Cardiovascular risk and prevention in diabetes mellitus

Key Points
Cardiovascular risk is linearly related to hyperglycaemia in diabetes mellitus (DM)
Reversal of hyperglycaemia using pharmacological agents alone has not been clearly shown to reduce cardiovascular disease (CVD) in type 2 DM (T2DM)
Multiple risk factors contribute to CVD in T1DM and T2DM; effective risk management requires lifestyle interventions, aggressive management of glucose control and other cardiovascular risk factors
Early, assiduous management of glucose control in DM may impart metabolic imprinting which reduces cardiovascular complications in the long term
Randomised controlled trials demonstrate that lipid and blood pressure lowering independently reduce cardiovascular events in T2DM
Historically, disease of the cardiovascular system accounts for the death of approximately 70% of people with diabetes mellitus (DM).1 Type 2 DM (T2DM) increases the risk of cardiovascular disease (CVD) 2–4 times.2 Type 1 DM (T1DM) also markedly increases the risk of premature CVD.3
The pathophysiology of CVD in diabetes is complex and not dependent on the effects of hyperglycaemia alone. In T2DM a constellation of risk factors contribute to the development of early CVD, including hypertension and dyslipidaemia. These result in metabolic changes which, coupled with a sedentary lifestyle, obesity and smoking, enhance the deleterious effects of hyperglycaemia and accelerate atherosclerotic disease in the vasculature. People with T1DM are generally diagnosed at a young age and exposure to hyperglycaemia takes place over a prolonged time period compared with T2DM. CVD in T1DM may relate more closely to the burden of hyperglycaemia and its complications.4
Over 90% of people with DM have T2DM, and the prevalence is accelerating in the developed and developing world. The current prevalence of diabetes in adults in the UK is estimated to be 7.4%,5 though rates may be higher in certain ethnic and patient subgroups. This article considers the pathophysiology of CVD in T2DM, the management of cardiovascular risk in this population and the tools available for assessment of cardiovascular risk in T2DM. A brief summary of the pathophysiology, assessment and management of cardiovascular risk in T1DM will also be provided. People with diabetes benefit from secondary prevention strategies at least as much as those without diabetes. This article focuses on primary prevention of cardiovascular events.
Cardiovascular risk in type 2 diabetes
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).
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.
Assessment of cardiovascular risk in type 2 diabetes
The use of epidemiological data to assess cardiovascular risk is well established. The Framingham risk charts11 have been used extensively and may be used to aid consideration for antihypertensive and lipid-lowering therapy in people with diabetes. The UK Prospective Diabetes Study (UKPDS) online risk calculator is recommended in National Institute for Health and Clinical Excellence (NICE) guideline CG66.12 The QRISK algorithm13 may be more applicable to populations in England and Wales as it factors ethnicity and social deprivation into the risk assessment.
Management of cardiovascular risk in type 2 diabetes
The first step in the management of cardiovascular risk in patients with T2DM should be a structured education programme incorporating dietary advice and an appropriate exercise plan.
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.
Clinical studies in cardiovascular risk management of type 2 diabetes (T2DM)
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 HbA1c 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.
Metabolic targets for type 2 diabetes mellitus (simplified adaptation from National Institute for Health and Clinical Excellence CG 66: for full guidance see Ref 12)
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.
Cardiovascular risk in type 1 diabetes
Traditionally, management of hyperglycaemia in T1DM has focused on the reduction of microvascular complications. However, cardiovascular risk is markedly elevated in people with T1DM, the age-adjusted relative risk for CVD being greater for T1DM than T2DM.28 The complications of T1DM, for instance nephropathy, as well as hypertension and dyslipidaemia, result in elevated cardiovascular risk. As with T2DM, hyperglycaemia promotes atherogenesis by means of increased oxidative stress, endothelial dysfunction, inflammation and prothrombotic changes. Tight management of glucose control in T1DM has been shown in the Epidemiology of Diabetes Interventions and Complications (EDIC)/Diabetes and Complications Trial (DCCT) follow-up data to reduce vascular events many years later, even as intensive control wanes.29 Current advice recommends control of glucose levels with the avoidance of significant hypoglycaemia to reduce cardiovascular risk in T1DM.
People with T1DM are less well represented in the large cholesterol lowering and blood pressure management studies. However in the Heart Protection Study,25 there was a non-significant reduction in vascular events in a small subset of patients with T1DM. The study was underpowered to detect a benefit from a generic approach to cholesterol lowering in T1DM and further studies in this area are warranted. Management of blood pressure and proteinuria with ACEIs may also result in significant cardiovascular benefits. Smoking cessation and lifestyle modulation remain central to the management of cardiovascular risk in this group.
Conclusions
DM confers a high degree of cardiovascular risk brought about by multiplicative risk factors. Early, aggressive glucose lowering results in cardiovascular risk reduction in T2DM but this effect may not become apparent for many years. However, multiple risk factor modulation, including lifestyle interventions, BP lowering and lipid management together with glucose control results in significant and early reductions in CVD end-points. Evidence supports the benefit of glucose lowering for cardiovascular risk reduction in T1DM. Lipid lowering and BP management with ACEIs and other antihypertensive therapies may also be beneficial in the reduction of cardiovascular events in people with T1DM and elevated cardiovascular risk.
- © 2010 Royal College of Physicians
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