ESC Guidelines on diabetes,pre-diabetes,and cardiovascular diseases developed in collaboration with the EASD – Summary

4.1.1 Diet

Dietary interventions recommended by the EASD Diabetes and Nuitrition Study Group are less prescriptive than earlier dietary advice, ³⁴ but emphasise an appropriate intake of total energy and a diet in which fruits, vegetables, wholegrain cereals, and low-fat protein sources predominate. It has been suggested that there is no benefit in a high protein over a high carbohydrate diet in T2DM. ⁵⁵ Specific dietary recommendations include limiting saturated and trans-fats and alcohol intake, monitoring carbohydrate consumption, and increasing dietary fibre. Routine supplementation with anti-oxidants, such as vitamins E and C and carotene, is not advised. ⁵⁶ For those who prefer a higher intake of fat, a Mediterranean-type diet is acceptable, provided that fat sources are mainly derived from monounsaturated oils using virgin olive oil. ⁵⁷

4.1.2 Physical activity

Aerobic and resistance training improve insulin action, plasma glucose (PG) and lipid levels, blood pressure, and card ovascular risk. ⁵⁸ 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.^{59 –61} Systematic reviews reported that structured aerobic exercise or resistance exercise reduced HbA_1c by about 0.6% in T2DM.^59,60 Combined aerobic and resistance training has a more favourable impact on HbA_1c than aerobic or resistance trainingalone. ⁶² In a recent meta-analysis of 23 studies, structured exercise training was associated with a 0.7% fall in HbA_1c when compared with controls. ⁵⁹ Structured exercise of >150 min/week was associated with a fall in HbA_1c of 0.9%; <150 min/week with a fall of 0.4%. Overall, interventions of physical activity advice were only associated with lower HbA_1c levels when combined with dietary advice. ⁶²

OPEN IN VIEWER

Recommendations on life style modifications in diabetes.

Life Style modifications in diabetes
Recommendations	Class a	Level b	Ref. c
Smoking cessation guided by structured advice is recommended in all subjects with DM and IGT.	I	A	63
It is recommended that in the prevention of T2DM and control of DM total fat intake should be <35%, saturated fat <10%, and monounsaturated fatty acids >10% of total energy.	I	A	34, 55, 66, 67
It is recomended that dietary fibre intake should be >40 g/day (or 20 g/1000 Kcal/day) in the prevention of T2DM and control of DM.	I	A	34, 55, 66, 67
Any diet with reduced energy intake can be recommended in lowering excessive body weight in DM.	I	B	66, 67
Vitamin or micronutrient supplementation to reduce the risk of T2DM or CVD in DM is not recommended.	III	B	56, 66
Moderate to vigorous physical activity of ≥150 min/week is recommended for the prevention and control of T2DM, and prevention of CVD in DM.	I	A	58, 68
Aerobic exercise and resistance training are recommended in the prevention of T2DM and control of DM, but best when combined.	I	A	60

CVD = cardiovascular disease; DM = diabetes mellitus; T2DM = type 2 diabetes mellitus.

a

Class of recommendation.

b

Level of evidence.

c

Reference(s) supporting levels of evidence.

4.1.3 Smoking Cessation

Smoking increases the risk of T2DM, ⁶³ CVD, and premature death, ⁶⁴ and smoking cessation decreases risk of CVD. ⁶⁵ Current smokers with DM should be offered a structured smoking cessation programme, including pharmacological support if needed. Detailed instructions on smoking cessation are presented in the 2012 Joint European Prevention Guidelines. ⁴²

4.2.1 Microvascular disease (retinopathy, nephropathy and neuropathy)

Retinopathy is the most frequent microvascular complication in DM. Although its incidence has declined following the implementation of intensive treatment regimens, vision-threatening proliferative retinopathy affects 50% of subjects with type 1 diabetes mellitus (T1DM), and 29% with T2DM develop vision-threatening macular oedema.^{75 –77} Rapidly progressive retinopathy indicates increased cardiovascular risk and the combination of retinopathy and nephropathy predicts excess morbidity and mortality; in T2DM advanced retinopathy more than doubles this risk. ⁷⁸

Intensified glucose lowering, targeting an HbA_1c of 6.0–7.0%, (42–53 mmol/mol), ⁷⁹ has consistently been associated with decreased frequency and severity of microvascular complications. This applies to both T1DM and T2DM, although it is less apparent in T2DM with established complications.^{80 –84} Analyses from the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated a continuous relationship between increasing HbA_1c and microvascular complications, without an apparent threshold.^85,86 In the DCCT, a decrease in HbA_1c of 2% (22 mmol/mol) significantly lowered the riskofthe development and progression of retinopathy and nephropathy, ⁶⁹ although the absolute reduction was low at HbA_1c <7.5% (58 mmol/mol).

4.2.2 Macrovascular disease: medium-term effects of glycaemic control

Action to Control Cardiovascular Risk in Diabetes (ACCORD). A total of 10 251 T2DM subjects at high cardiovascular risk were randomized to intensive glucose control. They achieved an HbA_1c of 6.4% (46 mmol/mol) or to standard treatment reaching an HbA_1c of 7.5% (58 mmol/mol). ⁸¹ 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 patients/year deaths), which was pronounced in those with multiple cardiovascular risk factors and driven mainly by cardiovascular mortality. Hypoglycaemia was more common with intensive treatment and in patients with poorer glycaemic control, although the role of hypoglycaemia for the development of CVD events is not entirely clear. Further analysis revealed that the higher mortality may be due to fluctuations in glucose, in combination with an inability to control glucose to target, despite aggressive glucose-lowering treatment. ⁸⁷ A follow-up of ACCORD did not support severe symptomatic hypoglycaemia as being related to higher mortality. ⁸⁸

Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE). Eleven thousand, one hundred and forty T2DM subjects at high cardiovascular risk were randomized to intensive or conventional glucose-lowering therapy. ⁸² The intensive arm achieved an HbA_1c 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 [hazard ratio (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 (HR0.94; 95% CI 0.84–1.06). In contrast with ACCORD, there was no increase in mortality (HR0.93; 95% CI 0.83–1.06) despite a similar decrease in HbA_1c. Severe hypoglycaemia was three times lower in the intensive arm of ADVANCE, compared with ACCORD, and HbA_1c lowering to target was achieved at a slower rate. 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). One thousand, seven hundred and ninety-one T2DM patients were randomized to intensive or standard glucose control, reaching an HbA_1c of 6.9% (52 mmol/mol) in the intensive-therapy group, compared with 8.4% (68 mmol/mol) in the standard-therapy group. ⁸³ There was no significant reduction in the primary composite cardiovascular endpoint in the intensive-therapy group (HR 0.88; 95% CI 0.74–1.05).

ORIGIN (Outcome Reduction with Initial Glargine Intervention). Twelve thousand, five hundred and thirty-seven people (mean age 63.5 years) at high CVD risk plus IFG, IGT or T2DM were randomized to receive insulin glargine (with a target fasting blood glucose level of 5.3 mmol/L (≤95 mg/dL) or standard care. After follow-up of 6.2 years, CV outcomes were similar in the insulin glargine and standard care groups. Rates of severe hypoglycaemia were 1.0 vs. 0.31 per 100 person-years. Median weight increased by 1.6 kg with insulin-glargine and fell by 0.5 kg with standard care. ⁸⁹

Conclusion. A meta-analysis of cardiovascular outcomes based on VADT, ACCORD and ADVANCE suggested that an HbA_1c reduction of ~1% was associated with a 15% relative risk reduction (RRR) in non-fatal Ml, without benefits in terms of stroke or all-cause mortality. ⁹⁰ However, patients with a short duration of T2DM, lower baseline HbA_1c at randomization, and without a history of CVD seemed to benefit from intensive glucose-lowering strategies. This is supported by ORIGIN, which did not demonstrate either benefit or detriment to cardiovascular endpoints, even though insulin was associated w th ncreased 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.

