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See article on page 1577
Diabetes mellitus (diabetes), in particular type 2 diabetes, constitutes one of the largest emerging threats to health in the 21st century. It is estimated that by 2030 as many as 360 million people world wide will be affected.1
The cause of death in those with diabetes is dominated by coronary heart disease, accompanied by increased rates of stroke and peripheral vascular disease: so called macrovascular complications. At least two‐thirds of deaths are attributable to these cardiovascular diseases and their sequelae.2 A true picture of the extent of macrovascular complications is obscured, however, by inaccurate death certification3 and diagnostic criteria4 based on the development of microvascular complications (retinopathy, neuropathy, nephropathy). The Euro Heart5 Survey demonstrated that if one applied oral glucose tolerance tests to those presenting with all forms of acute coronary syndrome, two‐thirds display impaired glucose regulation.
In the USA, although the overall mortality rate associated with coronary heart disease has declined over the past 20 years, this trend has not been reflected in a decline of mortality rates in patients with diabetes.6 Results published in this issue of Heart from the Swedish registry on coronary care (RIKS‐HIA) confirm this trend (see article on page 1577).7 After a myocardial infarction (MI), patients with diabetes had an increased mortality rate compared with non‐diabetic patients. Moreover, despite the existence of treatments which may benefit diabetic patients disproportionately, the relative hazard of mortality in diabetic patients has improved little compared with non‐diabetic patients between the time periods 1995–8 and 1999–2002. These observations give us a glimpse of the vast epidemic that is approaching, if not upon us.
In the Multiple Risk Factor Intervention Trial (MRFIT), men with diabetes had a threefold higher absolute risk of cardiovascular death than non‐diabetic men (160 vs 53 cardiovascular deaths per 10000 person‐years) even after controlling for age, race, income, cholesterol levels, blood pressure and smoking.8
The Framingham Study9 20‐year follow‐up similarly demonstrated that patients with diabetes not only had a higher mortality with their index event, they also had a higher incidence of reinfarction and heart failure in the acute and postinfarction periods.
The FINMONICA Study,10 which looked at out‐of‐hospital deaths as well as deaths from index admission, showed that while diabetic women have a higher in‐hospital and 1‐year mortality, diabetic men have a higher overall mortality due to out‐of‐hospital death.
The risk of a first cardiovascular event in patients with diabetes is as high as in non‐diabetic patients who have already had a cardiovascular event.11 Guidelines reflect this concept by treating diabetes without overt coronary disease as a “postinfarct” equivalent.12,13,14
Patients with diabetes have more multivessel, diffuse and distal coronary disease, smaller reference vessels, poorer coronary collateral circulation and more left main stem disease.15,16,17 In a study more plaque ulceration and intracoronary thrombus was observed in diabetic arteries18 than in those without diabetes. These features in combination with upregulated glycoprotein IIb/IIIa receptors, inflammation and endothelial dysfunction, make these patients particularly vulnerable to the atherosclerotic process and its sequelae.
Diabetes doubles the risk for ACS with an additional doubling of the clinical risk once the event has occurred.19,20,21,22 Among diabetic patients who have had an acute MI about half were not known to be diabetic at the time of presentation.23 According to registry data, patients with diabetes present acutely more often with heart failure or non‐ST elevation ACS than ST elevation MI.24
Hyperglycaemia in the setting of an ACS is associated with poor outcome. The DIGAMI Study investigated intensive insulin treatment at the time of an index acute MI and for a minimum of 3 months.25 They found an 11% absolute reduction in mortality at 1 year among those randomised to insulin. DIGAMI 2 investigated those with hyperglycaemia and overt type 2 diabetes using different glucose lowering regimens.26 Glycaemic targets were not achieved and no difference in mortality was detected.
Diabetic patients benefit from prompt revascularisation in acute STEMI, both with fibrinolysis and primary percutaneous coronary intervention (PCI). The magnitude of benefit and access to reperfusion is greater with a primary PCI strategy.27 A systematic review by Keeley et al28 and also subgroup analysis data from PRAGUE‐229 confirm that those with the highest risk, including those with diabetes, can achieve 30‐day mortality rates of 7% with primary PCI compared with 23% for a similar group of patients receiving lysis.
