines for hypertension 2013.
6.3.4 Gaps in Knowledge.
6.3.5 Recommendations for Blood Pressure Control in Diabetes.
6.4.1 Pathophysiology. In individuals with T1DM and good glycaemic control, the pattern of lipid abnormalities contrasts with that of T2DM since, in T1DM, serum TG is normal and high-density lipoprotein cholesterol (HDL-C) is within the upper normal range or slightly elevated. This pattern is linked to insulin therapy, which increases lipoprotein lipase activity in adipose tissue, and the turnover rate of very low-density lipoprotein (VLDL) particles. However, qualitative changes in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles may potentially be atherogenic.
A cluster of lipid and apoprotein abnormalities accompanies T2DM, affecting all lipoprotein classes ( Table 9 ). The two core components are a moderate elevation of fasting and non-fasting triglycerides (TGs) and low HDL-C. Other features comprise elevations of TG-rich lipoprotein (TRLs), including chylomicron and VLDL remnants, small dense LDL particles.
These components are not isolated abnormalities but are metabolically linked. Overproduction of large VLDL particles with increased secretion of both TGs and Apo B 100 leads to the generation of small, dense LDL particles and lowering of HDL-C. As VLDL, remnant and LDL particles carry a single Apo B 100 molecule, the dyslipidaemia is characterized by elevation of the Apo B concentration. Therefore, the malignant nature of dyslipidaemia in T2DM is not always revealed by routine lipid measures, as LDL-C remains within a normal range and it may often be better-characterized by using non-HDL-C. Substantial evidence indicates that an imbalance between the hepatic import and export of lipids results in excess liver fat accumulation (non-alcoholic fatty liver disease). Increased flux of FFA comes from both the systemic FFA pools and de novo lipogenesis in the setting of IR. Thus the content of liver fat and hepatic IR seem to be driving the overproduction of large VLDL particles in people with T2DM.
Impaired clearance of large VLDL particles, linked to increased concentration of Apo C, contributes to a more robust hypertriglyceridaemia. Thus dual metabolic defects contribute to the hypertriglyceridaemia in people with T2DM. Recent data suggest that part of the lipid oversupply to the liver in the presence of obesity may be due to a maladaptive response of adipose tissue to store circulating FFAs, leading to ectopic fat deposition and lipotoxicity that underlies dyslipidaemia in DM and IR.
6.4.2 Epidemiology. The European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE III) survey reported that the overall prevalence of high TG and low HDL–C has almost doubled, compared with the prevalence seen by EUROASPIRE II, due to the increase in T2DM and obesity. A population-based survey of 75 048 patients with T2DM in the National Diabetes register in Sweden reported that 49% of patients did not receive lipid-lowering drugs. Fifty-five per cent of those treated had a TG <1.7 mmol/L and around two-thirds a normal HDL-C. Data from the same survey revealed that two-thirds of patients on lipid-lowering drugs achieved an LDL-C <2.5 mmol/L. However, in those with a history of CVD, more than 70% had LDL-C >1.8 mmol/L. Notably, only moderate doses of the different statins were used, highlighting the need for intensification of therapy and better management of the existing treatment gap.
Dyslipidaemia and Vascular Risk in Type 2 Diabetes Mellitus: A wealth of data from case-control, mechanistic, genetic and large observational studies indicate that a causal association exists between elevation of triglyceride-rich particles and their remnants, low HDL-C and CVD risk. Data from statin trials strengthen the position of low HDL as an independent CVD risk marker, even in patients with an LDL-C level that is not elevated. Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study and ACCORD demonstrated that cardiovascular event rates were significantly higher in those with dyslipidaemia (LDL-C 2.6 mmol/L (100 mg/dL), TG ≥2.3 mmol/L and HDL-C ≤0.88 mmol/L). In FIELD, the baseline variables best predicting CVD events over a 5-year follow-up were lipid ratios (non-HDL/HDL-C and total/HDL-C). Apo B–Apo A is related to CVD outcomes, but this ratio was not superior to traditional lipid ratios. Of the single baseline lipid and lipoprotein concentrations, HDL-C, Apo A, non-HDL-C and Apo B individually predicted CVD events, although Apo A and Apo B did not perform better than HDL-C or non-HDL-C. The power of serum TG to predict CVD events was attenuated by adjustment for HDL-C. These results were unexpected, since the dyslipidaemia in DM is a cluster of abnormalities featuring elevations of Apo B and small dense LDL particles. The data are, however, in full agreement with results from the Emerging Risk Factor Collaboration (ERFC) study, based on 68 studies that included 302 430 participants without a history of CVD. In this analysis, non-HDL-C and Apo B each had very similar association with coronary heart disease irrespective of the presence of DM. The ERFC study reported that an increase of one standard deviation in HDL-C (0.38 mmol/L or 15 mg/dL) was associated with a 22% reduction in risk of coronary heart disease. HRs for non-HDL and HDL-C were similar to those observed for Apo B and Apo A and non-HDL-C was the best tool to capture the risk associated with elevation of triglyceride rich proteins in clinical practice. The use of Apo B and Apo B–Apo A are also advocated as CVD risk markers in T2DM.
6.4.3 Management of Dyslipidaemia. Type 2 Diabetes Mellitus: Comprehensive and consistent data exist on the mechanism of action and efficacy of statins in the prevention of CVD events in T2DM. The benefits of statin therapy in lowering LDL-C and reducing CVD events are seen in all subgroup analyses of major RCTs. In a meta-analysis of 14 RCTs covering 18 686 people with DM, the mean duration of follow-up was 4.3 years, with 3247 major vascular events. The study reported a 9% reduction in all-cause mortality and a 21% reduction in the incidence of major vascular outcomes per mmol/L of LDL-C lowering (RR 0.79; 99% Cl 0.72–0.87; P < 0.0001), similar to that seen in non-DM. The magnitude of the benefit was associated with the absolute reduction in LDL-C, highlighting a positive relationship between LDL-C and CVD risk, and was seen at a starting LDL-C as low as 2.6 mmol/L.
The results of the first meta-analyses of cardiovascular events of intensive vs. moderate statin therapy show a 16% risk reduction of coronary death or MI. Data from 10 RCTs, studying 41 778 patients followed for 2.5 years, showed that intensive statin dosage reduced the composite endpoint of CAD by 10% (95% Cl 0.84–0.96; P < 0.0001), but did not reduce CVD mortality. In a subgroup of patients with ACS, intensive statin therapy reduced both all-cause and CVD mortality. Intensive lowering of LDL-C by statins had a beneficial effect on progression of atheroma in DM and non-DM.
Intensification of LDL-C lowering can also be achieved by adding ezetimibe to a statin, however, there are still no data from an RCT that this combination has a significant impact on CVD outcome. The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT: ClinicalTrials.gov: NCT00202878) is, however, under way. An analysis of pooled safety data comparing the efficacy and safety profile of combination therapy with ezetimibe/statin vs. statin monotherapy in DM and non-DM (n = 21 794) reported that combination therapy provided larger effects on all major lipid measures. The Study of Heart and Renal Protection (SHARP) trial reported a 17% reduction of major atherosclerotic events in chronic kidney disease treated with simvastatin plus ezetimibe daily vs. placebo. In this context it should be emphasized that, although relative reduction of events may be similar for people with and without DM, the absolute benefit is greater in DM-patients due to their higher risk.
Type 1 Diabetes Mellitus: The Cholesterol Treatment Trialists (CTT) analysis included 1466 T1DM patients with an average age of 55 years and a majority with prior CVD events. This analysis showed a similar reduction of risk of CVD events (RR 0.79; 95% CI 0.62–1.01) to that seen in T2DM and with a P value for interaction of 1.0, verifying the result despite only a borderline significance in the subgroup. It should be recognized that no trial data exist on the efficacy of statin therapy in a younger population with T1DM. However, in T1DM, statin therapy should be considered on an individual basis in those at high risk for CVD events, irrespective of LDL-C concentration—for example T1DM patients with renal impairment.
Primary Prevention: The Collaborative Atorvastatin Diabetes Study (CARDS) evaluated the benefits of a statin in patients with T2DM and at least one of the following risk factors: hypertension, current smoking, retinopathy, or albuminuria. In CARDS, 2838 T2DM patients were randomized to atorvastatin 10 mg/day or placebo. The study was terminated prematurely, due to a 37% reduction (95% CI -52 to -17; P = 0.0001) in the primary endpoint (first acute coronary heart disease event). The Heart Protection Study (HPS) recruited 2912 patients (mainly T2DM) without pre-existing CVD. Simvastatin (40 mg/day) reduced the composite primary endpoint by 33% (P = 0.0003; 95% Cl 17–46). In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) subgroup analyses of DM patients free from CVD, 10 mg of atorvastatin reduced the rate of major CVD events and procedures by 23% (95% Cl 0.61–0.98; P = 0.04).
Safety of Statin Therapy: Reports from major RCTs demonstrate that statins are safe and well-tolerated. The frequency of adverse events, except for muscle symptoms, is rare. In the majority of cases of myopathy or rhabdomyolysis there are drug interactions with a higher-than-standard dose of statin. The combination of gemfibrozil and statins should be avoided due to pharmacokinetic interaction, but there are no safety issues with fenofibrate and statins.
A meta-analysis including 91 140 participants reported that statin therapy was associated with risk of new-onset T2DM (OR 1.09; 95% Cl 1.0–1.2; I = 11%), which increased with age. The data translate to one case of T2DM when 255 patients have been treated for 4 years. Over the same time, statins would prevent 5.4 CVD events for each mmol/L reduction in LDL-C. A meta-analysis of five statin trials reported that the risk of new onset DM increased with intensive statin (atorvastatin or simvastatin 80 mg daily) therapy (OR 1.12; 95% Cl 1.04–1.22; I = 0%), compared with moderate (simvastatin 20 mg or pravastatin 40 mg) doses. In the intensive group, two additional cases of new-onset DM per 1000 patient years were observed, whereas the number of CVD events was 6.5 cases fewer. Recently the Food and Drug Administration (FDA) of the USA approved label changes on increases of blood glucose and HbA1c for the statin class of drugs (www.fda.gov/downloads/Drugs/DrugSafety/UCM293474.pdf). The FDA still considers that the small risk of developing DM is clearly outweighed by the reduction of cardiovascular events. Further support for the safety of statins comes from a meta-analysis of 27 randomized trials that demonstrated that, in individuals with a five-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL-C produced an absolute reduction in major vascular events of about 11 per 1000 over five years, without an increase in incidence of cancer or deaths from other causes. This benefit greatly exceeds any known hazards of statin therapy.