4.2.3 Macrovascular Disease: Long-term effects of glycaemic control

Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC). In DCCT, cardiovascular events were not altered in the intensive-treatment group. ⁶⁹ After termination of the study, 93% of the cohort were followed for an additional 11 years (EDIC), during which time the differences in HbA_1c disappeared. ⁷² During the 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 Ml was only 16% (P = 0.052). In the extension phase, a risk reduction in MI remained at 15%, which became significant as the number of cased increased. ⁷³ It should be noted that this study was performed when lipid-lowering and blood pressure were less-effectively managed and it may have been easier to verify a beneficial effect of glucose-lowering agents than in subsequent trials.

Conclusion. DCCT and UKPDS show that in T1DM and T2DM: (i) glycaemic control is importantto reduce long-term macrovascular complications; (ii) a very long follow-up period is required to demonstrate an effect and (iii) early glucose control is important.

4.2.4 Glycaemic targets

An HbA_1c target of <7.0% (<53 mmol/mol) to reduce microvascular disease is a generally recommended.^{69 –71,73,81} The evidence for an HbA_1c target in relation to macrovascular risk is less compelling, due to the complexities surrounding the chronic, progressive nature of DM and the effects of metabolic memory.^71,73,90 Consensus indicates that an HbA_1c of <7% should be targeted but with acknowledgement of individual patient requirements. Ideally, tight control should be instigated early in younger subjects without attendant co-morbidities. Successful glucose-lowering is assisted by self-monitoring of blood glucose, most notably in patients with insulin-treated DM. ⁹¹ Although postprandial hyperglycaemia is associated with an increased incidence of CVD events, it is controversial as to whether addressing this is of benefit for CVD outcomes.^{92 –95} More stringent targets (e.g. HbA_1c 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 achieved without hypoglycaemia or other adverse effects. As discussed, the accumulated results from T2DM cardiovasculartrials suggest that not everyone benefits from aggressive glucose management, and it is importantto individualize treatment targets. ⁹⁶

4.2.5 Glucose-lowering agents

A detailed description of the choice of glucose-lowering agents and the role of combination therapy is beyond the scope of this document and has extensively been reviewed in the recent joint ADA/EASD guidelines. ⁹⁶

Cardiovascular safety of glucose-lowering agents. The possible adverse cardiovascular effects of irosiglitazone ⁹⁷ raised quesitions as to the cardiovascular safety of glucose-lowering drugs, particularly in combination. A 10-year post-trial follow-up of UKPDS revealed that patients treated with sulphonylurea–insulin had a risk ratio (RR) for Ml of 0.85 (P = 0.01) and for death of 0.87 (P < 0.007).^71,73 The correspond ng RRs for metformin in overweight patients were 0.67 (P = 0.005) and 0.73 (P = 0.002). Although UKPDS indicated that metformin has a beneficial effect on CVD outcomes, there is no other clear evidence to support this view and metformin in combination with sulphonylurea may be detrimental. However, the results of this meta-analysis also suggest a benefit after a long duration of treatment in younger patients. ⁹⁸ Pioglitazone reduced a secondary vascular composite in the PROactive (PROspective pioglit Azone Clinical Trial In macroVascular Events) study (HR 0.84; 95% CI 0.72–0.98; P = 0.027), ⁹⁹ however, the primary outcome did not achieve significance and the interpretation of these results remains contentious. Pioglitazone is associated with fluid retention secondary to renal effects and peripheral oedoma, and worsening of established heart failure in susceptible individuals. In the STOP-NIDDM (Study to prevent non insulin-dependent diabetes) trial, acarbose in patients with IGT reduced the number of CVD events, including cardiovascular mortality. ⁹³ Meglitinides have not been formally tested in T2DM but, in high-risk patients with IGT, nateglinide did not reduce fatal or non-fatal cardiovascular events. ¹⁰⁰ No outcome data from RCTs have so far been published for glucagon-like peptide 1 agonists, dipeptidylpeptidase-4 (DPP-4) inhibitors, or sodium–glucose co-transporter-2 (SGLT-2) inhibitors but prospective trials are ongoing.

4.2.6 Special considerations

Hypoglycaemia. Intensive glucose-lowering increases the incidence of severe hypoglycaemia three- to four-fold in both T1DM and T2DM.^69,84 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 considiered. ¹⁰¹ In addition to the short-term risks of cardiac arrhythmia and cardiovascular events, longer-term risks include dementia and cognitive dysfunction.^102,103 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. ¹⁰² 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 common in both T1 and T2DM.

Glucose-lowering agents in chronic kidney disease. Around 25% of T2DM subjects have chronic kidney disease (CKD) stages 3–4 [estimated glomerular filtration rate (eGFR)] <50 mL/min].

OPEN IN VIEWER

Recommendations for glycaemic control in diabetes.

Glycaemic control in diabetes
Recommendations	Class a	Level b	Ref. c
It is recommended that glucose lowering is instituted in an individualized manner taking duration of DM, co-morbidities and age into account.	I	C	–
It is recommended to apply tight glucose control, targeting a near-normal HbA1c (<7.0% or <53 mmol/mol) to decrease microvascular complications in T1DM and T2DM.	I	A	69–71, 73, 81
A HbA1c target of ≤7.0% (≤53 mmol/mol) should be considered for the prevention of CVD in T1 and T2 DM.	IIa	C	–
Basal bolus insulin regimen, combined with frequent glucose monitoring, is recommended for optimizing glucose control in T1DM.	I	A	69, 72
Metformin should be considered as first-line therapy in subjects with T2DM following evaluation of renal function.	IIa	B	71

CVD = cardiovascular disease; DM = diabetes mellitus; HbA_1c = glycated haemoglobin A_1c; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

a

Class of recommendation.

b

Level of evidence.

c

Reference(s) supporting levels of evidence.

Aside from the increased CV risk associated with this, glucose-lowering agents may need to be modified, either because the drug is contra-indicated in CKD or because the dosage needs to be altered. ¹⁰⁴ Metformin, acarbose and most sulphonylureas should be avoided in stage 3–4 CKD, whilst insulin and pioglitazone can be used. The DPP-4 inhibitors require dose adjustment with progressive CKD with the exception of linagliptin, which is well tolerated in these circumstances. SGLT2 inhibitors have not been evaluated in CKD.

Elderly subjects. Glycaemic targets for elderly people with long-standing, complicated diabetes should be less ambitious than for younger, healthier individuals. If lower targets cannot be achieved, an HbA_1c 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. ⁹⁶

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. 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.

4.3.1 Treatment targets

Randomized, controlled trials in T2DM have shown the positive effects on cardiovascular outcomes of reducing BP below 140 mm Hg systolic and 85 mm Hg diastolic.^{107 –110} In ACCORD, the relative reduction of the composite endpoint (non-fatal MI, non-fatal stroke, or CVD death) by intensive treatment (achieved mean systolic BP 119 mm Hg) compared with standard treatment (mean systolic BP 134 mm Hg) did not reach statistical significance. ¹⁰⁸ The proportion of patients with serious side-effects (hypotension and declining renal function) increased from 1.3 to 3.3% with aggressive treatment. Accordingly, this study does not support a reduction of systolic BP below 130 mm Hg. Bangalore et al. ¹¹¹ reported a meta-analysis of 13 RCTs in patients with DM, IFG, or IGT who, in the intensive group, had a systolic BP ≤135 mm Hg and in the standard group ≤140 mm Hg. The intensive blood pressure 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. Sys tolic BP ≤130 mm Hg related to a reduction in stroke but did not affect other CVD events.