Nevertheless, diabetes portends a higher mortality even if epicardial reperfusion is attained using either lysis30 or PCI. Patients with a recurrent MI fare worse still than those with a first MI. The angioplasty substudy of GUSTO‐IIb demonstrated that the incidence of multivessel disease among patients with diabetes is greater than in those without (45.3% vs 32.4%), mean ejection fraction was also lower. Death or reinfarction was higher in diabetic patients both at 30 days (13.1% vs 8.5%) and at 6 months (18.8% vs 11.4%,).31
Given the poor outcomes, contemporary guidelines also mandate early invasive investigation and interventional management of non‐ST elevation ACS.32 The FRISC II33 study, again via subgroup analysis, demonstrated that diabetic patients with non‐ST elevation ACS benefited from revascularisation using a composite end point of death and reinfarction.
The advent of the “Heart Attack Centre” strategy may provide an opportunity for aggressive interventional and medical management to reduce the excess mortality in diabetic patients further.
ACS are the most common presentation of coronary disease in patients with diabetes. Two‐thirds of patients display glucometabolic disorders in the coronary care unit and in the cardiac catheter laboratory, patients with diabetes have worse disease than non‐diabetic patients on initial presentation.
Underdiagnosis of diabetes is a manifest problem. Using fasting plasma glucose instead of oral glucose tolerance tests fails to detect 40–60% of those with dysglycaemia.
Cardiologists must help to identify these patients more accurately34,35,36 with programmes to screen patients in clinic, in the coronary care unit and in the cardiac catheter laboratory. Conversely, greater cooperation between cardiologists and diabetologists to identify coronary disease in known diabetic patients will allow a fast track for coronary investigation and intervention in this group and enhance access to proven treatments which are underused in patients with diabetes.
Although there is a consensus from trial data that diabetic patients constitute a high‐risk group worthy of aggressive identification and management, observational registries paint a different picture. The findings of the GRACE37 investigators provide an insight into “real‐world” practice and are at odds with acknowledged guidelines. Their data suggest that there is an underuse of invasive investigation and percutaneous revascularisation in high‐risk patients with ACS. The RIKS‐HIA data in this issue of the journal also confirm the underuse of treatment in patients with diabetes.7
Risk modification works well in diabetic patients, as highlighted in a randomised controlled environment, where adherence to strict targets is maintained (STENO‐2).38 The RIKS‐HIA data mirror that of revascularisation—namely, underprovision of secondary prevention treatments, notably statins, in diabetic patients. Contemporary data from the latest Euro Heart Survey demonstrate that this trend continues. Clearly there is a “practice” gap as well as a knowledge gap that needs to be bridged.
A valid criticism of our knowledge in managing such patients is that we are still reliant for the most part on substudies of clinical trials. To rectify this, a series of trials designed to investigate patients with diabetes and using cardiac outcome end points has begun. These may allow an improvement in existing treatments to narrow the gap and may even result in new treatments or strategies that may be beneficial in patients with diabetic coronary disease but not those with non‐diabetic coronary disease. CARDS,39 looking at primary prevention with a statin, is probably the first major contemporary study in this mould to have reported, and more trials dedicated to patients with diabetic coronary disease are on their way.
BARI 2D40 is assessing revascularisation against aggressive medical treatment in diabetic patients. CARDia,41 with recruitment now complete, is investigating the outcomes of symptomatic patients with multivessel or complex single‐vessel disease randomised to contemporary PCI or surgical revascularisation. FREEDOM42 is a larger but similar surgery versus PCI trial, recruiting globally.
It is therefore at an opportune moment that the comprehensive European Society of Cardiology Guidelines43 on “diabetes, prediabetes, and cardiovascular diseases” have been published. Their clarion call to cardiologists and diabetologists to join forces to diagnose, prevent and treat glucometabolic disorders aggressively is an important message. Registry data like RIKS‐HIA further remind us that ignoring the guidance may undo the progress in beneficial clinical outcomes achieved to date in patients with cardiovascular disease.
ACS - acute coronary syndrome(s)
MI - myocardial infarction
PCI - percutaneous coronary intervention
Conflict of interest: None declared.