Residual Risk in People on LDL-lowering Therapy: T2DM patients at the LDL-C target remain at high risk of CVD events, and this residual risk is linked to many factors including elevation of TG-rich proteins, low HDL-C and small, dense LDL particles. It has been suggested that targeting elevated TG (>2.2 mmol/L) and/or low HDL-C (<1.0 mmol/L) may provide further benefits. In the FIELD study, fenofibrate therapy did not reduce the primary endpoint (CAD-related death and non-fatal MI), but total CVD events were reduced from 14 to 12.5% (HR 0.9; 95% Cl 0.80–0.99; P = 0.035). In the ACCORD trial, 5518 patients were assigned to fenofibrate plus simvastatin (20–40 mg daily) or placebo without any additional effect on the primary endpoint. In a pre-specified subgroup analysis of people with TG >2.3 mmol/L (>204 mg/dL) and HDL-C <0.9 mmol/L (<34 mg/dL), cardiovascular risk was reduced by 31% in the fenofibrate-plus-simvastatin group (for interaction between patients with this lipid profile vs. those without, P = 0.06). A subgroup analysis of dyslipidaemic people (TG >2.3 mmol/L and HDL-C <0.9 mmol/L) in the FIELD study revealed a 27% reduction in CVD risk. In both FIELD and ACCORD, fenofibrate therapy was associated with robust reduction of TG (22%), whereas elevation of HDL-C remained less than expected (+2% and +2.4%, respectively). Meta-analyses have confirmed the clinical benefits of fibrates on major CVD events but not on cardiovascular mortality. The effects seem to be linked to improvement in TGs.
Strategies to Elevate High-density Lipoprotein Cholesterol: The level of HDL-C is inversely related to CVD in epidemiological studies, as well as in many statin trials. Low levels of HDL-C are associated with increased levels of triglycerides and are often seen in patients with metabolic syndrome and/or DM. Targeting low HDL-C for CVD prevention is, however, not supported by evidence. Two recently reported RCTs, using the cholesterylester transfer protein (CETP) inhibitors torcetrapib and dalcetrapib, failed to reduce cardiovascular events despite a 30–40% increase in HDL-C. One explanation for these findings may relate to abnormal functional characteristics of HDL particles. If this is true, merely increasing the number of such particles without any improvement of their function may not alter CVD risk.
The pharmacological tools currently available to raise HDL-C in DM patients remain limited. Fenofibrate has trivial efficacy in this regard, while niacin (N-ER) has potentially useful properties, increasing HDL-C by 15–30%, with an associated increase in Apo A-1, besides lowering TG (up to 35%), LDL-C (about 20%) and Apo B and lipoprotein a (Lp a) (about 30%). Although a study showed favourable effects on angiographic measures, and on reduction of carotid wall area quantified with magnetic resonance imaging after one year of therapy, two recent clinical studies did not confirm the usefulness of N-ER for cardiovascular prevention. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) study showed no additional benefit of N-ER in patients with metabolic syndrome. In the Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS-2 THRIVE) trial, 25 673 patients with known vascular disease were randomized to placebo or N-ER/laropiprant on a background of statin or statin/ezetimibe therapy. The trial was stopped prematurely after a median follow up of 3.9 years. At that time, 15.0% of patients in the control arm and 14.5% in the N-ER/laropiprant arm (ns) had reached the primary endpoint, a composite of coronary death, non-fatal MI, stroke, or coronary revascularization. Moreover, there was a significant 3.7% absolute excess risk of DM complications and a significant 1.8% excess risk of new-onset DM. In addition, N-ER treatment caused a 1.4% higher risk of infection and a 0.7% higher risk of bleeding, including an increased risk of haemorrhagic stroke.. Based on these results, the EMA has withdrawn the marketing licence for N-ER/laropiprant.
So far, lifestyle intervention with smoking cessation, increased physical activity, weight reduction and decreased consumption of fast-absorbed carbohydrates remains the cornerstone of HDL-increasing therapy.
In patients with high TG (>5.4 mmol/L) lifestyle advice (with a focus on weight reduction and alcohol abuse if relevant) and improved glucose control are the main targets. Risks associated with TG are acute pancreatitis and polyneuropathy. In a pooled analysis of randomized trial data, use of statins was associated with a lower risk of pancreatitis in patients with normal or mildly elevated triglyceride levels. Fibrates were not protective and may even have enhanced the risk. Omega-3 fatty acids (2–4 g/day) may be used for TG-lowering in people with high levels. There is, however, no evidence that such supplements are of cardiovascular benefit in patients with DM.
6.4.4 Gaps in Current Knowledge.
6.4.5 Recommendations on Management of Dyslipidaemia in Diabetes.
Platelet activation plays a pivotal role in the initiation and progression of atherothrombosis. Abnormalities in the aggregation of platelets in DM ex vivo have been described by numerous groups, and both post-prandial and persistent hyperglycaemia have been identified as major determinants of in vivo platelet activation in the early and late phases of the natural history of T2DM.
6.5.1 Aspirin. Aspirin inhibits thromboxane (TX) A2-dependent platelet activation and aggregation through irreversible inactivation of platelet cyclo-oxygenase 1 (COX-1) activity. No formal studies have specifically examined the dose- and time-dependence of its antiplatelet effect in patients with T2DM and aspirin is currently recommended at 75–162 mg once daily, i.e. at the same dose and dosing interval used in people without DM. However, once-daily administration of low-dose aspirin may be associated with incomplete inhibition of platelet COX-1 activity and TXA2-dependent platelet function, perhaps due to increased platelet turnover in DM. Evidence to support this view indicates the potentially beneficial effects of sustained efficacy using twice-daily aspirin in people with DM and CVD.
Secondary Prevention: The first collaborative overview of the Antiplatelet Trialists' Collaboration found that antiplatelet therapy (mostly with aspirin) is similarly effective among patients with pre-existing symptomatic CVD, regardless of the presence of DM. They analysed individual data on 'serious vascular events' (non-fatal MI, non-fatal stroke or vascular death) from approximately 4500 patients with DM in the randomized trials and found that treatment with antiplatelet drugs produced a proportional reduction of about one quarter. Therefore there is no apparent reason to treat patients with DM and CVD differently from non-DM patients and low-dose aspirin is uniformly recommended for both the acute treatment of ischaemic syndromes and their secondary prevention.
Primary Prevention: Low-dose aspirin is recommended by several North American organizations for the primary prevention of cardiovascular events in adults with DM. However, direct evidence of its efficacy and safety in this setting is lacking or, at best, inconclusive. Thus, in the most up-to-date meta-analysis, which includes three trials conducted specifically in patients with DM and six other trials in which such patients represent a subgroup within a broader population, aspirin was found to be associated with a non-significant 9% decrease in the risk of coronary events (RR 0.91; 95% CI 0.79–1.05) and a non-significant 15% reduction in the risk of stroke (RR 0.85; 95% CI 0.66–1.11). It should be emphasized that the total number of patients with DM enrolled in these nine trials was 11 787, with 10-year extrapolated coronary event rates ranging from as low as 2.5% to as high as 33.5%. These results have been interpreted as suggesting that aspirin probably produces a modest reduction in the risk of cardiovascular events, but the limited amount of available data precludes a precise estimate of the effect size. Consistent with this uncertainty, antiplatelet therapy with aspirin in adults at a low CVD risk is not recommended by the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on CVD Prevention in Clinical Practice.
The Risk–Benefit Ratio of Aspirin: Based on data from a meta-analysis of the six primary prevention trials, aspirin was associated with a 55% increase in the risk of extracranial (mainly gastro-intestinal) bleeding, both in people without- (the majority) and with DM. In terms of the balance between the potential benefit and hazard of aspirin in primary prevention, these results probably represent a best-case scenario, as people at increased risk of gastro-intestinal bleeding were excluded and elderly people were under-represented. In the same analyses, the presence of DM at baseline was associated with a two-fold increase in vascular events but also with a 50% increased risk of major extracranial bleeds during follow-up.
Both the Endocrine Society Clinical Practice Guideline and the ADA/AHA/ACCF Scientific Statement favour aspirin use in adults with DM when the 10-year risk of cardiovascular events is >10%. However, relatively little emphasis is placed in either statement on the need to evaluate the variable bleeding risk of the patient. While the annual risk of cardiovascular events can vary approximately 10-fold in DM, the annual risk of upper gastro-intestinal bleeding has been estimated to vary by up to 100-fold in the general population, depending on age and history of peptic ulcer disease.
6.5.2 P2Y12 Receptor Blockers. Clopidogrel, an irreversible blocker of the adenosine diphosphate (ADP) receptor P2Y12, provides a valid alternative for patients who are aspirin-intolerant or have symptomatic peripheral vascular disease, because it has broad indications for long-term secondary prevention similar to aspirin. Moreover, clopidogrel (75 mg once daily) produced additive cardio-protective effects when combined with low-dose aspirin (75–160 mg once daily) in patients with ACS and those undergoing percutaneous coronary intervention (PCI). There is, however, evidence from the Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management and Avoidance (CHARISMA) study to indicate that clopidogrel, added to background aspirin, may have deleterious effects in patients with advanced nephropathy. More effective P2Y12 blockers include prasugrel and ticagrelor, a reversible P2Y12 blocker. In the TRITON-TIMI 38 trial, prasugrel (60 mg loading dose, followed by 10 mg daily) showed clear superiority over clopidogrel (300 mg loading dose, followed by 75 mg daily) in the prevention of recurrent ischaemic events post-acute coronary syndrome (ACS): however, in the general cohort, this benefit carried a risk of increased thrombolysis in myocardial infarction (TIMI) major bleeding. In a DM sub-study, a similar reduction in recurrent ischaemic events was seen, but in the DM cohort this was not accompanied by an increase in bleeding. Ticagrelor (180 mg loading dose, followed by 90 mg twice daily), was also more effective than clopidogrel (300–600 mg loading dose, followed by 75 mg daily) in reducing death from CV causes and total mortality at 12 months in a general post-ACS cohort, and decreased ischaemic events in DM patients without causing increased bleeding. Importantly, ticagrelor was shown to be superior to clopidogrel in ACS patients with renal impairment. There is no convincing evidence that either clopidogrel or the newer drugs are any more or less effective in people with DM than in those without. For the use of these drugs in connection to PCI, see Section 7.2.