In summary, present evidence suggests that the BP target should be <140/85 mm Hg in patients with DM. A lower BP (systolic <130 mm Hg) may be considered in patients with hypertension and nephropathy with overt proteinuria. Further reduction might be associated with an increased risk of adverse events, especially with advanced age and longer duration of T2DM, and the risk-benefit of intensive BP management needs to be considered on an individual basis.

4.3.2 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 BP control.

Pharmacological treatment has only been tested in a few RCTs comparing cardiovascular outcomes with BP-lowering agents, specially targetting patients with DM.^107,112,113 However, several RCTs with sizeable DM subgroups reported specifically on the outcome in this subgroup.^{114 –121} Blockade of the renin-angiotensin-aldosterone system (RAAS), by an ACE-inhibitor (ACE-I) or an angiotensin-receptor blocker (ARB), is of particular value when treating hypertens on in DM at high card ovascular risk.^{114,115,119 –121} As a primary intervention, BP control using RAAS blockers prevents the on set of microalbuminuria in T2DM,^107,109 but not in T1DM.^{122 –124} As a secondary intervention, intensified BP control using ACE-I slowed progression of kidney disease in T1DM and reduced end-stage renal failure.^125,126 In T2DM, high doses of ramipril prevented both renal and cardiovascular outcomes. ¹²⁷ ARBs reduced progression from microalbuminur a to proteinuria and prevented renal outcomes but not cardiovascular death.^128,129 The DIRECT (DIabetic REtinopathy Candesartan Trials) studies investigated the effects of blood pressure-lowering with candesartan on the development and progression of retinopathy and there was a non-significant favourable trend in T1DM and T2DM.^130,131

Evidence supports the use of an ACE-I, rather than a calcium channel blocker, as initial therapy to prevent or retard the occurrence of microalbuminuria in hypertensive patients with DM. ¹³² Dual RAAS blockade, combining an ACE-I with an ARB, did not show further benefit in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and was associated with more adverse events. In the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), the addition of aliskiren to RAAS-blockadein high-riskT2DM did not result in a decrease in cardiovascular events and may even have been harmful.^133,134

Thiazides and beta-blockers are associated with an increased risk of developing T2DM, compared with calcium channel blockers and RAAS inhibitors, ¹³⁵ but it is not known whether they result in meta bolic adverse events of clinical importance in established T2DM. A recent meta-analys is emphasized the priority of BP lowering over choice of drug. ¹³⁶ In the absence of cardiac co-morbidity, beta-blockers are not first choice and appropriate BP control often requires combined therapy with a RAAS inhibitor and a calcium channel blocker or a diuretic.^119,120 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. ¹²¹

A combination of drugs is needed in most patients. All available drugs can be used but evidence strongly supports the inclusion of an inhibitor of the RAAS (ACE-I/ARB) in the presence of proteinuria. Since DM patients tend to have high BP during the night, administration of anti-hypertensive drugs at bedtime should be considered and deally after evaluat on of the 24-hour ambulatory blood pressure profile of the patient.

OPEN IN VIEWER

Recommendations for blood pressure control in diabetes.

Blood pressure control in diabetes
Recommendations	Class a	Level b	Ref. c
Blood pressure control is recommended in patients with DM and hypertension to lower the risk of cardiovascular events.	I	A	105–107, 109, 110, 137
It is recommended that a patient with hypertension and DM is treated in an individualized manner, targeting a blood pressure of <140/85 mm Hg.	I	A	107–109, 137
It is recommended that a combination of blood pressure lowering agents is used to achieve blood pressure control.	I	A	108–110, 119–121, 137
A RAAS blocker (ACE-I or ARB) is recommended in the treatment of hypertension in DM, particularly in the presence of proteinuria or microalbuminuria.	I	A	114, 119–121
Simultaneous administration of two RAAS blockers should be avoided in patients with DM.	III	B	133, 134

ACE-I = angiotensin converting enzyme-inhibitors; ARB = angiotensin receptor blockers; DM = diabetes mellitus; RAAS = renin angiotensin aldosterone system.

a

Class of recommendation.

b

Level of evidence.

c

Reference(s) supporting levels of evidence.

4.4.1 Management of dyslipidaemia

Type 2 diabetes mellitus: primary prevention. In the Collaborative Atorvastatin Diabetes Study (CARDS), 2838 patients were randomized to atorvastatin or placebo. ¹⁴⁹ and the study was terminated prematurely, due to a 37% reduction (P = 0001) in the primary end-point (first acute coronary heart disease event). In the Heart Protection Study (HPS) sim-vastatin (40 mg/day) reduced the primary endpoint by 33% (P = 0.0003) ¹⁵⁰ and in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) DM subgroup, atorvastatin reduced major CVD events and procedures by 23% (P = 0.04). ¹⁵¹

Type 2 diabetes mellitus: secondary prevention. The benefits of statin therapy in DM are seen in all subgroup analyses of major RCTs. ¹⁵² A meta-analysis of 14 RCTs, including 18 686 people with DM, 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 (P < 0.0001), similar to non-DM. This was associated with absolute reduction in LDL-C and was seen at an LDL-C as low as 2.6 mmol/L. ¹⁵³ Data from 10 RCTs reported that initensive statin dosage reduced the composite endpoint of CAD by 10% (P < 0.0001), but did not reduce mortality. ¹⁵⁴ Intensive lowering of LDL-C had a beneficial effect on progression of atheroma in DM and non-DM subjects. ¹⁵⁵

Intensification of LDL-C lowering can be achieved by adding ezetimibe to a statin. Although there are no RCT data on CVD outcome, a trial is under way (IMPROVE-IT [IMProved Reduction of Outcomes: Vytorin Efficacy International Trial]: ClinicalTrials.gov: NCT00202878). 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 subjects (n = 21,794) ¹⁵⁶ reported that the combination provided greater effects on all major lipid measures. The Study of Heart and Renal Protection (SHARP) trial reported a 17% reduction of major atherosclerotic events in CKD treated with simvastatin plus ezetimibe daily, when compared with placebo. ¹⁵⁷ It should be emphasized that, although the relative reduction of events maybe similar for subjects 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 of 1466 T1DM patients, most with prior CVD, reported a similar reduction in risk of CVD events (RR 0.79) to that seen in T2DM. ¹⁵³ Although there are no trial data on statin use in younger T1DM, statins should be considered in those at high risk of CVD, irrespective of LDL-C levels.

