Cardiovascular risk and prevention in diabetes mellitus

Pathophysiology

The earliest stages in the development of atherosclerosis involve the adhesion and migration of monocytes through the vascular endothelium and into the vascular intima. This may be facilitated by the pro-inflammatory, procoagulant and vasoconstricted state associated with diabetes. Within the intima, monocytes transform into macrophages and take up modified lipoproteins resulting in foam cell formation. Foam cells accumulate within the vascular wall to form a fatty streak. With the recruitment of smooth muscle cells, low-grade chronic inflammation and modulation of the extracellular matrix, the atherosclerotic plaque develops. This comprises a fibrous outer layer in contact with the plasma overlying a procoagulant lipid-rich core. The rupture or erosion of any part of this fibrous cap exposes the procoagulant lipid to the circulating plasma, resulting in platelet activation, thrombosis and an acute vascular event. This atherosclerotic process is accelerated in T2DM (summarised in Fig 1).

• Download figure
• Open in new tab
• Download powerpoint

Fig 1.

Effects of hyperglycaemia on the atherosclerotic process including cell adhesion molecule expression, monocyte recruitment and migration into the vascular intima, involvement of oxidised low-density lipoprotein (OxLDL), foam cell formation and vascular smooth muscle cell (SMC) migration and proliferation, resulting in fatty streak formation. Adapted from Ref 7

Many people with T2DM are also hypertensive⁶ which contributes to the premature development of vascular disease. Diabetes is associated with a typical dyslipidaemia comprising mildly elevated levels of small dense low-density lipoprotein (LDL), reduced levels and altered composition of high-density lipoprotein (HDL) and increased triglyceride-rich lipoprotein particles. Glycated, small dense LDL is associated with increased oxidative stress within the vasculature, while reduced concentrations of altered HDL are less able to participate in atheroprotective functions such as reverse cholesterol transport.

Insulin resistance is an early and major component of T2DM and an independent risk factor for CVD.⁸ Endothelial dysfunction⁹ and increased carotid intima-media thickness¹⁰ may be early, reversible features of CVD and can be assessed non-invasively. Thus, early identification of insulin resistance and impaired endothelial function may identify those at particular risk of CVD and enable targeting of aggressive risk factor control to those who will most benefit.

Glucose control

Increasing fasting glucose in T2DM is related to increased cardiovascular event rates¹⁴ but the relationship between glucose lowering and CVD risk reduction is complex (Table 1). The UKPDS study group showed a reduction of myocardial infarction rates with metformin monotherapy in a small subgroup of obese individuals.¹⁵ The putative beneficial effects of metformin on cardiovascular events have made it the first-line therapy for the management of T2DM. However, none of the other glucose lowering agents in monotherapy or in combination has been shown in the UKPDS or other clinical studies to significantly reduce major cardiovascular events. Recent meta-analyses have suggested that intensive glucose lowering with multiple glucose lowering therapies reduces major cardiovascular events, but not mortality.¹⁶ However, a report of 10-year follow-up data from the UKPDS group¹⁷ suggests that early intensive glucose lowering has a metabolic memory effect – significantly lowering cardiovascular events, but with a considerable time lag over a long time period.

The recent Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial¹⁸ which targeted intensive glucose control in high-risk individuals with established T2DM, aiming for an HbA_1c below 6%, raised concerns when it reported increased CVD events in the intensive glucose lowering arm. The Action in Diabetes and Vascular Disease (ADVANCE)¹⁹ study and the Veterans Affairs Diabetes Trial (VADT)²⁰ showed no benefit of intensive over standard glucose control on CVD rates, with no excess CVD events in the intensive arms.

Contentious meta-analysis data have linked one of the glucose lowering therapies (the thiazolidinedione, rosiglitazone) with an adverse cardiovascular event profile,²¹ and rosiglitazone is now not recommended in subjects with CVD. More recent retrospective data have raised similar concerns over elevated CVD events with sulphonylureas compared with other glucose lowering agents.²²

Thus tight control of blood glucose at the time of diagnosis is likely to be more beneficial than tightening control later when years of glucose elevation have contributed to accumulation of subclinical vascular disease. The choice of glucose lowering agent may also be an important factor in reducing cardiovascular events long term.

Blood pressure

Blood pressure (BP) lowering in people with T2DM independently reduces major cardiovascular events (Table 1).²³ The NICE guideline CG66 recommends a target BP of 140/80 mmHg (Table 2), though in patients with renal, ophthalmic or cerebrovascular damage a level of 130/80 mmHg is suggested. In the presence of microalbuminuria, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) are indicated regardless of the presence of hypertension.²⁴ ACEIs should be the initial antihypertensive therapy in T2DM if lifestyle intervention does not result in BP lowering. In people of Afro-Caribbean descent an ACEI should be prescribed with a calcium-channel blocker (CCB) or thiazide diuretic. Most hypertensive people with T2DM are likely to require multiple agents to manage hypertension. After an ACEI/ARB, guidelines recommend the addition of CCBs, then a thiazide diuretic followed by beta-blockers, alpha-blockers or potassium-sparing diuretics.

Lipids

Total cholesterol and LDL lowering reduces major cardiovascular events in people with T2DM.²⁵ Lipid management is central to the management of cardiovascular risk in all adults over 40 years of age with T2DM (Table 2). People with diabetes over 40 years of age at perceived low cardiovascular risk should have their risk assessed using the UKPDS risk engine.²⁷ If cardiovascular risk is greater than 20% over 10 years, lipid-lowering therapy should be initiated. NICE CG66 recommends target levels of total cholesterol and LDL of 4 mmol/l and 2 mmol/l, respectively. Initial therapy should be with 40 mg of generic simvastatin, with the use of a more potent statin or ezetimibe, should target levels not be achieved.

NICE guidelines suggest that triglyceride levels over 4.5 mmol should also be managed actively with a fibrate if lifestyle measures and optimisation of glucose control fail to control the hypertriglyceridaemia, though evidence that this impacts on CVD rates is limited.

Antithrombotic therapy

Current NICE guidelines advise low-dose aspirin (75 mg) for people with diabetes over 50 years of age with BP less than 145/75 mmHg and for those below 50 years if significant cardiovascular risk factors are present. The risks and benefits of aspirin therapy as primary prevention should be considered for each individual, though in those with low CVD risk, aspirin may not be of benefit.