6.5.3 Gaps in Knowledge.
6.5.4 Recommendations for Antiplatelet Therapy in Patients With Diabetes.
6.6.1 Principles of Multifactorial Management. Patients with glucose perturbations are in need of early risk assessment to identify co-morbidities and factors that increase cardiovascular risk. This includes evaluation of: (i) risk factors (e.g. lifestyle habits including smoking, hypertension and dyslipidaemia); (ii) microvascular and macrovascular disease and autonomic dysfunction; (iii) co-morbidities (e.g. heart failure and arrhythmias); (iv) inducible ischaemia by means of exercise testing, stress echocardiography, or myocardial scintigraphy and (v) myocardial viability and LV function by means of echo-Doppler and/or magnetic resonance imaging. The reliability of exercise testing, stress echocardiography, or myocardial scintigraphy is of a particular concern in the detection of ischaemia in DM. Confounders are a high threshold for pain due to autonomic dysfunction, the multi-vessel nature of coronary disease, ECG abnormalities, co-existence of PAD and use of multiple medications.
The total risk for cardiovascular complications is, to a large extent, related to synergistic interactions between IR, beta-cell dysfunction and subsequent hyperglycaemia but also the accumulation of cardiovascular risk factors. Accordingly, successful risk prevention depends on a comprehensive detection and management of all modifiable risk factors, as can be visualized by the use of risk engines (e.g. the UKPDS). It should be noted, however, that such engines need to be continuously updated. Further information can be obtained in Section 5.
The feasibility of intensified, multifactorial treatment for patients with T2DM in general practice was studied in the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen Detected Diabetes in Primary Care (ADDITION). The incidence of a first cardiovascular event was 7.2% (13.5 per 1000 person-years) in the intensive care group and 8.5% (15.9 per 1000 person-years) in the routine care group (HR 0·83; 95% CI 0·65–1·05), and incidence of all-cause mortality was 6.2% (11.6 per 1000 person-years) and 6.7% (12.5 per 1000 person-years), respectively (HR 0.91; 95% CI 0.69–1.21). It was concluded that an intervention to promote early intensive management of patients with T2DM was associated with a small but non-significant reduction in the incidence of cardiovascular events and death. A caveat in respect of ADDITION was the only slightly better control of important cardiovascular risk factors (HbA1c, cholesterol concentrations and blood pressure) in the intensive group. In contrast, the value of a multifactorial intervention in patients with DM and established microalbuminuria was demonstrated by the STENO 2 study which, in a highly specialized setting, randomized 160 participants to an intensive, target-driven multifactorial therapy or to conventional management. The targets in the intensively treated group were HbA1c <6.5%, total cholesterol <4.5 mmol/L (175 mg/dL) and blood pressure <130/80 mm Hg. All patients in this group received RAAS blockers and low-dose aspirin. Although treatment targets were not always attained in the intensive-treatment group, their overall management was considerably better than in routinely handled patients. This resulted in a reduction in microvascular and macrovascular events of about 50% after 7.8 years of follow-up. The target most successfully attained was that for cholesterol, probably making crucial the role of statins in the overall prevention strategy. Subsequently, target-driven therapy was recommended to patients in both groups. They were followed for 13 years after randomization. By that time, patients originally allocated to the intensively managed group had an absolute mortality reduction of 20% and the HR for death, compared with that in the conventional group, was 0.54 (95% CI 0.3–0.9; P < 0.02). The absolute risk reduction in cardiovascular events was 29%. In addition, there was a substantial reduction in diabetic nephropathy (relative risk 0.4; 95% CI 0.3–0.8; P < 0.004) and progression of retinopathy (relative risk 0.6; 95% CI 0.4–0.9; P = 0.01). In a health-economic analysis, intensive patient management was reported as more cost-effective than conventional care. Since increased expenses relating to intensive care were driven by pharmacy and consultation costs, such treatment would be dominant (i.e. cost- and life-saving with the use of generic drugs in a primary care setting).
Data from the Euro Heart Survey on Diabetes and the Heart support a multifactorial approach as a cornerstone of patient management. Among 1425 patients with known T2DM and CAD, 44% received evidence-based pharmacological therapy, defined as a combination of aspirin, beta-blockade, RAAS inhibitors and statins in the absence of contra-indications. Patients on such drug combination had a significantly lower all-cause mortality (3.5 vs. 7.7%; P = 0.001) and fewer combined cardiovascular events (11.6 vs. 14.7%; P = 0.05) after one year of follow up, compared with those who did not receive a full combination of such drugs. The adjusted HR for the interaction between DM and treatment revealed that the use of evidence-based treatment in T2DM had an independent protective effect (HR for death: 0.4). An example of the inadequacy of a single drug approach to decrease the incidence of CVD originates from a study that randomized 37 overweight/obese insulin-resistant participants, still without DM, to fenofibrate, rosiglitazone, or a calorie-restricted diet. None of the tested treatments appeared to be a therapeutic intervention that, in isolation, had the capacity to normalize all—or at least a majority—of the metabolic disturbances (e.g. weight, insulin sensitivity, cholesterol, TG, post-load PG) in these patients at a greatly increased cardiovascular risk.
Treatment targets are summarized in Table 10 .
6.6.2 Gaps in Knowledge.
6.6.3 Recommendations for Multifactorial Risk Management in Diabetes.
6. Prevention of Cardiovascular Disease in Patients With Diabetes
6.1 Lifestyle
A joint scientific statement from the ADA and EASD advocates lifestyle management (including healthy eating, physical activity and cessation of smoking) as a first measure for the prevention and/or management of T2DM, with targets of weight loss and reduction of cardiovascular risk. An individualized approach to T2DM is also recommended by other organizations. A recent Cochrane review concluded that data on the efficacy of dietary intervention in T2DM are scarce and of relatively poor quality. The ADA position statement, Nutrition Recommendations and Interventions for Diabetes provides a further review of these issues.
Most European people with T2DM are obese, and weight control has been considered a central component of lifestyle intervention. 'Look AHEAD (Action for Health in Diabetes)' was a large clinical trial of the effects of long-term weight loss on glycaemia and prevention of CVD events in T2DM. One-year results of the intensive lifestyle intervention showed an average 8.6% weight loss, a significant reduction in HbA1c and a reduction in several CVD risk factors—benefits that were sustained after four years. The trial was, however, stopped for reasons of futility in 2012, since no difference in CVD events was detected between groups. Weight reduction—or at least stabilization in overweight or moderately obese people—will still be an important component in a lifestyle programme and may have pleiotropic effects. In very obese individuals, bariatric surgery causes long-term weight loss and reduces the rate of incident T2DM and mortality.
6.1.1 Diet. Dietary interventions recommended by the EASD Diabetes and Nutrition Study Group are less prescriptive than many earlier sets of dietary advice. They acknowledge that several dietary patterns can be adopted and emphasize that an appropriate intake of total energy and a diet in which fruits, vegetables, wholegrain cereals and low-fat protein sources predominate are more important than the precise proportions of total energy provided by the major macronutrients. It is also considered that salt intake should be restricted.
It has been suggested that there is no benefit in a high-protein- over a high-carbohydrate diet in T2DM. Specific dietary recommendations include limiting saturated and trans fats and alcohol intake, monitoring carbohydrate consumption and increasing dietary fibre. Routine supplementation with antioxidants, such as vitamins E and C and carotene, is not advised because of lack of efficacy and concern related to long-term safety. For those who prefer a higher intake of fat, a Mediterranean-type diet is acceptable, provided that fat sources are derived primarily from monounsaturated oils—as shown by the Primary Prevention of Cardiovascular Disease with a Mediterranean Diet (PREDIMED) study using virgin olive oil.
Recommended Distributions of Macronutrients:
Proteins: 10–20% of total energy in patients without nephropathy (if nephropathy, less protein).
Saturated and transunsaturated fatty acids: combined <10% of the total daily energy. A lower intake, <8%, may be beneficial if LDL-C is elevated.
Oils rich in monounsaturated fatty acids are useful fat sources and may provide 10–20% total energy, provided that total fat intake does not exceed 35% of total energy.
Polyunsaturated fatty acids: up to 10% total daily energy.
Total fat intake should not exceed 35% of total energy. For those who are overweight, fat intake <30% may facilitate weight loss. Consumption of two to three servings of—preferably—oily fish each week and plant sources of n-3 fatty acids (e.g. rapeseed oil, soybean oil, nuts and some green leafy vegetables) are recommended to ensure an adequate intake of n-3 fatty acids. Cholesterol intake should be <300 mg/day and be further reduced if LDL-C is elevated. The intake of trans fatty acids should be as small as possible, preferably none from industrial origin and limited to <1% of total energy intake from natural origin.
Carbohydrate may range from 45–60% of total energy. Metabolic characteristics suggest that the most appropriate intakes for individuals with DM are within this range. There is no justification for the recommendation of very low carbohydrate diets in DM. Carbohydrate quantities, sources and distribution should be selected to facilitate near-normal long-term glycaemic control. In those treated with insulin or oral hypoglycaemic agents, timing and dosage of the medication should match quantity and nature of carbohydrate. When carbohydrate intake is at the upper end of the recommended range, it is important to emphasize foods rich in dietary fibre and with a low glycaemic index.
Vegetables, legumes, fruits and wholegrain cereals should be part of the diet.
Dietary fibre intake should be >40 g/day (or 20 g/1000 Kcal/day), about half of which should be soluble. Daily consumption of ≥5 servings of fibre-rich vegetables or fruit and ≥4 servings of legumes per week can provide minimum requirements for fibre intake. Cereal-based foods should be wholegrain and high in fibre.
Alcohol drinking in moderate amounts, not exceeding two glasses or 20 g/day for men and one glass or 10 g/day for women, is associated with a lower risk of CVD, compared with teetotallers and heavy alcohol drinkers, both in individuals with and without DM. Excessive intake is associated with hypertriglyceridaemia and hypertension.
Coffee drinking: >4 cups/day is associated with a lower risk of CVD in people with T2DM, but it should be noted that boiled coffee without filtering raises LDL-C and should be avoided.
6.1.2 Physical Activity. Physical activity is important in the prevention of the development of T2DM in people with IGT and and for the control of glycaemia and related CVD complications. Aerobic and resistance training improve insulin action and PG, lipids, blood pressure and cardiovascular risk. Regular exercise is necessary for continuing benefit.