Safety of statin therapy. RCTs demonstrate that statins are safe and well-tolerated. ¹⁵⁸ Adverse events—other than aching muscles—are rare. In the majority of cases of myopathy or rhabdomyolysis there are drug interactions with a higher-than-standard dose of statin. ¹⁵⁹ The combination of gemfibrozil and statins should be avoided, due to pharmacokinetic interaction, but there are no safety issues with fenofibrate and statins.^144,145 A meta-analysis including 91,140 participants reported that statin therapy was associated with risk of new-onset T2DM (OR 1.09) ¹⁶⁰ that translates to one case of T2DM in 255 patients treated for 4 years. Over the same period, 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) compared with moderate (simvastatin 20 mg or pravastatin 40 mg) doses. ¹⁶¹ In the intensive group, two cases of new-onset DM per 1000 patient-years were seen, whilst CVD events were reduced by 6.5 cases. The Food and Drug Administration (FDA) approved label changes for statins (www.fda.gov/downloads/Drugs/DrugSafety/UCM293474.pdf), but emphasized that the small risk of developing DM is outweighed by the reduction in vascular events.^161,162 A meta-analysis of 27 randomized trials demonstrated that, in individuals with a five-year risk of major vascular events lower than 10%, each mmol/L reduction in LDL-C produced an absolute reduction in events of 11 per 1000 over five years, without increases in cancer or deaths from other causes. This benefit greatly exceeds any risks from statin therapy. ¹⁶³

Residual risk in subjects on low-density lipoprotein-lowering therapy. Type 2 DM patients at the LDL-C target remain at high risk of CVD events, ¹⁴⁰ and targeting elevated TG (>2.2 mmol/L) and/or low HDL-C (<1.0 mmol/L) may provide further benefits. In the FIELD, fenofibrate 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; P = 0.035).^144,164 In ACCORD, patients were assigned to fenofibrate plus simvastatin (20–40 mg daily) or placebo without an additional effect on the primary endpoint. In a pre-specified subgroup analysis of subjects with TG >2.3 mmol/L (>204 mg/dL) and HDL-C <0.9 mmol/L (<34 mg/dL), cardiovascular risk was reducod 31% in the fenofibrate-plus-simuastatin group. ¹⁴⁵ A subgroup analysis of dyslipidaemic subjects (TG >2.3 mmol/L and HDL-C <0.9 mmol/L) in the FIELD study revealed a 27% reduction in CVD risk. ¹⁴⁴ In both FIELD and ACCORD, fenofibrate was associated with a robust (22%) reduction of TG, whereas elevation of HDL-C was 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.^165,166

Strategies to elevate high-density lipoprotein cholesterol C. High-density lipoprotein cholesterol C is inversely related to CVD in epidemiological studies and in many statin trials. ²¹⁸ 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 CETP (cholesteryl ester transfer protein) inhibitors torcetrapib and dalcetrapib,^167,168 failed to reduce cardiovascular events despite a 30–40% increase in HDL-C. Fenofibrate has trivial efficacy in elevating HDL-C and, whilst niacin increases HDL-C (~15–30%), recent studies have not shown any cardiovascular benefit of niacin, ¹⁶⁹ but have been associated with an increased risk of adverse side-effects, ¹⁷⁰ which led to withdrawal ofthe marketing licence.

OPEN IN VIEWER

Recommendations on management of dyslipidaemia in diabetes.

Dyslipidaemia in diabetes
Recommendations	Class a	Level b	Ref. c
Statin therapy is recommended in patients with T1DM and T2DM at very high-risk (i.e. if combined with documented CVD, severe CKD or with one or more CV risk factors and/or target organ damage) with an LDL-C target of <1.8 mmol/L (<70 mg/dL) or at least a ≥50% LDL-C reduction if this target goal cannot be reached.	I	A	143, 153, 157
Statin therapy is recommended in patients with T2DM at high risk (without any other CV risk factor and free of target organ damage) with an LDL-C target of <2.5 mmol/L (<100 mg/dL).	I	A	143, 153
Statins may be considered in T1DM patients at high risk for cardiovascular events irrespective of the basal LDL-C concentration.	IIb	C	–
It may be considered to have a secondary goal of non–HDL-C <2.6 mmol/L (<100 mg/dL) in patients with DM at very high risk and of <3.3 mmol/L (<130 mg/dL) in patients at high risk.	IIb	C	–
Intensification of statin therapy should be considered before the introduction of combination therapy with the addition of ezetimibe.	IIa	C	–
The use of drugs that increase HDL-C to prevent CVD in T2DM is not recommended.	III	A	167, 168, 170

CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus; HDL-C = high density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; T1DM = type 1 diabetes mellitus, T2DM = type 2 diabetes mellitus.

a

Class of recommendation.

b

Level of evidence.

c

Reference(s) supporting levels of evidence.

4.5.1 Aspirin

Aspirin inhibits thromboxane (TX) A₂-dependent platelet activation and aggregation through irreversible inactivation of platelet cyclooxygenase 1 (COX-1) activity. ¹⁷⁵ There are no outcome studies of dose- and time-dependence of aspirin’s antiplatelet effect in T2DM and it is currently recommended at 75–162 mg daily (as used in subjects without DM).^175,176 However, daily administration of low-dose aspirin may be associated with incomplete inhibition of platelet COX-1 activity ¹⁷⁷ and TXA₂-dependent platelet function,^178,179 perhaps due to increased platelet turnover in DM. ¹⁸⁰ There is emerging evidence of sustained efficacy using twice-daily aspirin in subjects with DM and CVD.^180,181

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. ¹⁸² 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. ¹⁸² Therefore there is no 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. ¹⁷⁵

Primary prevention. Low-dose aspirin is recommended by several North American organizations for the primary prevention of cardiovascular events in adults with DM.^176,183 However, direct evidence for its efficacy and safety in this setting is lacking—or at best inconclusive.^184,185 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). ¹⁷⁶ 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%. ¹⁷⁶ 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. ⁴²

The risk-benefit ratio of aspirin. In a meta-analysis of six primary prevention trials, aspirin was associated with a 55% increase in extracranial (mainly gastro-intestinal) bleeding in both DM and non-DM patients. ¹⁸⁶ In terms of the risk-benefit balance in primary prevention, these results probably represent a best case, as those at increased risk of gastro-intestinal bleeding were excluded, and elderly subjects were under-represented. ¹⁸⁶ In this analysis, DM at baseline was associated with a two-fold increase in vascular events and a 50% increased risk of major extracranial bleeds. ¹⁸⁶

The ADA/AHA/ACCF Scientific Statement and the Endocrine Society Clinical Practice Guideline favour aspirin use in adults with DM when the 10-year risk of cardiovascular events is >10%.^176,183 However, relatively little emphasis is placed on the need to evaluate bleeding risk. The annual risk of cardiovascular events is increased in people with compared to those without DM, ¹⁷⁶ but this has to be balanced against the annual risk of upper gastro-intestinal bleeding which varies considerably depending on age and history of peptic ulcer disease.^175,187

4.5.2 P2Y12 receptor blockers

Clopidogrel, an irreversible blocker of the adenosine diphosphate (ADP) receptor P2Y₁₂, is a valid alternative for patients who are aspirin-intolerant or have symptomatic peripheral vascular disease.^188,189 Clopidogrel (7 mg once daily) produces additive cardio-protective effects when combined with low-dose aspirin (7–160 mg once daily) in patients with acute coronary syndrome (ACS) and those undergoing percutaneous coronary intervention (PCI). ¹⁸⁸ However, evidence from the CHARISMA (Trial to assess improvement in therapeutico by optimizing platelet inhibition with prasugrel–thrombolysis in myocardial infarction) study indicates that clopidogrel added to aspirin may have deleterious effects in patients with advanced nephropathy. ¹⁹⁰ More effective P2Y₁₂ blockers include prasugrel and ticagrelor, which is reversible. ¹⁸⁸ In TRITON-TIMI (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction) 38, prasugrel showed superiority over clopidogrel in post-ACS prevention of recurrent ischaemic events: however prasugrel carried a risk of increased thombosis in myocardial infarction (TIMI) major bleeding. ¹⁹¹ In a DM sub-study, a similar reduction in recurrent ischaemic events was seen, but this was not accompanied by an increase in bleed ing. ¹⁹² Ticagrelor was also more effective than clopidogrel in reducing12-month mortality post-ACS, ¹⁹³ and decreased ischaemic events in DM patients withoutincreased bleeding. ¹⁹⁴ Ticagrelor was superiorto clopidogrel in ACS with renal impairment. ¹⁹⁵ There is no convincing evidence that clopidogrel or the newer drugs are any more or less effective with DM than without. ¹⁸⁸

OPEN IN VIEWER

Recommendations for antiplatelet therapy in patients with diabetes.

