Diabetes and Cardiovascular Disease

Prof  D John Betteridge

Cardiovascular events are the greatest cause of mortality in patients with type 2 diabetes and account for substantial morbidity within this population. Whilst modern treatments have undoubtedly improved outcomes, with both improved post-event invasive techniques (e.g. PCI) and better prophylactic control (e.g. statins and anti-hypertensives), people with diabetes continue to suffer far greater cardiovascular risk compared to non-diabetic individuals.

Diabetes not only causes microvascular disease invoving the kidneys, retinae and nerves but also macrovascular disease characterized by premature and extensive atherosclerosis leading to myocardial infarction, stroke, peripheral artery disease and ultimately death. For cardiologists, the concern of note is that for both those with low and preserved ejection fraction (EF), patients with diabetes suffer higher all-cause mortality than otherwise similar non-diabetic patients such that those with diabetes and preserved EF have similar mortality to those without diabetes with low EF The same pattern is seen for CV death or hospitalisation for heart failure(1).
STENO 2 has shown us that multifactorial intervention has a positive effect upon outcomes, however this effect does not become apparent for 8 to 9 years(2). Such studies suggest that decreases in blood pressure (-14 mmHg) and HbA1c (-0.5%) have a relatively small effect on event rates, approximately -10% and -15%, compared to the substantial almost -70% that can be achieved by correcting dyslipidaemia (TC -50mg/dl, LDL -47mg/dl and HDL +6mg/dl)4.

Long term glycaemic control has been demonstrated to reduce microvascular events, however its effect upon macrovascular outcomes remains less clear (5). Achievement of cardiovascular protection shown in a number of recent trials, including the ACCORD, ADVANCE and VADT studies, have suggested that intensive glucose-lowering effect does not reduce the risk of cardiovascular events and might even increase the risk of some events (6-8). It has been multifactorial interventions, e.g.STENO-2, addressing concomitant risk factors, which have been demonstrated to have the greatest positive effect upon outcomes. Diabetic patients are typically dyslipidaemic and hypertensive and it is clear that these risk factors need to be addressed. The 2009 position statement by the American Diabetes Association, the American College of Cardiology Foundation and the American Heart Association stressed that comprehensive care for diabetes should involve treatment of all cardiovascular risk factors (9)
.
Most of the current antihyperglycaemic drugs do not have any clinically significant effect on these factors, two exceptions being the GLP-1 receptor agonists and pioglitazone, a thiazolidinedione (TZD). The former have been shown to reduce blood pressure independently of weight loss and improve the lipid profile (10,11), and also markers of NAFLD/ steatohepatitis (12,13)

TZD's, diabetes and cardiovascular disease

Pioglitazone, too, has been demonstrated to have potentially beneficial effects on blood pressure and dyslipidaemia and, unlike rosiglitazone, is associated with improved CV outcomes.(14) Pioglitazone has been demonstrated to increase HDL, increase LDL particle size without increasing apoprotein B and reduces plasma triglycerides (15) Furthermore, pioglitazone has been demonstrated to reduce the progression of atherosclerosis in both coronary and carotid arteries (16). On the contrary rosiglitazone does not have these positive effects on cardiovascular risk factors and indeed is associated with increased cardiovascular events (17-20). On 23rd of September 2010 the European Medicines Agency suspended the marketing authorisation for all rosiglitazone containing medicines, due to cardiovascular safety concerns, whilst US Food and Drug Administration has significantly restricted the use of rosiglitazone to patients with Type-2 diabetes who cannot control their diabetes on other medications (21). The significant differences between pioglitazone and rosiglitazone are not mirrored in the pioglitazone database.