Little is known about the best way to promote physical activity; however, data from a number of RCTs support the need for reinforcement by healthcare workers. Systematic reviews found that structured aerobic exercise or resistance exercise reduced HbA1c by about 0.6% in T2DM. Since a decrease in HbA1c is associated with a long-term decrease in CVD events and a reduction in microvascular complications, long-term exercise regimens that lead to an improvement in glycaemic control may ameliorate the appearance of vascular complications. Combined aerobic and resistance training has a more favourable impact on HbA1c than aerobic or resistance training alone. In a recent meta-analysis of 23 studies, structured exercise training was associated with a 0.7% fall in HbA1c, compared with controls. Structured exercise of >150 min/week was associated with a fall in HbA1c of 0.9% <150 min/week with a fall of 0.4%. Overall, interventions of physical activity advice were associated with lower HbA1c levels only when combined with dietary advice.
6.1.3 Smoking. Smoking increases the risk of T2DM, CVD and premature death, and should be avoided. Stopping smoking decreases risk of CVD. People with DM who are current smokers should be offered a structured smoking cessation programme including pharmacological support with, for example, buproprion and varenicline if needed. Detailed instruction on smoking cessation should be given according to the five A principles ( Table 7 ) as is further elaborated in the 2012 Joint European Prevention guidelines.
6.1.4 Gaps in Knowledge.
Lifestyles that influence the risk of CVD among people with DM are constantly changing and need to be followed.
The CVD risk, caused by the increasing prevalence of T2DM in young people due to unhealthy lifestyles, is unknown.
It is not known whether the remission in T2DM seen after bariatric surgery will lead to a reduction in CVD risk.
6.1.5 Recommendations on Life Style Modifications in Diabetes.
6.2 Glucose Control
Randomized controlled trials provide compelling evidence that the microvascular complications of DM are reduced by tight glycaemic control, which also exerts a favourable, although smaller, influence on CVD that becomes apparent after many years. However, intensive glucose control, combined with effective blood pressure control and lipid lowering, appear to markedly shorten the time needed to make improvements in the rate of cardiovascular events.
6.2.1 Microvascular Disease (Retinopathy, Nephropathy and Neuropathy). Intensified glucose lowering, targeting an HbA1c of 6.0–7.0%, (42–53 mmol/mol), has consistently been associated with a decreased frequency and severity of microvascular complications. This applies to both T1DM and T2DM, although the outcomes are less apparent in T2DM with established complications, for which the number needed to treat (NNT) is high. Analyses from the Diabetes Control and Complications Trial (DCCT) and the UKPDS demonstrated a continuous relationship between increasing HbA1c and microvascular complications, without an apparent threshold. In the DCCT, a decrease in HbA1c of 2% (21.9 mmol/mol) significantly lowered the risk of the development and progression of retinopathy and nephropathy, although the absolute reduction was low at HbA1c <7.5% (58 mmol/mol). The UKPDS reported a similar relationship in people with T2DM.
6.2.2 Macrovascular Disease (Cerebral, Coronary and Peripheral Artery Disease). Although there is a strong relationship between glycaemia and microvascular disease, the situation regarding macrovascular disorders is less clear. Hyperglycaemia in the high normal range, with minor elevations in HbA1c, has been associated with increased cardiovascular risk in a dose-dependent fashion. However, the effects of improving glycaemia on cardiovascular risk remain uncertain and recent RCTs have not provided clear evidence in this area. The reasons, of which there are several, include the presence of multiple co-morbidities in long-standing T2DM and the complex risk phenotype generated in the presence of IR (for further details see Section 4).
6.2.3 Medium-term Effects of Glycaemic Control. Action to Control Cardiovascular Risk in Diabetes (ACCORD): A total of 10 251 T2DM participants at high cardiovascular risk were randomized to intensive glucose control achieving an HbA1c of 6.4% (46 mmol/mol), or to standard treatment achieving an HbA1c of 7.5% (58 mmol/mol). After a mean follow-up of 3.5 years the study was terminated due to higher mortality in the intensive arm (14/1000 vs. 11/1000 patient deaths/year), which was pronounced in those with multiple cardiovascular risk factors and driven mainly by cardiovascular mortality. As expected, the rate of hypoglycaemia was higher under intensive treatment and in patients with poorer glycaemic control, although the role of hypoglycaemia in the CVD outcomes is not entirely clear. Further analysis revealed that the higher mortality may have been due to fluctuations in glucose, in combination with an inability to control glucose according to target, despite aggressive glucose lowering treatment. A recent extended follow-up of ACCORD did not support the hypothesis that severe symptomatic hypoglycaemia was related to the higher mortality.
Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE): A total of 11 140 T2DM participants at high cardiovascular risk were randomized to intensive or conventional glucose-lowering therapy. The intensive arm achieved an HbA1c of 6.5% (48 mmol/mol), compared with 7.3% (56 mmol/mol) in the standard arm. The primary endpoint (major macrovascular or microvascular complications) was reduced in the intensive arm (HR 0.90; 95% CI 0.82–0.98) due to a reduction in nephropathy. Intensive glycaemic control failed to influence the macrovascular component of the primary endpoint (HR 0.94; 95% CI 0.84–1.06). In contrast to ACCORD, there was no increase in mortality (HR 0.93; 95% CI 0.83–1.06) despite a similar decrease in HbA1c. Severe hypoglycaemia was reduced by two thirds in the intensive arm of ADVANCE, compared with ACCORD, and HbA1c lowering to target was achieved at a slower rate than in ACCORD. In addition, the studies had a different baseline CVD risk, with a higher rate of events in the control group of ADVANCE.
Veterans Administration Diabetes Trial (VADT): In this trial, 1791 T2DM patients were randomized to intensive or standard glucose control, achieving an HbA1c of 6.9% (52 mmol/mol) in the intensive therapy group, compared with 8.4% (68 mmol/mol) in the standard therapy group. There was no significant reduction of the primary composite cardiovascular endpoint in the intensive therapy group (HR 0.88; 95% CI 0.74–1.05).
Outcome Reduction With an Initial Glargine Intervention Trial (ORIGIN): This study randomized 12 537 people (mean age, 63.5 years) at high CVD risk plus IFG, IGT or T2DM to receive insulin glargine (with a target fasting blood glucose level of 5.3 mmol/L (≤95 mg/dL) or to standard care. After a median follow-up of 6.2 years, the rates of incident CV outcomes were similar in the insulin glargine and standard care groups. Rates of severe hypoglycaemia were 1.00 vs. 0.31 per 100 person-years. Median weight increased by 1.6 kg in the insulin glargine group and fell by 0.5 kg in the standard care group. There was no indication that insulin glargine was associated with cancer.
Conclusion: A meta-analysis of cardiovascular outcomes based on VADT, ACCORD and ADVANCE suggested that an HbA1c reduction of ~1% was associated with a 15% relative risk reduction (RRR) in non-fatal MI but without benefits on stroke or all-cause mortality. However, patients with a short duration of T2DM, lower baseline HbA1c at randomization, and without a history of CVD seemed to benefit from more-intensive glucose-lowering strategies. This interpretation is supported by ORIGIN, which did not demonstrate benefit or detriment on cardiovascular end-points by early institution of insulin-based treatment, even though insulin glargine was associated with increased hypoglycaemia. This suggests that intensive glycaemic control should be appropriately applied in an individualized manner, taking into account age, duration of T2DM and history of CVD.
6.2.4 Long-term Effects of Glycaemic Control. Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC): In DCCT, the rate of cardiovascular events was not significantly altered in the intensive-treatment group. After termination of the study, 93% of the cohort were followed for an additional 11 years under EDIC, during which the differences in HbA1c disappeared. During the combined 17-year follow-up, the risk of any cardiovascular event was reduced in the intensive group by 42% (9–63%; P < 0.01).
United Kingdom Prospective Diabetes Study (UKPDS): Although a clear reduction in microvascular complications was evident, the reduction in MI was only 16% (P = 0.052). In the extension phase of the study, a risk reduction in MI remained at 15%, which became significant as the number of cases increased. Furthermore, the beneficial effects persisted for any DM-related end point; MI and death from any cause was reduced by 13%. It should be noted that this study was performed when lipid lowering and blood pressure were less effectively managed, partially due to the lack of availability of potent, currently available drugs. Thus UKPDS was performed when other important parts of a multifactorial management were less efficient. One may speculate that it may have been easier to verify a beneficial effect of glucose-lowering agents at that time, than in subsequently performed trials.
Conclusion: DCCT and UKPDS showed that, in T1DM and T2DM: (i) glycaemic control is important for reducing long-term macrovascular complications; (ii) a very long follow-up period is required to demonstrate an effect and (iii) early glucose control is important (metabolic memory).
6.2.5 Glycaemic Targets. An HbA1c target of <7.0% (<53 mmol/mol) to reduce microvascular disease is a generally accepted level. The evidence for an HbA1c target in relation to macrovascular risk is less compelling, in part due to the complexities surrounding the chronic, progressive nature of DM and the effects of metabolic memory. Consensus indicates that an HbA1c of ≤7% should be targeted, but with acknowledgement of the need to pay attention to the individual requirements of the patient. Ideally, tight control should be instigated early in the course of the disorder in younger people and without attendant co-morbidities. Fasting plasma glucose (FPG) should be <7.2 mmol/L (<120 mg/dL) and post-prandial <9–10 mmol/L (<160–180 mg/dL) on an individualized basis. Successful glucose-lowering therapy is assisted by self-monitoring of blood glucose, most notably in patients with insulin-treated DM. When near-normoglycaemia is the objective, post-prandial glycaemia needs to be taken into account in addition to fasting glycaemia. However, although post-prandial hyperglycaemia is associated with an increased incidence of CVD events (see section 3:4) it remains controversial as to whether treatment targets addressing post-prandial hyperglycaemia are of added benefit to CVD outcomes.
More stringent targets (e.g. HbA1c 6.0–6.5% (42–48 mmol/mol]) might be considered in selected patients with short disease duration, long life expectancy and no significant CVD, if it can be achieved without hypoglycaemia or other adverse effects. As discussed above, the accumulated results from T2DM cardiovascular trials suggest that not everyone benefits from aggressive glucose management. It follows that it is important to individualize treatment targets.