Antiplatelet therapy in patients with diabetes
Recommendations	Class a	Level b	Ref. c
Antiplatelet therapy with aspirin in DM-patients at low CVD risk is not recommended.	III	A	184–186
Antiplatelet therapy for primary prevention may be considered in high risk patients with DM on an individual basis.	IIb	C	–
Aspirin at a dose of 75–160 mg/day is recommended as secondary prevention in DM.	I	A	182
A P2Y 12 receptor blocker is recommended in patients with DM and ACS for 1 year and in those subjected to PCI (duration depending on stent type). In patients with PCI for ACS preferably prasugrel or ticagrelor should be given.	I	A	188, 189, 192, 194, 196
Clopidogrel is recommended as an alternative antiplatelet therapy in case of aspirin intolerance.	I	B	192, 197

ACS = acute coronary syndrome; CVD = cardiovascular disease; DM = diabetes mellitus; PCI = percutaneous coronary intervention.

a

Class of recommendation.

b

Level of evidence.

c

Reference(s) supporting levels of evidence.

5.1.1 Pharmacological treatment

β-Adrenergic blockers. As outlined in current European Guidelines β-blockers are advocated for the whole spectrum of CAD with different levels of recommendations and different levels of evidence. ^{208 – 212} β-Blockers relieve symptoms of myocardial ischaemia (angina pectoris) in patients with stable CAD and may provide prognostic benefits suggested by retrospective analysis of placebo-controlled trials. ²⁰⁹ β-Blockers are effective in improving prognosis in post-MI patients with DM by reducing the likelihood of reinfarction, sudden death and ventricular arrhythmias.^213,214 β-Blockers may have negative metabolic effects by increasing IR and masking hypoglycaemic symptoms and there seems to be a difference between non- vasodilating, β-1 antagonists (e.g. metoprolol and atenolol) and β-blockers with vasodilating properties (e.g. the (β/α-adrenoblockers, carvedilol and labetalol, and b1-blockers which modulate NO synthesis, such as nebivolol). ²¹⁵ Overall, the positive effects of β-blockade on prognosis far outweigh the negative glucometabolic effects.

Blockers of the renin-angiotensin-aldosterone system. Treatment with ACE-I or ARB should be started during hospitalization for ACS and continued in patients with DM and LVEF <40%, hypertension, or chronic kidney disease,^208,210,211 and considered in all patients with ST-elevation myocardial infarction (STEMI). Patients with DM and stable CAD are also recommended to receive an ACE-I. ²⁰⁹ The Heart Outcomes Prevention Evaluation (HOPE) study showed a 25% reduction in MI, stroke, or cardiovascular death for patients with known vascular disease or DM, randomized to placebo or ramipril. This finding was consistent in the pre-specified subgroup of patients with DM. ²¹⁶ A proportionately similar trend towards benefit was observed in the subgroup of DM in the European trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease.

(EUROPA). ²¹⁷ In the ONTARGET trial, telmisartan was equivalent to ramipril as regards a primary composite of death from cardiovascular causes, MI, stroke or hospitalization for heart failure, while combining the two drugs caused adverse events without further benefit. ¹³⁴

Lipid-lowering drugs. The beneficial effects of statins are established as described (see 4.4.1).

Nitratesand calcium channel blockers. There is no evidence for a prognostic impact of nitrates but they may be used for symptomaticirelief.^208,210,211

Calcium channel blockers. are efficacious in relieving ischaemic symptoms, and verapamil and diltiazem may prevent re-infarction and death. ^{208 – 211} These drugs may be appropriate for long-term use in patients without heart failure, as an alternative to β-blockers or when β-blockers may be a less attractive choice, e.g. due to obstructive airways disease. The combination of these drugs and β-blockers should be avoided with bradycardia, atrioventricular conduction disturbances or compromised LV function. An alternative is the use of a dihydropyridine calcium channel blocker, such as amlodipine, felodipine or nicardipine.

Ivabradine. This specific, heart rate-lowering anti-anginal drug inhibits the I_f current—the primary modulator of spontaneous diastolic depolarization in the sinus node. Ivabradine is indicated in the treatment of chronic stable angina in CAD patients with a contraindication or intolerance to (β-blockers, or in combination with β-blockers if the patient remains symptomatic or has a heart rate >70 bpm, especially if there is also LV dysfunction. It can be used in selected patients with non-ST-elevation ACS in the event of β-blocker intolerance or insufficient heart rate reduction despite maximal tolerated β-blocker dose.^209,210

Antiplatelet and antithrombotic drugs. In secondary prevention, antiplatelet therapy in the form of low-dose aspirin (75–60 mg) or clopidogrel (separately or in combination) reduces risk of stroke, Ml, or vascular death although the benefits are less in DM (see 4.5.1). ²¹⁸ Thienopyridines (ticlopidine, clopidogrel, prasu grel and ticagrelor) reduce cardiovascular events when added to aspirin in patients with ACS.^196,208,211 In the Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study, the annual event rate in DM was 5.6% with clopidogrel and 7.7% with aspirin, i.e. an absolute risk reduction of 2.1 %, which corresponds to a relative risk reduction of 13% with less bleeding. Due to the elevated event rates in patients with DM, the absolute benefit of clopidogrel is amplified. ¹⁹⁷ In TRITON, DM subjects tended towards a greater reduction in ischaemic events with prasugrel than clopidogrel, without an increase in major bleeding. ¹⁹²

5.1.2 Glucose control in acute coronary syndromes

Elevated PG during ACS is associated with a more serious prognosis in DM.^{219 –223} Glycaemic control has been tested in the Diabetes and Insulin–Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 1 and 2 and Hyperglycaemia: Intensive Insulin Infusion in Infarction (HI-5) trials. ²²⁴ , ²²⁵ , ²²⁶ The first DIGAMI trial randomized 620 patients with DM and acute Ml to a ≥24 h insulin–glucose infusion followed by multi-dose insulin, or to routine glucose-lowering therapy. ²²⁴ Mortality after 3.4 years was 33% in the insulin group and 44% (P = 0.011) in the control group. ²²⁷ In contrast, DIGAMI 2 failed to demonstrate prognostic benefits, ²²⁵ and a plausible explanation for this is that admission HbA_1c decreased by 1.5% from a higher starting value of 9.1% in DIGAMI 1,^224,228 compared with a fall of only 0.5% from 8.3% in DIGAMI 2. ²²⁵ In addition, the use of β-blockade, statins and revascularization was more extensive in DIGAMI 2. The difference in glucose level between the control and insulin groups In the HI-5 study was also small and there was no reduction in mortality with insulin. ²²⁶ Pooled data from the three studies confirmed that insulin–glucose infusion did not reduce mortality in the absence of glucose control in patients with acute MI and DM (RR 1.07; P = 0.547). ²²⁹ The Heart2D (Hyperglycaemia and its effect after acute myocardial infarction on cardiovascular outcomes in patients with Type 2 diabetes mellitus) compared the effects of prandial (pre-meal insulin three times daily; n = 557) vs. basal glycaemic control (long-acting insulin once or twice daily; n = 558) on cardiovascular events in T2DM. Glucose targets were a post- prandial glucose (PPG) of 7.5 mmol/L (135 mg/dL) and an FPG of 6.7 mmol/L (121 mg/dL), respectively. The study was stopped after an average follow-up of 963 days, due to lack of efficacy. ⁹⁴

Some registry studies suggest there is a J- or U-shaped relationship between PG and prognosis,^220,222,223 with the implication that both hypoglycaemia and hyperglycaemia are unfavourable. Compensatory mechanisms induced by hypoglycaemia, such as enhanced catecholamine release, may aggravate myocardial ischaemia and provoke arrhythmias.^230,231 Recent data indicate that hypoglycaemic episodes identify patients at risk for other reasons (e.g. heart failure, renal dysfunction and malnutrition) and hypoglycaemia does not remain as an independent risk factor after correcting for such variables.^232,233

A reasonable conclusion is that DM and acute Ml will benefit fromglycaemic contol if hyporlycaemia is significant (>10 mmol/L or >180 mg/dL). An approximation towards normoglycaemia, with less stringent targets in those with severe co-morbidities, is a reasonable goal but exact targets are still to be defined. Insulin infusion is the most efficient way to achieve rapid glucose control under these circumstances.

OPEN IN VIEWER

Recommendations for the management of patients with stable and unstable coronary artery disease and diabetes.

Management of patients with stable and unstable coronary artery disease and diabetes
Recommendations	Class a	Level b	Ref. c
It is recommended that patients with CVD are investigated for disorders of glucose metabolism.	I	A	234, 235
Beta-blockers should be considered to reduce mortality and morbidity in patients with DM and ACS.	IIa	B	213, 214
ACE-I or ARBs are indicated in patients with DM and CAD to reduce the risk for cardiovascular events.	I	A	134, 216, 217
Statin therapy is indicated in patients with DM and CAD to reduce the risk for cardiovascular events.	I	A	143
Aspirin is indicated in patients with DM and CAD to reduce the risk for cardiovascular events.	I	A	186, 218
Platelet P2Y12 receptor inhibition is recommended in patients with DM and ACS in addition to aspirin.	I	A	192, 194, 196, 197, 208, 211
Insulin-based glycaemic control should be considered in ACS patients with significanthyperglycaemia (>10 mmol/L or >180 mg/dL) with the target adapted to possible comorbidities.	IIa	C	–
Glycaemic control, that may be accomplished by different glucose-lowering agents, should be considered in patients with DM and ACS.	IIa	B	224, 226, 228

ACE-I = angiotensin converting enzyme inhibitor; ACS = acute coronary syndrome; ADP = adenosine diphosphate; ARB = angiotensin receptor blockers; CAD = coronary artery disease; CVD = cardiovascular disease; DM = diabetes mellitus.

a

Class of recommendation.

b

Level of evidence.

c

Reference(s) supporting levels of evidence.

5.2.1 Myocardial revascularization in stable and unstable coronary artery disease

Stable coronary artery disease. A randomized comparison of myocardial revascularization—either with CABG or PCI—against optimal medical treatment (OMT) in DM patients considered eligible for these treatments, was performed in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. ²³⁸ After five years, no significant differences were noted in the combined endpoint of death, MI, or stroke between the OMT (12%) and revascularization (12%) arms. In the surgical group, freedom from major adverse cardiac and cerebrovascular events (MACCE) was significantly higher with CABG (78%) than with OMT alone (70%; P = 0.01), but there was no difference in survival (CABG 86%; OMT 84%; P = 0.33). In the PCI group, made up of patients with less-extensive CAD than in the CABG stratum, there were no significant differences in MACCE or survival between PCI and OMT. During subsequent follow-up, 38% of patients assigned to OMT underwent at least one revascularization for symptomatic reasons, compared with 20% in the revascularization stratum, showing that an initial conservative strategy with OMT saved about 80% of interventions over the next five years. Overall, except in specific situations such as left main coronary artery stenosis ≥50%, proximal LAD stenosis or triple-vessel disease with impaired LV function, myocardial revascularization in patients with DM did not improve survival, compared with medical treatment. It is noteworthy is that patients were excluded if they required immediate revascularization or had left main coronary disease, a creatinine level >2.0 mg/dL (>177 µmol/L), HbA_1c >13.0%, Class III–IV heart failure or if they had undergone PCI or CABG within the previous 12 months.

Acute coronary syndromes. No interaction between the effect of myocardial revascularization and the presence of DM has been documented in trials in non-ST-elevation ACS. An early invasive strategy improved outcomes in the overall population, with a greater benefit in patients with DM in the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction (TACTICS-TIMI 18) trial.^{239 –241} In STEMI patients, a pooled analysis of individual patient data, from 19 RCTs comparing primary PCI with fibrinolysis, showed that patients with DM treated with reperfusion had an increased mortality, compared with those without DM. The benefits of a primary PCI, compared with fibrinolysis were, however, consistent in patients with and without DM. ²⁴² Patients with DM had significantly delayed initiation of reperfusion treatments and longer ischaemic time, but the reduction in 30-day mortality observed in PCI-treated patients was most pronounced in this group. Due to a higher absolute risk, the NNT to save one life at 30 days was significantly lower for DM (NNT 17; 95% CI 11–28) than non-DM patients (NNT 48; 95% CI 37–60).

5.2.2 Type of intervention: coronary bypass graft vs. percutaneous intervention

A meta-analysis based on individual data, from 10 RCTs comparing both types of revascularizations, suggested a distinct survival advantage for CABG in DM patients. ²³⁷ Five-year mortality was 20% with PCI, compared with 12% with CABG (OR 0.7; 95% CI 0.6–0.9), whereas no difference was found for patients without DM. A specific comparison of the efficacy and safety of PCI and CABG in patients with DM was performed in theCoronary Artery Revascularization in Diabetes (CARDia) trial. ²⁴³ The introduction of drug-eluting stents (DES) coincided with the enrolment period, leading to a mixed use of bare metal stents (BMS) (31%) and DES (69%). After one year there was a non-significantly higher rate of the composite of death, MI, and stroke (driven by a higher rate of MI), and significantly higher rates of repeat revascularization in the PCI group (2 vs. 12%; P < 0.001).