6.2.6 Glucose-lowering Agents. The choice of pharmacological agent, the combinations employed and the potential side-effects are related to the mode of action of the drug. The choice of agent, the conditions of their use and the role of combination therapy is beyond the scope of this document and has been extensively reviewed in the joint ADA/EASD guidelines. In brief, therapeutic agents for managing hyperglycaemia can be broadly characterized as belonging to one of three groups: (i) insulin providers [insulin, sulphonylureas, meglitinides, glucagon-like peptide-1(GLP-1) receptor agonists, dipeptidylpeptidase-4 (DPP-4) inhibitors]; (ii) insulin sensitizers (metformin, pioglitazone) and (iii) glucose absorption inhibitors [alpha-glucosidase inhibitors, sodium-glucose co-transporter-2 (SGLT2) inhibitors]. The sulphonylureas, meglitinides and incretin mimetics (GLP-1 receptor agonists and DPP-4 inhibitors) all act by stimulating the pancreatic beta-cell to increase endogenous insulin secretion. The GLP-1 receptor agonists and the DPP-4 inhibitors have additional actions on the gastro-intestinal tract and brain, which have a beneficial effect on satiety (weight neutral for DPP-4 inhibitors, weight loss-associated with GLP-1 receptor agonists), although transient nausea occurring in about 20% of those treated may persist for 4–6 weeks after initiation of therapy. Pioglitazone is a PPARγ agonist with partial peroxisome proliferator-activated receptor alpha (PPARα) effects, which lowers glucose by ameliorating insulin resistance, while metformin is a biguanide that exerts similar effects through AMP kinase activation. Both agents tend to reduce insulin requirements in insulin-treated T2DM and, in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROActive) study, pioglitazone use was associated with prolonged reductions in insulin requirements. Acarbose reduces glucose absorption from the gastro-intestinal tract, whilst the SGLT2 inhibitors act on the proximal renal tubule to reduce glucose absorption. The expected decrease in HbA1c with each of the oral treatments, or with subcutaneous administration of GLP-1 agonists as monotherapy, is generally about 0.5–1.0%, although this can vary between individuals, depending on the duration of DM and other factors. Triple therapy—metformin plus two from pioglitazone, sulphonylurea, incretin mimetics, meglitinides and glucose absorption inhibitors—is commonly required as the disorder progresses.
In T1DM, intensive glucose-lowering therapy using a basal-bolus regimen, delivered either by multiple insulin injections or using an insulin pump, is the 'gold standard'. In T2DM, metformin is the first-line drug treatment, especially in overweight patients. A concern over the use of metformin has been the risk of lactic acidosis, especially in patients with impaired renal function and hepatic disease. In systematic reviews of trial data with selected patients, lactic acidosis is not over-represented. Despite this, metformin is not recommended if the estimated eGFR is <50 mL/min. There is an ongoing debate as to whether these thresholds are too restrictive. The UK National Institute for Health and Clinical Excellence (NICE) guidelines are more flexible, allowing use down to a eGFR of 30 mL/min, with dose reduction advised at 45 mL/min.
To attain glucose targets, a combination of glucose-lowering drugs is often required soon after diagnosis. Early aggressive therapy seems to have a role in reducing cardiovascular complications, but has not been formally tested in prospective trials.
Cardiovascular Safety of Glucose-lowering Agents ( Table 8 ): Concerns initiated by possible adverse cardiovascular effects of rosiglitazone raised questions as to the cardiovascular safety of glucose-lowering drugs, particularly when used in combination. A 10-year post-trial follow-up of UKPDS revealed that patients treated with sulphonylurea-insulin had a risk reduction (RR) for MI of 0.85 (95% CI 0.74–0.97; P = 0.01) and for death of 0.87 (95% CI 0.79–0.96; P < 0.007). The corresponding RRs for metformin in overweight patients were 0.67 (95% CI 0.51–0.89; P = 0.005) and 0.73 (95% CI 0.59–0.89; P = 0.002). Although UKPDS indicated that metformin has a beneficial effect on CVD outcomes—which led to metformin being adopted as first line treatment in overweight T2DM—it is important to underline that, overall, there is no clear evidence to support this view and there is a suggestion that, in combination with sulphonylurea, there may be detrimental effects related to both morbidity and mortality. However, the results of this meta-analysis also suggest a benefit after a long duration of treatment in younger patients. Pioglitazone reduced a secondary composite of all-cause mortality, fatal MI and stroke in the PROactive study (HR 0.84; 95% CI 0.72–0.98; P = 0.027) in T2DM patients at high risk of macrovascular disease. However, because the primary outcome in PROactive did not achieve statistical significance, the interpretation of these results remains contentious. The use of pioglitazone is associated with fluid retention secondary to renal effects, and this is associated with peripheral oedoma and worsening of established heart failure in susceptible individuals. Diuretic therapy can be initiated to ameliorate these side-effects. In the STOP-NIDDM trial, acarbose, when given to patients with IGT, reduced the number of CVD events, including cardiovascular mortality. Meglitinides have not been formally tested in T2DM but, in high-risk patients with IGT nateglinide, did not reduce either fatal or non-fatal cardiovascular events. No outcome data from RCTs have so far been published for glucagon-like peptide 1 agonists, DPP-4 inhibitors or SGLT-2 inhibitors, but large prospective trials with cardiovascular outcomes are in progress for GLP-1 receptor agonists and DPP-4 inhibitors and for SGLT2 inhibitors.
6.2.7 Special Considerations. Hypoglycaemia: Intensive glucose lowering increases the incidence of severe hypoglycaemia three- to four-fold in both T1DM and T2DM. Impaired hypoglycaemic awareness increases with duration of DM and is a significant risk factor for hypoglycaemia, which must be taken into account when glucose-lowering therapy is considered. In addition to the short-term risks of cardiac arrhythmia and cardiovascular events, longer-term risks include dementia and cognitive dysfunction. The outcome of glucose-lowering studies has raised the question as to whether hypoglycaemia is an important risk factor for MI in patients with DM. Frier et al. have extensively reviewed this topic, providing evidence for a number of adverse effects of hypoglycaemia on the CV system, particularly in the presence of autonomic neuropathy. Insulin, meglitinides and sulphonylureas are particularly associated with hypoglycaemia, which is a common occurrence in both T1 and T2DM. Attention should be paid to avoidance of hypoglycaemia, whilst achieving glycaemic goals in an individualized manner.
Glucose Lowering Agents in Chronic Kidney Disease: Around 25% of people with T2DM have chronic kidney disease (CKD) stages 3–4 (eGFR <50 mL/min). Aside from the increased CV risk associated with this condition, the use of glucose-lowering agents may need to be modified, either because a particular agent is contra-indicated in CKD or because the dosage needs to be altered. Metformin, acarbose and most sulphonylureas should be avoided in stage 3–4 CKD, whilst insulin therapy and pioglitazone can be used in their place as required. The DPP-4 inhibitors require dose adjustment with progressive CKD with the exception of linagliptin, which is well tolerated in these circumstances. The SGLT2 inhibitors have not been evaluated in CKD.
Elderly People: Older people have a higher atherosclerotic disease burden, reduced renal function and greater co-morbidity. Life expectancy is reduced, especially in the presence of long-term complications. Glycaemic targets for elderly people with long-standing or more complicated disease should be less ambitious than for younger, healthier individuals. If lower targets cannot be achieved with simple interventions, an HbA1c of <7.5–8.0% (<58–64 mmol/mol) may be acceptable, transitioning upwards as age increases and capacity for self-care, cognitive, psychological and economic status and support systems decline.
Individualized Care: The influences on quality of life, adverse effects of polypharmacy and inconvenience of intensified glucose-lowering regimens have to be carefully evaluated for each individual with DM (for further information see Section 9). From a public health perspective, even minor decreases in mean glycaemia may prove advantageous. On the other hand, the intensified glucose-lowering treatment may impose a considerable burden and possible harm on the individual. Each individual should be encouraged to achieve the best compromise between glucose control and vascular risk and, if intensified therapy is instituted, the patients must be informed and understand the benefits and risks.
6.2.8 Gaps in Knowledge.
Long-term CVD outcomes for most glucose-lowering treatments are not known.
The consequences of polypharmacy for quality of life and the most appropriate choice of treatment in DM-patients with comorbidities, particularly in the elderly, are unclear.
The level of glycaemia (FPG, 2hPG, HbA1c) at which CV benefits can be seen in T2DM is not known, since no studies with this aim have been carried out.
6.2.9 Recommendations for GLycaemic Control in Diabetes.
6.3 Blood Pressure
The prevalence of hypertension is higher in patients with T1DM than in the general population (up to 49% in DCCT/EDIC) and more than 60% of patients diagnosed with T2DM have arterial hypertension. According to current pathophysiological considerations, this is related to: (i) hyperinsulinaemia linked to increased renal reabsorption of sodium; (ii) increased sympathetic tone and (iii) increased renin-angiotensin-aldosterone system activity. Obesity, aging and the appearance of renal disease further increase the prevalence of hypertension. DM and hypertension are additive risk factors for CVD. While the development of T2DM doubles the cardiovascular risk in men and more than triples the risk in women, hypertension causes a four-fold increase in cardiovascular risk in people with DM. Although treatment targets are presented, it should be recognised that blood pressure management needs to be implemented on an individualized basis. For example, multiple co-morbidities, increasing age, drug interactions and the pattern of vascular disease may all influence the therapeutic approach and individual target.
6.3.1 Treatment Targets. In DM, the recommended level of blood pressure has been debated. In general, measures to lower elevated blood pressure should be applied in all patients with DM, due to the substantially enhanced cardiovascular risk associated with increased blood pressure levels in such patients. RCTs in T2DM have shown the positive effects on cardiovascular outcomes of lowering blood pressure at least below 140 mm Hg systolic and 85 mm Hg diastolic. The Hypertension Optimal Treatment (HOT) trial demonstrated that risk decreased when the diastolic target was below 80 mm Hg. However, the mean diastolic blood pressure in this group was still above 80 and the systolic pressure was as high as 144 mm Hg. The UKPDS showed that 'tight' (mean 144/82), compared with 'less tight' (154/87) control reduced macrovascular events by 24%. In a post-hoc observational analysis of the UKPDS trial, DM-related mortality decreased 15% with each 10 mm Hg drop, down to a systolic blood pressure of 120 mm Hg, with no indication of a threshold. In the more recent ACCORD trial, more than 4700 patients were assigned to intensive- (achieved mean systolic blood pressure 119 mm Hg) or standard treatment [mean systolic blood pressure (BP) 134 mm Hg] over a mean follow-up of 4.7 years. The relative reduction of the composite endpoint (non-fatal MI, non-fatal stroke, or CVD death) by the intensive treatment did not reach statistical significance. The average number of blood pressure-reducing drugs was 3.5 in the intensive group, against 2.1 in the standard group. The proportion of patients with serious side-effect—such as hypotension and declining renal function—increased from 1.3 to 3.3% with aggressive treatment. Since the risk–benefit ratio tipped towards harm, this study does not support a reduction of systolic blood pressure below 130 mm Hg. Bangalore et al. reported a meta-analysis of 13 RCTs with 37 736 patients with DM, IFG or IGT who, in the intensive group, had a systolic pressure ≤135 mm Hg and, in the standard group, ≤140 mm Hg. The more intensive control related to a 10% reduction in all-cause mortality (95% CI 0.83–0.98), a 17% reduction in stroke but a 20% increase in serious adverse events. Systolic BP ≤130 mm Hg was related to a greater reduction in stroke but did not affect other cardiovascular events.
In summary, present evidence makes it reasonable to reduce blood pressure in patients with DM to <140/85 mm Hg. It should be noted that further reduction might be associated with an increased risk of serious adverse events, especially in patients of advanced age and with longer duration of T2DM. Thus the risks and benefits of more intensive blood pressure management need to be carefully considered on an individual basis.
6.3.2 Managing Blood Pressure-lowering. Lifestyle Intervention including salt restriction and weight loss is the therapeutic basis for all patients with hypertension; however, it is usually insufficient for adequate blood pressure control (for details see Section 6.1).
Pharmacological treatment has only been tested in a few RCTs comparing cardiovascular outcomes with blood pressure-lowering agents and specifically targeting patients with DM. However, several RCTs with sizeable DM subgroups reported specifically on the outcome in this subgroup. It appears that blockade of the renin-angiotensin-aldosterone system (RAAS), by means of an angiotensin converting enzyme inhibitor (ACE-I ) or an angiotensin-receptor-blocker (ARB), is of particular value, especially when treating hypertension in patients with DM at high cardiovascular risk. Evidence also supports the efficacy of an ACE-I, rather than a calcium channel blocker, as initial therapy when the intention is to prevent or retard the occurrence of microalbuminuria in hypertensive patients with DM. Dual RAAS blockade combining an ACE-I with an ARB did not show any further benefit in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), but was associated with more adverse events. In the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial, the addition of aliskiren to RAAS blockade in patients with T2DM at high risk for cardiovascular and renal events did not result in a decrease in cardiovascular events and may even have been harmful. Since DM patients tend to have high blood pressure during the night, administration of antihypertensive drugs at bedtime should be considered —ideally after evaluation of the 24-ambulatory blood pressure profile of the patient.
A matter that has been intensively discussed over the past decades is whether the metabolic actions of various blood pressure-lowering drugs are important for long-term cardiovascular outcome. It is well established that the use of thiazides and beta-blockers is associated with an increased risk of developing T2DM, compared with treatment with calcium channel blockers and inhibitors of the RAAS. It is not known whether treatment with beta-blockers and/or thiazides or thiazide-like diuretics in patients with established T2DM has any metabolic adverse events of clinical importance. The observation from UKPDS, that control of hyperglycaemia—in contrast to an effective blood pressure control—had a relatively minor influence on cardiovascular outcome, indicates that negative metabolic effects may be less important when treating hypertension in patients with DM, at least as regards macrovascular complications. Thus, while drugs with negative metabolic effects—especially the combination of a diuretic and a beta-blocker—should be avoided as first-line treatment in hypertensive patients with metabolic syndrome, the objective of lowering blood pressure seems more important than minor alterations in metabolic status in patients with established DM. A recent meta-analysis emphasized the priority of blood pressure lowering over choice of drug class. In the absence of cardiac co-morbidity, beta-blockers are not the first choice for the treatment of hypertension. Appropriate blood pressure control does often require combined therapy with a RAAS inhibitor and a calcium channel blocker or a diuretic. The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial indicated that the calcium channel antagonist amlodipine is superior to hydrochlorothiazide in combination treatment with an ACE-I. In 6946 patients with DM, the number of primary events was 307 in the group treated with amlodipine and 383 in the group treated with hydrochlorothiazide as the add-on to benazepril (P = 0.003), despite a similar reduction of blood pressure in both groups.
6.3.3 Conclusion. The main aim when treating hypertension in patients with DM should be to lower blood pressure to <140/85 mm Hg. To achieve this goal, a combination of blood pressure-lowering drugs is needed in most patients. In patients with hypertension and nephropathy with overt proteinuria, an even lower BP (SBP <130 mm Hg) may be considered if tolerated by the patient (see Section 8). All available blood pressure-lowering drugs can be used, but evidence strongly supports the inclusion of an inhibitor of the RAAS (ACE-I/ARB) in the presence of proteinuria. It should be borne in mind that many DM patients do not reach the recommended BP target. It is also noteworthy that, in contrast to that reported with glycaemic control and statins, there is no hypertensive legacy or memory effect. As a consequence, sustained control and monitoring and consistent medical adjustment are recommended.
These main conclusions regarding treatment of patients with DM and hypertension are consistent with the Re-appraisal of the European Guidelines on Hypertension (2009) and the updated European Guidelines for hypertension 2013.
6.3.4 Gaps in Knowledge.
The consequences of blood pressure-lowering multi-drug combinations in the elderly are poorly understood.
The evidence base for efficacy or harm for microvascular complications for both individual blood pressure-lowering drugs alone or in combination is weak.
The understanding of the role of arterial stiffness in predicting CV risk in patients with DM, over and above the role of conventional risk factors is poor.
Optimal blood pressure targets are unknown.
Are the metabolic side-effects of beta-blockers or diuretics clinically relevant?
6.3.5 Recommendations for Blood Pressure Control in Diabetes.
6.4 Dyslipidaemia
6.4.1 Pathophysiology. In individuals with T1DM and good glycaemic control, the pattern of lipid abnormalities contrasts with that of T2DM since, in T1DM, serum TG is normal and high-density lipoprotein cholesterol (HDL-C) is within the upper normal range or slightly elevated. This pattern is linked to insulin therapy, which increases lipoprotein lipase activity in adipose tissue, and the turnover rate of very low-density lipoprotein (VLDL) particles. However, qualitative changes in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles may potentially be atherogenic.
A cluster of lipid and apoprotein abnormalities accompanies T2DM, affecting all lipoprotein classes ( Table 9 ). The two core components are a moderate elevation of fasting and non-fasting triglycerides (TGs) and low HDL-C. Other features comprise elevations of TG-rich lipoprotein (TRLs), including chylomicron and VLDL remnants, small dense LDL particles.
These components are not isolated abnormalities but are metabolically linked. Overproduction of large VLDL particles with increased secretion of both TGs and Apo B 100 leads to the generation of small, dense LDL particles and lowering of HDL-C. As VLDL, remnant and LDL particles carry a single Apo B 100 molecule, the dyslipidaemia is characterized by elevation of the Apo B concentration. Therefore, the malignant nature of dyslipidaemia in T2DM is not always revealed by routine lipid measures, as LDL-C remains within a normal range and it may often be better-characterized by using non-HDL-C. Substantial evidence indicates that an imbalance between the hepatic import and export of lipids results in excess liver fat accumulation (non-alcoholic fatty liver disease). Increased flux of FFA comes from both the systemic FFA pools and de novo lipogenesis in the setting of IR. Thus the content of liver fat and hepatic IR seem to be driving the overproduction of large VLDL particles in people with T2DM.
Impaired clearance of large VLDL particles, linked to increased concentration of Apo C, contributes to a more robust hypertriglyceridaemia. Thus dual metabolic defects contribute to the hypertriglyceridaemia in people with T2DM. Recent data suggest that part of the lipid oversupply to the liver in the presence of obesity may be due to a maladaptive response of adipose tissue to store circulating FFAs, leading to ectopic fat deposition and lipotoxicity that underlies dyslipidaemia in DM and IR.
6.4.2 Epidemiology. The European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE III) survey reported that the overall prevalence of high TG and low HDL–C has almost doubled, compared with the prevalence seen by EUROASPIRE II, due to the increase in T2DM and obesity. A population-based survey of 75 048 patients with T2DM in the National Diabetes register in Sweden reported that 49% of patients did not receive lipid-lowering drugs. Fifty-five per cent of those treated had a TG <1.7 mmol/L and around two-thirds a normal HDL-C. Data from the same survey revealed that two-thirds of patients on lipid-lowering drugs achieved an LDL-C <2.5 mmol/L. However, in those with a history of CVD, more than 70% had LDL-C >1.8 mmol/L. Notably, only moderate doses of the different statins were used, highlighting the need for intensification of therapy and better management of the existing treatment gap.
Dyslipidaemia and Vascular Risk in Type 2 Diabetes Mellitus: A wealth of data from case-control, mechanistic, genetic and large observational studies indicate that a causal association exists between elevation of triglyceride-rich particles and their remnants, low HDL-C and CVD risk. Data from statin trials strengthen the position of low HDL as an independent CVD risk marker, even in patients with an LDL-C level that is not elevated. Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study and ACCORD demonstrated that cardiovascular event rates were significantly higher in those with dyslipidaemia (LDL-C 2.6 mmol/L (100 mg/dL), TG ≥2.3 mmol/L and HDL-C ≤0.88 mmol/L). In FIELD, the baseline variables best predicting CVD events over a 5-year follow-up were lipid ratios (non-HDL/HDL-C and total/HDL-C). Apo B–Apo A is related to CVD outcomes, but this ratio was not superior to traditional lipid ratios. Of the single baseline lipid and lipoprotein concentrations, HDL-C, Apo A, non-HDL-C and Apo B individually predicted CVD events, although Apo A and Apo B did not perform better than HDL-C or non-HDL-C. The power of serum TG to predict CVD events was attenuated by adjustment for HDL-C. These results were unexpected, since the dyslipidaemia in DM is a cluster of abnormalities featuring elevations of Apo B and small dense LDL particles. The data are, however, in full agreement with results from the Emerging Risk Factor Collaboration (ERFC) study, based on 68 studies that included 302 430 participants without a history of CVD. In this analysis, non-HDL-C and Apo B each had very similar association with coronary heart disease irrespective of the presence of DM. The ERFC study reported that an increase of one standard deviation in HDL-C (0.38 mmol/L or 15 mg/dL) was associated with a 22% reduction in risk of coronary heart disease. HRs for non-HDL and HDL-C were similar to those observed for Apo B and Apo A and non-HDL-C was the best tool to capture the risk associated with elevation of triglyceride rich proteins in clinical practice. The use of Apo B and Apo B–Apo A are also advocated as CVD risk markers in T2DM.
6.4.3 Management of Dyslipidaemia. Type 2 Diabetes Mellitus: Comprehensive and consistent data exist on the mechanism of action and efficacy of statins in the prevention of CVD events in T2DM. The benefits of statin therapy in lowering LDL-C and reducing CVD events are seen in all subgroup analyses of major RCTs. In a meta-analysis of 14 RCTs covering 18 686 people with DM, the mean duration of follow-up was 4.3 years, with 3247 major vascular events. The study reported a 9% reduction in all-cause mortality and a 21% reduction in the incidence of major vascular outcomes per mmol/L of LDL-C lowering (RR 0.79; 99% Cl 0.72–0.87; P < 0.0001), similar to that seen in non-DM. The magnitude of the benefit was associated with the absolute reduction in LDL-C, highlighting a positive relationship between LDL-C and CVD risk, and was seen at a starting LDL-C as low as 2.6 mmol/L.