The literature on CABG vs. PCI is confused by confounder bias in registries, the ongoing development of DES and—apart from the FREEDOM trial—a lack of prospective RCTs. The implication is that much of the available information is based on subgroup analyses of trials in which DM patients may be relatively few or selected. As a consequence of increased repeat revascularization in the SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) trial, ²⁴⁴ performed in the DES era (using paclitaxel-eluting stents), the rate of MACCE after one year was twice as high with PCI, as compared with CABG. After 5 years, follow-up rates of MACCE were significantly higher in DM, comparing PCI with CABG (PCI 46% vs. CABG 29%; P < 0.001) as well as for repeat revascularization (PCI 35.3% vs. CABG 14.6%; P < 0.001). There was no difference in the composite of all-cause death/ stroke/ MI (PCI 23.9% vs. CABG 19.1%; P = 0.26). It was concluded that, although PCI is a potential treatment option in patients with less complex lesions CABG should be the revascularization choice for DM patients with complex anatomic disease. ²⁴⁵

Data obtained in recent registries support a better outcome for DM treated with CABG, compared with DES even in terms of mortality, at the expense of a higher stroke rate with CABG. ²⁴⁶ In an analysis of 86,244 patients ≥65 years of age undergoing CABG and 103,549 patients undergoing PCI from 2004 to 2008, four-year survival was significantly higher with surgery and the association of surgery with improved survival was most marked in insulintreated DM. ²⁴⁷

The FREEDOM trial randomized 1900 patients, a majority with three-vessel disease, to treatment with CABG or PCI with sirolimus-eluting and paclitaxel-eluting stents. They were all pre- scribed currently recommended medical therapies for the control of LDL-C, systolic BP and HbA_1c. The primary results were a composite of total mortality and non-fatal MI or stroke. After a median of 3.8 years the primary outcome occurred more frequently in the PCI group (P = 0.005), with a five-year rate of 26.6%, compared with 18.7% in the CABG group. The benefit of CABG was driven by differences in both MI (P < 0.001) and mortality (P = 0.049) It was concluded that CABG is superior to PCI for patients with DM and advanced CAD (Figure 3). There was no significant interaction based on SYNTAX score, since the absolute differences in the primary endpoint, between PCI and CABG, were similar in patients with a low, intermediate and high SYNTAX score. Given the wide variability of the patients enrolled in Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM), the trial represents real-world practice. Further analysis revealed that, compared with PCI, CABG was a cost- effective strategy.^248,249 An individualized risk assessment and discussion with the patient is mandatory before the type of intervention is decided. ²¹²

OPEN IN VIEWER

Figure 3.

Kaplan-Meier estimates of the primary outcome and death. A: rates of the composite primary outcome of death, myocardial infarction or stroke and B: death from any cause truncated at five years after randomization. The P-value was calculated by means of the log-rank test on the basis of all available follow-up data. Reproduced by permission from Farkouh et al. ²⁴⁸

5.2.3 Specific aspects of percutaneous and surgical revascularization in diabetes mellitus

The DIABETES trial (the diabetes and sirolimus-eluting stent trial) demonstrated a substantial reduction in target vessel revascularization in DM patients treated with sirolimus-eluting stents (7%) vs. BMS (31%). ²⁵⁰ This finding received further support from a meta-analysis of 35 trials comparing DES with BMS, ²⁵¹ which revealed a similar efficacy of sirolimus-eluting and paclitaxel-eluting stents in this regard (OR 0.29 for sirolimus; 0.38 for paclitaxel) provided dual antiplatelet therapy after DES implantation was continued for >6 months. The risk of death associated with sirolimus-eluting stents was more than twice that associated with BMS in eight trials with dual antiplatelet therapy during less than six months. In contrast, there was no increased risk associated with the use of DES in 27 trials with dual antiplatelet therapy maintained for more than six months. An analysis of the National Heart, Lung and Blood Institute Dynamic Registry data revealed that, compared with BMS, DES were associated with fewer repeat revascularizations—to a similar extent in insulin-treated or non-insulin-treated DM. ²⁵² Finally, the secondgeneration everolimus-eluting stents were not superior in terms of target lesion failure after one year of follow-up in a head-to-head comparison with paclitaxel-eluting stents, while zotarolimus-eluting stents were inferior to sirolimus-eluting stents in patients with DM.^253,254

Antithrombotic treatment in DM patients undergoing coronary revascularization for stable angina or ACS is no different from those without DM.^255–257 Initial trials in glycoprotein IIb/IIIa inhibitors reported an interaction with DM, but this was not confirmed in the recent Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 2) trial. ²⁵⁸ Prasugrel is superior to clopidogrel in reducing the composite endpoint of cardiovascular death or MI or stroke without excess major bleeding. Similarly, ticagrelor, in comparison to clopidogrel in the PLATO (Platelet inhibition and patient outcomes) trial, reduced the rate of ischaemic events in ACS patients, irrespective of the presence of DM, without an increase in major bleeding events.^192,194

Patients with DM who undergo CABG often require multiple grafts. There is no randomized evidence regarding the use of one vs. two internal thoracic artery (ITA) conduits in DM. Although observational evidence suggests that using bilateral ITA conduits improves patient outcome without compromising sternal stability, the use of bilateral ITA conduits is still debatable, given the higher prevalence of wound infection and mediastinitis with DM. ²⁵⁹ A recent meta-analysis has shown that ITA harvesting by skeletonization (without the satellite veins and fascia) reduces the risk of sterna wound infection in DM patients undergoing bilateral ITA grafting, ²⁶⁰ although there are no randomized studies on this subject.

5.2.5 Glucose-lowering treatments and coronary angiography and interventions

Few trials have addressed interactions between hypoglycaemic medications and coronary angiography or myocardial revascularization in DM. There is no scientific support for the frequent practice of stopping metformin prior to angiography or PCI, and more recent recommendations are less restrictive. ²¹² Rather than stopping metformin, a reasonable approach is to withhold metformin for 48 h if renal function deteriorates and until renal function has resumed to its previous level.

Observational data reported concern over the use of sulphonylureas in patients treated with primary PCI for acute MI; this has not been confirmed by post hoc analysis of the DIGAMI-2 trial, although the number of patients undergoing primary PCI in this trial was low. ²⁶¹ Arrhythmias and ischaemic complications were also less frequent in patients receiving gliclazide/glimepiride. ²⁶² Thiazolidinediones might be associated with lower restenosis rates after PCI with BMS, ²⁶³ but carry an increased risk of heart failure due to fluid retention.

No trial has demonstrated that insulin or glucose-insulinpotassium (GIK) improves PCI outcome after STEMI. Observational data in CABG suggest that continuous intravenous insulin infusion achieving moderately tight glycaemic control (6.6–9.9 mmol/L or 120–180 mg/dL) is independently associated with lower mortality and major complications, than has been observed after tighter (<6.6 mmol/L or <120 mg/dL) or more lenient (>9.9 mmol/L or >180 mg/dL) glycaemic control. ²⁶⁴ In the BARI 2D trial, outcomes were similar in patients receiving insulin sensitization vs. insulin provision to control blood glucose. In the CABG stratum, insulin use was associated with more cardiovascular events than insulin-sensitization.^238,265

OPEN IN VIEWER

Recommendations for coronary revascularization of patients with diabetes.

Coronary revascularization of patients with diabetes
Recommendations	Class a	Level b	Ref. c
Optimal medical treatment should be considered as preferred treatment in patients with stable CAD and DM Unless there are large areas of ischaemia or siginificant leaft main or proximal Lad lesions.	IIa	B	238
CABG is recommended in patients with DM and multivessel or complex (SYNTAX Score >22) CAD to improve survival free from major cardiovascular events.	I	A	237, 238, 244, 246,248, 266
PCI for symptom control may be considered as an alternative to CABG in patients with DM and less complex multivessel CAD (SYNTAX score ≤22) in need of revascularization.	IIb	B	246, 267, 268
Primary PCI is recomended over fibrinolysis in DM patients presenting with STEMI if performed within recomended time limits.	I	B	242
In DM patients subjected to PCI, DES rather than BMS are recommended to reduce risk of target vessel revascularization.	I	A	247, 269
Renal function should be carefully monitored after coronary angiography/PCI in all patients on metformin.	I	C	–
If renal function deteriorates in patients on metformin undergoing coronary angiography/PCI it is recommended to withhold treatment for 48 h or until renal function has returned to its initial level.	I	C	–

BMS = bare-metal stent; CABG = coronary artery bypass grafting; CAD = coronary artery disease; DES = drug-eluting stent; DM = diabetes mellitus; LAD = left anterior descending coronary artery; PCI ¼ percutaneous coronary intervention; STEMI = ST-elevation myocardial infarction.

a

Class of recommendation.

b

Level of evidence.

c

Reference(s) supporting levels of evidence.