The results of the first meta-analyses of cardiovascular events of intensive vs. moderate statin therapy show a 16% risk reduction of coronary death or MI. Data from 10 RCTs, studying 41 778 patients followed for 2.5 years, showed that intensive statin dosage reduced the composite endpoint of CAD by 10% (95% Cl 0.84–0.96; P < 0.0001), but did not reduce CVD mortality. In a subgroup of patients with ACS, intensive statin therapy reduced both all-cause and CVD mortality. Intensive lowering of LDL-C by statins had a beneficial effect on progression of atheroma in DM and non-DM.
Intensification of LDL-C lowering can also be achieved by adding ezetimibe to a statin, however, there are still no data from an RCT that this combination has a significant impact on CVD outcome. The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT: ClinicalTrials.gov: NCT00202878) is, however, under way. An analysis of pooled safety data comparing the efficacy and safety profile of combination therapy with ezetimibe/statin vs. statin monotherapy in DM and non-DM (n = 21 794) reported that combination therapy provided larger effects on all major lipid measures. The Study of Heart and Renal Protection (SHARP) trial reported a 17% reduction of major atherosclerotic events in chronic kidney disease treated with simvastatin plus ezetimibe daily vs. placebo. In this context it should be emphasized that, although relative reduction of events may be similar for people with and without DM, the absolute benefit is greater in DM-patients due to their higher risk.
Type 1 Diabetes Mellitus: The Cholesterol Treatment Trialists (CTT) analysis included 1466 T1DM patients with an average age of 55 years and a majority with prior CVD events. This analysis showed a similar reduction of risk of CVD events (RR 0.79; 95% CI 0.62–1.01) to that seen in T2DM and with a P value for interaction of 1.0, verifying the result despite only a borderline significance in the subgroup. It should be recognized that no trial data exist on the efficacy of statin therapy in a younger population with T1DM. However, in T1DM, statin therapy should be considered on an individual basis in those at high risk for CVD events, irrespective of LDL-C concentration—for example T1DM patients with renal impairment.
Primary Prevention: The Collaborative Atorvastatin Diabetes Study (CARDS) evaluated the benefits of a statin in patients with T2DM and at least one of the following risk factors: hypertension, current smoking, retinopathy, or albuminuria. In CARDS, 2838 T2DM patients were randomized to atorvastatin 10 mg/day or placebo. The study was terminated prematurely, due to a 37% reduction (95% CI -52 to -17; P = 0.0001) in the primary endpoint (first acute coronary heart disease event). The Heart Protection Study (HPS) recruited 2912 patients (mainly T2DM) without pre-existing CVD. Simvastatin (40 mg/day) reduced the composite primary endpoint by 33% (P = 0.0003; 95% Cl 17–46). In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) subgroup analyses of DM patients free from CVD, 10 mg of atorvastatin reduced the rate of major CVD events and procedures by 23% (95% Cl 0.61–0.98; P = 0.04).
Safety of Statin Therapy: Reports from major RCTs demonstrate that statins are safe and well-tolerated. The frequency of adverse events, except for muscle symptoms, is rare. In the majority of cases of myopathy or rhabdomyolysis there are drug interactions with a higher-than-standard dose of statin. The combination of gemfibrozil and statins should be avoided due to pharmacokinetic interaction, but there are no safety issues with fenofibrate and statins.
A meta-analysis including 91 140 participants reported that statin therapy was associated with risk of new-onset T2DM (OR 1.09; 95% Cl 1.0–1.2; I = 11%), which increased with age. The data translate to one case of T2DM when 255 patients have been treated for 4 years. Over the same time, statins would prevent 5.4 CVD events for each mmol/L reduction in LDL-C. A meta-analysis of five statin trials reported that the risk of new onset DM increased with intensive statin (atorvastatin or simvastatin 80 mg daily) therapy (OR 1.12; 95% Cl 1.04–1.22; I = 0%), compared with moderate (simvastatin 20 mg or pravastatin 40 mg) doses. In the intensive group, two additional cases of new-onset DM per 1000 patient years were observed, whereas the number of CVD events was 6.5 cases fewer. Recently the Food and Drug Administration (FDA) of the USA approved label changes on increases of blood glucose and HbA1c for the statin class of drugs (www.fda.gov/downloads/Drugs/DrugSafety/UCM293474.pdf). The FDA still considers that the small risk of developing DM is clearly outweighed by the reduction of cardiovascular events. Further support for the safety of statins comes from a meta-analysis of 27 randomized trials that demonstrated that, in individuals with a five-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL-C produced an absolute reduction in major vascular events of about 11 per 1000 over five years, without an increase in incidence of cancer or deaths from other causes. This benefit greatly exceeds any known hazards of statin therapy.
Residual Risk in People on LDL-lowering Therapy: T2DM patients at the LDL-C target remain at high risk of CVD events, and this residual risk is linked to many factors including elevation of TG-rich proteins, low HDL-C and small, dense LDL particles. It has been suggested that targeting elevated TG (>2.2 mmol/L) and/or low HDL-C (<1.0 mmol/L) may provide further benefits. In the FIELD study, fenofibrate therapy did not reduce the primary endpoint (CAD-related death and non-fatal MI), but total CVD events were reduced from 14 to 12.5% (HR 0.9; 95% Cl 0.80–0.99; P = 0.035). In the ACCORD trial, 5518 patients were assigned to fenofibrate plus simvastatin (20–40 mg daily) or placebo without any additional effect on the primary endpoint. In a pre-specified subgroup analysis of people with TG >2.3 mmol/L (>204 mg/dL) and HDL-C <0.9 mmol/L (<34 mg/dL), cardiovascular risk was reduced by 31% in the fenofibrate-plus-simvastatin group (for interaction between patients with this lipid profile vs. those without, P = 0.06). A subgroup analysis of dyslipidaemic people (TG >2.3 mmol/L and HDL-C <0.9 mmol/L) in the FIELD study revealed a 27% reduction in CVD risk. In both FIELD and ACCORD, fenofibrate therapy was associated with robust reduction of TG (22%), whereas elevation of HDL-C remained less than expected (+2% and +2.4%, respectively). Meta-analyses have confirmed the clinical benefits of fibrates on major CVD events but not on cardiovascular mortality. The effects seem to be linked to improvement in TGs.
Strategies to Elevate High-density Lipoprotein Cholesterol: The level of HDL-C is inversely related to CVD in epidemiological studies, as well as in many statin trials. Low levels of HDL-C are associated with increased levels of triglycerides and are often seen in patients with metabolic syndrome and/or DM. Targeting low HDL-C for CVD prevention is, however, not supported by evidence. Two recently reported RCTs, using the cholesterylester transfer protein (CETP) inhibitors torcetrapib and dalcetrapib, failed to reduce cardiovascular events despite a 30–40% increase in HDL-C. One explanation for these findings may relate to abnormal functional characteristics of HDL particles. If this is true, merely increasing the number of such particles without any improvement of their function may not alter CVD risk.
The pharmacological tools currently available to raise HDL-C in DM patients remain limited. Fenofibrate has trivial efficacy in this regard, while niacin (N-ER) has potentially useful properties, increasing HDL-C by 15–30%, with an associated increase in Apo A-1, besides lowering TG (up to 35%), LDL-C (about 20%) and Apo B and lipoprotein a (Lp a) (about 30%). Although a study showed favourable effects on angiographic measures, and on reduction of carotid wall area quantified with magnetic resonance imaging after one year of therapy, two recent clinical studies did not confirm the usefulness of N-ER for cardiovascular prevention. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) study showed no additional benefit of N-ER in patients with metabolic syndrome. In the Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS-2 THRIVE) trial, 25 673 patients with known vascular disease were randomized to placebo or N-ER/laropiprant on a background of statin or statin/ezetimibe therapy. The trial was stopped prematurely after a median follow up of 3.9 years. At that time, 15.0% of patients in the control arm and 14.5% in the N-ER/laropiprant arm (ns) had reached the primary endpoint, a composite of coronary death, non-fatal MI, stroke, or coronary revascularization. Moreover, there was a significant 3.7% absolute excess risk of DM complications and a significant 1.8% excess risk of new-onset DM. In addition, N-ER treatment caused a 1.4% higher risk of infection and a 0.7% higher risk of bleeding, including an increased risk of haemorrhagic stroke.. Based on these results, the EMA has withdrawn the marketing licence for N-ER/laropiprant.
So far, lifestyle intervention with smoking cessation, increased physical activity, weight reduction and decreased consumption of fast-absorbed carbohydrates remains the cornerstone of HDL-increasing therapy.
In patients with high TG (>5.4 mmol/L) lifestyle advice (with a focus on weight reduction and alcohol abuse if relevant) and improved glucose control are the main targets. Risks associated with TG are acute pancreatitis and polyneuropathy. In a pooled analysis of randomized trial data, use of statins was associated with a lower risk of pancreatitis in patients with normal or mildly elevated triglyceride levels. Fibrates were not protective and may even have enhanced the risk. Omega-3 fatty acids (2–4 g/day) may be used for TG-lowering in people with high levels. There is, however, no evidence that such supplements are of cardiovascular benefit in patients with DM.
6.4.4 Gaps in Current Knowledge.
The role of HDL particles in the regulation of insulin secretion in beta-cells needs further exploration.
Efficiency and safety of drugs increasing or improving HDL-C particles is unclear.
The relative contributions of HDL function and plasma HDL concentration in the pathogenesis of CVD should be clarified.
6.4.5 Recommendations on Management of Dyslipidaemia in Diabetes.
6.5. Platelet Function
Platelet activation plays a pivotal role in the initiation and progression of atherothrombosis. Abnormalities in the aggregation of platelets in DM ex vivo have been described by numerous groups, and both post-prandial and persistent hyperglycaemia have been identified as major determinants of in vivo platelet activation in the early and late phases of the natural history of T2DM.
6.5.1 Aspirin. Aspirin inhibits thromboxane (TX) A2-dependent platelet activation and aggregation through irreversible inactivation of platelet cyclo-oxygenase 1 (COX-1) activity. No formal studies have specifically examined the dose- and time-dependence of its antiplatelet effect in patients with T2DM and aspirin is currently recommended at 75–162 mg once daily, i.e. at the same dose and dosing interval used in people without DM. However, once-daily administration of low-dose aspirin may be associated with incomplete inhibition of platelet COX-1 activity and TXA2-dependent platelet function, perhaps due to increased platelet turnover in DM. Evidence to support this view indicates the potentially beneficial effects of sustained efficacy using twice-daily aspirin in people with DM and CVD.
Secondary Prevention: The first collaborative overview of the Antiplatelet Trialists' Collaboration found that antiplatelet therapy (mostly with aspirin) is similarly effective among patients with pre-existing symptomatic CVD, regardless of the presence of DM. They analysed individual data on 'serious vascular events' (non-fatal MI, non-fatal stroke or vascular death) from approximately 4500 patients with DM in the randomized trials and found that treatment with antiplatelet drugs produced a proportional reduction of about one quarter. Therefore there is no apparent reason to treat patients with DM and CVD differently from non-DM patients and low-dose aspirin is uniformly recommended for both the acute treatment of ischaemic syndromes and their secondary prevention.
Primary Prevention: Low-dose aspirin is recommended by several North American organizations for the primary prevention of cardiovascular events in adults with DM. However, direct evidence of its efficacy and safety in this setting is lacking or, at best, inconclusive. Thus, in the most up-to-date meta-analysis, which includes three trials conducted specifically in patients with DM and six other trials in which such patients represent a subgroup within a broader population, aspirin was found to be associated with a non-significant 9% decrease in the risk of coronary events (RR 0.91; 95% CI 0.79–1.05) and a non-significant 15% reduction in the risk of stroke (RR 0.85; 95% CI 0.66–1.11). It should be emphasized that the total number of patients with DM enrolled in these nine trials was 11 787, with 10-year extrapolated coronary event rates ranging from as low as 2.5% to as high as 33.5%. These results have been interpreted as suggesting that aspirin probably produces a modest reduction in the risk of cardiovascular events, but the limited amount of available data precludes a precise estimate of the effect size. Consistent with this uncertainty, antiplatelet therapy with aspirin in adults at a low CVD risk is not recommended by the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on CVD Prevention in Clinical Practice.
The Risk–Benefit Ratio of Aspirin: Based on data from a meta-analysis of the six primary prevention trials, aspirin was associated with a 55% increase in the risk of extracranial (mainly gastro-intestinal) bleeding, both in people without- (the majority) and with DM. In terms of the balance between the potential benefit and hazard of aspirin in primary prevention, these results probably represent a best-case scenario, as people at increased risk of gastro-intestinal bleeding were excluded and elderly people were under-represented. In the same analyses, the presence of DM at baseline was associated with a two-fold increase in vascular events but also with a 50% increased risk of major extracranial bleeds during follow-up.
Both the Endocrine Society Clinical Practice Guideline and the ADA/AHA/ACCF Scientific Statement favour aspirin use in adults with DM when the 10-year risk of cardiovascular events is >10%. However, relatively little emphasis is placed in either statement on the need to evaluate the variable bleeding risk of the patient. While the annual risk of cardiovascular events can vary approximately 10-fold in DM, the annual risk of upper gastro-intestinal bleeding has been estimated to vary by up to 100-fold in the general population, depending on age and history of peptic ulcer disease.
6.5.2 P2Y12 Receptor Blockers. Clopidogrel, an irreversible blocker of the adenosine diphosphate (ADP) receptor P2Y12, provides a valid alternative for patients who are aspirin-intolerant or have symptomatic peripheral vascular disease, because it has broad indications for long-term secondary prevention similar to aspirin. Moreover, clopidogrel (75 mg once daily) produced additive cardio-protective effects when combined with low-dose aspirin (75–160 mg once daily) in patients with ACS and those undergoing percutaneous coronary intervention (PCI). There is, however, evidence from the Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management and Avoidance (CHARISMA) study to indicate that clopidogrel, added to background aspirin, may have deleterious effects in patients with advanced nephropathy. More effective P2Y12 blockers include prasugrel and ticagrelor, a reversible P2Y12 blocker. In the TRITON-TIMI 38 trial, prasugrel (60 mg loading dose, followed by 10 mg daily) showed clear superiority over clopidogrel (300 mg loading dose, followed by 75 mg daily) in the prevention of recurrent ischaemic events post-acute coronary syndrome (ACS): however, in the general cohort, this benefit carried a risk of increased thrombolysis in myocardial infarction (TIMI) major bleeding. In a DM sub-study, a similar reduction in recurrent ischaemic events was seen, but in the DM cohort this was not accompanied by an increase in bleeding. Ticagrelor (180 mg loading dose, followed by 90 mg twice daily), was also more effective than clopidogrel (300–600 mg loading dose, followed by 75 mg daily) in reducing death from CV causes and total mortality at 12 months in a general post-ACS cohort, and decreased ischaemic events in DM patients without causing increased bleeding. Importantly, ticagrelor was shown to be superior to clopidogrel in ACS patients with renal impairment. There is no convincing evidence that either clopidogrel or the newer drugs are any more or less effective in people with DM than in those without. For the use of these drugs in connection to PCI, see Section 7.2.
6.5.3 Gaps in Knowledge.
The optimal antithrombotic regimen for the primary prevention of CVD in DM is not established.
6.5.4 Recommendations for Antiplatelet Therapy in Patients With Diabetes.
6.6 Multifactorial Approaches
6.6.1 Principles of Multifactorial Management. Patients with glucose perturbations are in need of early risk assessment to identify co-morbidities and factors that increase cardiovascular risk. This includes evaluation of: (i) risk factors (e.g. lifestyle habits including smoking, hypertension and dyslipidaemia); (ii) microvascular and macrovascular disease and autonomic dysfunction; (iii) co-morbidities (e.g. heart failure and arrhythmias); (iv) inducible ischaemia by means of exercise testing, stress echocardiography, or myocardial scintigraphy and (v) myocardial viability and LV function by means of echo-Doppler and/or magnetic resonance imaging. The reliability of exercise testing, stress echocardiography, or myocardial scintigraphy is of a particular concern in the detection of ischaemia in DM. Confounders are a high threshold for pain due to autonomic dysfunction, the multi-vessel nature of coronary disease, ECG abnormalities, co-existence of PAD and use of multiple medications.
The total risk for cardiovascular complications is, to a large extent, related to synergistic interactions between IR, beta-cell dysfunction and subsequent hyperglycaemia but also the accumulation of cardiovascular risk factors. Accordingly, successful risk prevention depends on a comprehensive detection and management of all modifiable risk factors, as can be visualized by the use of risk engines (e.g. the UKPDS). It should be noted, however, that such engines need to be continuously updated. Further information can be obtained in Section 5.
The feasibility of intensified, multifactorial treatment for patients with T2DM in general practice was studied in the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen Detected Diabetes in Primary Care (ADDITION). The incidence of a first cardiovascular event was 7.2% (13.5 per 1000 person-years) in the intensive care group and 8.5% (15.9 per 1000 person-years) in the routine care group (HR 0·83; 95% CI 0·65–1·05), and incidence of all-cause mortality was 6.2% (11.6 per 1000 person-years) and 6.7% (12.5 per 1000 person-years), respectively (HR 0.91; 95% CI 0.69–1.21). It was concluded that an intervention to promote early intensive management of patients with T2DM was associated with a small but non-significant reduction in the incidence of cardiovascular events and death. A caveat in respect of ADDITION was the only slightly better control of important cardiovascular risk factors (HbA1c, cholesterol concentrations and blood pressure) in the intensive group. In contrast, the value of a multifactorial intervention in patients with DM and established microalbuminuria was demonstrated by the STENO 2 study which, in a highly specialized setting, randomized 160 participants to an intensive, target-driven multifactorial therapy or to conventional management. The targets in the intensively treated group were HbA1c <6.5%, total cholesterol <4.5 mmol/L (175 mg/dL) and blood pressure <130/80 mm Hg. All patients in this group received RAAS blockers and low-dose aspirin. Although treatment targets were not always attained in the intensive-treatment group, their overall management was considerably better than in routinely handled patients. This resulted in a reduction in microvascular and macrovascular events of about 50% after 7.8 years of follow-up. The target most successfully attained was that for cholesterol, probably making crucial the role of statins in the overall prevention strategy. Subsequently, target-driven therapy was recommended to patients in both groups. They were followed for 13 years after randomization. By that time, patients originally allocated to the intensively managed group had an absolute mortality reduction of 20% and the HR for death, compared with that in the conventional group, was 0.54 (95% CI 0.3–0.9; P < 0.02). The absolute risk reduction in cardiovascular events was 29%. In addition, there was a substantial reduction in diabetic nephropathy (relative risk 0.4; 95% CI 0.3–0.8; P < 0.004) and progression of retinopathy (relative risk 0.6; 95% CI 0.4–0.9; P = 0.01). In a health-economic analysis, intensive patient management was reported as more cost-effective than conventional care. Since increased expenses relating to intensive care were driven by pharmacy and consultation costs, such treatment would be dominant (i.e. cost- and life-saving with the use of generic drugs in a primary care setting).
Data from the Euro Heart Survey on Diabetes and the Heart support a multifactorial approach as a cornerstone of patient management. Among 1425 patients with known T2DM and CAD, 44% received evidence-based pharmacological therapy, defined as a combination of aspirin, beta-blockade, RAAS inhibitors and statins in the absence of contra-indications. Patients on such drug combination had a significantly lower all-cause mortality (3.5 vs. 7.7%; P = 0.001) and fewer combined cardiovascular events (11.6 vs. 14.7%; P = 0.05) after one year of follow up, compared with those who did not receive a full combination of such drugs. The adjusted HR for the interaction between DM and treatment revealed that the use of evidence-based treatment in T2DM had an independent protective effect (HR for death: 0.4). An example of the inadequacy of a single drug approach to decrease the incidence of CVD originates from a study that randomized 37 overweight/obese insulin-resistant participants, still without DM, to fenofibrate, rosiglitazone, or a calorie-restricted diet. None of the tested treatments appeared to be a therapeutic intervention that, in isolation, had the capacity to normalize all—or at least a majority—of the metabolic disturbances (e.g. weight, insulin sensitivity, cholesterol, TG, post-load PG) in these patients at a greatly increased cardiovascular risk.
Treatment targets are summarized in Table 10 .
6.6.2 Gaps in Knowledge.
Pleiotropic effects of glucose-lowering therapies on CVD outcomes are not fully understood.
6.6.3 Recommendations for Multifactorial Risk Management in Diabetes.
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