8.1.1 Lower extremity artery disease

Vascular obstructions are often located distally in patients with DM and typical lesions occur in the popliteal artery or in the vessels of the lower leg. In a cohort of 6880 patients over 65 years, one in five patients had LEAD, though only 10% were symptomatic. ³⁵³ The incidence and prevalence of LEAD increase with age and duration of DM. The National Health and Nutrition Examination Survey (NHANES II) determined pulse amplitudes in adults, and diminished or absent pulsation of the dorsalis pedis artery was found in 16% of adults with DM aged 35–54 years and in 24% of those aged 55–74. ³⁵⁴ In many older patients, LEAD is present at the time of diagnosis of DM. Progression of LEAD may result in foot ulceration, gangrene and, ultimately, amputation. DM accounts for approximately 50% of all non-traumatic amputations in the United States and a second amputation is common. Mortality is increased in patients with LEAD and three-year survival after an amputation is less than 50%. ³⁵¹ Early diagnosis is important for the prevention of progression of LEAD and for prediction of overall cardiovascular risk.

Diagnosis. Symptoms suggestive of claudication are walking impairment, e.g. fatigue, aching, cramping, or pain with localization to buttock, thigh, calf, or foot, particularly when symptoms are quickly relieved at rest. An objective measure of LEAD is the ankle-brachial index (ABI), calculated by dividing the systolic blood pressure at the posteriortibial or dorsalis pedal level with the brachial systolic blood pressure. An index of <0.9 is suggestive of LEAD, particularly in the presence of symptoms or clinical findings such as bruits or absent pulses. An ABI <0.8 indicates PAD, regardless of symptoms. Sensitivity of ABI measurement may be increased after exercise. Postexercise ABI may identify significant LEAD, even in subjects with a normal resting ABI. ³⁵⁵ An ABI >1.40 indicates poorly compressible vessels as a result of stiff arterial walls (medial calcinosis) that can impede the estimation of arterial pressure in the artery.

Primary and secondary prevention of LEAD in patients with DM consists of lifestyle changes (addressing obesity, smoking and lack of exercise) and control of risk factors, including hyperglycaemia, hyperlipidaemia and hypertension.

Treatment. In a systematic review of RCTs of exercise programmes in symptomatic claudication, supervised exercise therapy was effective in increasing walking time, compared with standard care. ³⁵⁶ Although cilostazol, naftidrofuryl and pentoxifylline increase walking distance in intermittent claudication, their role remains uncertain. In addition, statin therapy has been reported to be beneficial by increasing walking distance in patients with PAD.^347,357 If conservative therapy is unsuccessful, revascularization should be considered. In case of disabling claudication with culprit lesions located at aorta/iliac arteries, revascularization should be the first choice, along with risk factor management. ³⁴⁷

Critical limb ischaemia. (CLI) is defined by the presence of is chaemic pain at rest and ischaemic lesions or gangrene attributable to arterial occlusive disease that is chronic and distinguishable from acute limb ischaemia. Importantly, β-blockers are not contra-indicated in patients with LEAD and DM. A meta-analysis of 11 RCTs found that β-blockers do not adversely affect walking capacity or symptoms of intermittent claudication in patients with mild-to-moderate PAD. ³⁵⁸ At 32-month follow-up of 490 patients with PAD and prior Ml, β-blockers caused a 53% significant and independent decrease in new coronary events. ³⁵⁹ Comprehensive management requires multidisciplinary care to control atherosclerotic risk factors, provision of revascularization where possible, optimization of wound care, appropriate shoe wear, treatment of infection, and rehabilitation. ³⁴⁷ The cornerstone of management is arterial reconstruction and limb salvage. Medical baseline therapy, including platelet inhibitors and statins, should be initiated according to principles outlined elsewhere in this document.^347,360,361

The choice of revascularization strategy depends primarily on the anatomy of the arterial lesion. Outcomes of endovascular iliac artery repair in DM have been reported as similar to, or worse than, those without DM, and long-term patency is lower. ³⁶² Long-term patency rates of intravascular interventions in the tibio-peroneal region are low in patients with and without DM, but may be sufficient in the short term to facilitate healing of foot ulcers. ³⁶²

The diabetic foot is a specific clinical entity that may involve neuropathy, trauma, arterial disease, infection and inflammation, often in combination. The serious consequences are ulceration, gangrene, and high rates of amputation. In DM patients, LEAD is typically diffuse, and particularly severe in distal vessels. When the ABI is inconclusive, toe pressure, distal Doppler waveform analyses, or transcutaneous oxygen can assess the arterial status. When ischaemia is present, imaging should be used to plan revascularization, employing the same criteria as for CLI. Follow-up includes patient education, smoking cessation, protective shoes, periodic foot care, and recon- structive foot surgery as needed. The management of risk factors and revascularization surveillance are mandatory. ³⁶³

8.1.2 Carotid artery disease

Diabetes mellitus is an independent risk factor for ischaemic stroke with an incidence 2.5–3.5 times higher than in non-DM.^364,365 The discussion of stroke and transient ischaemic attack (TIA) prevention will be limited to the aspects relating to carotid artery disease, which is causally related to about 20% of all ischaemic strokes. ³⁶⁶ Although DM increases the likelihood of carotid artery disease, it does not change the general diagnostic and therapeutic approach.

OPEN IN VIEWER

Recommendations for management of peripheral artery disease in diabetes.

Management of peripheral artery disease in diabetes
Recommendations	Class a	Level b	Ref. c
It is recommended that patients with DM have annual screening to detect PAD and measurement of the ABI to detect LEAD.	I	C	–
It is recommended that all patients with PAD and diabetes who smoke are advised to stop smoking.	I	B	348
It is recommended that patients with PAD and DM have LDL-C lowered to <1.8 mmol/L (<70 mg/dL) or by ≥50% when the target level cannot be reached.	I	A	349
It is recommended that patients with PAD and DM have their blood pressure controlled to<140/85 mm Hg.	I	C	–
Antiplatelet therapy is recommended in all patients with symptomatic PAD and DM without contraindications.	I	A	186

ABI = ankle-brachial index; DM = diabetes mellitus; LDL-C = low-density lipoprotein cholesterol; LEAD = lower extremity artery disease;

PAD = peripheral artery disease.

a

Class of recommendation.

b

Level of evidence.

c

Reference(s) supporting levels of evidence.

Diagnosis. Carotid bruits are common although many remain asymptomatic, regardless of lesion severity. Although the spectrum of symptoms is wide, only those who have suffered a stroke or TIA within the past six months are regarded as symptomatic.^367,368 In this group of patients, the probability of recurrent stroke or TIA is high. ³⁶⁹ Therefore urgent imaging of the brain and supra-aortic vessels is mandatory in patients presenting with TIA or stroke. Duplex ultrasonography, computed tomography angiography, and magnetic resonance imaging are indicated to evaluate carotid artery stenosis.

Treatment. Whilst carotid endarterectomy seems to offer a clear advantage over conservative treatment in patients with symptomatic carotid artery disease, the role of revascularization in asymptomatic patients remains less clear. ³⁴⁷ It needs to be emphasized that most data in symptom-free patients were collected before statins and antiplatelet agents became standard therapy.