It is almost a truism that diabetes is a ‘coronary heart disease equivalent’: the risk of a person with diabetes experiencing a first heart attack is very similar to that of an individual without diabetes who has already had an attack having another one (Haffner et al, 1998). The Joint British Societies’ (JBS 2) guidelines on prevention of cardiovascular disease in clinical practice (British Cardiac Society et al, 2005) aim to be both evidence based and easy to implement in everyday clinical practice.
They will be of particular interest to practitioners in primary care, where the majority of diabetes management takes place. Most of the interventions advised will be initiated in primary care. Even when they are commenced in secondary care – for example, on discharge from hospital – primary care teams will be responsible for follow-up and monitoring.
Integrated diabetes management
Two decades ago diabetes care was concerned primarily with management of glycaemia. It is now universally recognised that we need an integrated approach which addresses all risk factors for both microvascular and macrovascular complications, and which manages those complications effectively when they do occur. The impact of good glycaemic control on macrovascular disease is relatively small: its benefit is evident mainly in the prevention of microvascular complications (United Kingdom Prospective Diabetes Study [UKPDS] Group, 1998b). However, it is premature accelerated cardiovascular disease which shortens the lives of people with diabetes.
Diabetes care is complex, involves a wide range of professionals working across healthcare boundaries and is of limited effectiveness without the active involvement of the user. Cardiovascular disease prevention must be integrated with all other aspects of management, otherwise care becomes fragmented by focusing on specific complications rather than the person with diabetes as a whole.
The Alphabet Strategy, which was developed at the George Eliot Hospital, combines all dimensions of diabetes care into a single multidisciplinary user-centred approach and is endorsed by the JBS 2 guidelines. The strategy is a mnemonic-based template designed to ensure that all elements of management are delivered in a systematic, coherent and timely fashion (Morrissey et al, 2005). These elements are listed in Table 1. This approach delivers in everyday practice results comparable to those in clinical trials (Jaiveer et al, 2003).
Statins for everyone?
The most effective single intervention to reduce cardiovascular risk in individuals with diabetes is lipid lowering with a statin. A retrospective study of people attending our secondary care diabetes clinic showed that no less than 85–90% of the improvement in their coronary heart disease risk (calculated using the UKPDS Risk Engine) could be attributed to this one simple measure (Lee et al, 2004).
Jarvis (2006) chronicled the progressive downward trend in cholesterol targets over the past 8 years. American Diabetes Association (ADA; 2006) guidelines now recommend a target low-density lipoprotein (LDL)-cholesterol of less than 2.6 mmol/l. However, they also suggest statin therapy in all individuals with diabetes older than 40 years to reduce LDL-cholesterol by 30–40%, irrespective of baseline lipid profile.
Two recent large-scale clinical trials have fundamentally altered the landscape with regard to statin treatment in diabetes: the Heart Protection Study (HPS; HPS Collaborative Group, 2002) and the Collaborative AtoRvastatin Diabetes Study (CARDS; Colhoun et al, 2004).
The former compared the effect of simvastatin 40mg against placebo in over 20 000 high-risk individuals, including a large number who were at risk simply because of having diabetes. In the treatment group, major vascular events were reduced by 24%. Importantly, people with diabetes benefited to the same extent as individuals who had previously had a myocardial infarction. Furthermore, benefit was independent of baseline lipid profile: those with an LDL-cholesterol less than 3 mmol/l gained the same benefit as those above 3.5 mmol/l.
CARDS was smaller than the HPS, with slightly fewer that 3000 participants, but all had type 2 diabetes as well as one other cardiovascular risk factor. Treatment with atorvastatin 10 mg reduced coronary events by 36% and stroke by 48% compared with placebo. Because of the dramatic reduction in stroke the trial was terminated early. As in the HPS, benefit was irrespective of baseline lipid profile except, intriguingly, in people with low triglyceride levels, who benefited less.
A mere 5 years ago, the Scottish Intercollegiate Guidelines Network recommended lipid lowering in diabetes when calculated 10-year cardiovascular risk exceeded 30% (SIGN, 2001). The JBS 2 guidelines eschew any mention of either risk calculation or a target for LDL-cholesterol; nor do the guidelines seek to distinguish between type 1 and type 2 diabetes. The JBS 2 authors concur with the ADA (2006) that all those with diabetes, type 1 or type 2, aged over 40 years should receive statin therapy. They also spell out in detail which high-risk individuals under the age of 40 years should be treated. The recommendations are summarised in Table 2. They fall short of suggesting that literally everybody with diabetes should be prescribed a statin. However, the evidence suggests that the overwhelming majority will benefit.
Low high-density lipoprotein-cholesterol and raised serum triglyceride levels are risk factors for cardiovascular disease and it is disappointing that studies show little benefit from agents which improve them, in particular fibrates and nicotinic acid. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, testing fenofibrate against placebo, showed a non-significant reduction in events, although extensive co-prescription of statins was a confounding factor (Keech et al, 2005). The therapeutic role of lipid-lowering agents other than statins remains uncertain.
Blood pressure: The lower the better
The JBS 2 guidelines propose, for individuals with diabetes, the daunting blood pressure target of less than 130/80 mmHg, which is considerably lower than the new General Medical Service Quality and Outcomes Framework (QOF) indicator of 145/85 mmHg (Kenny, 2006). However, the QOF is designed to provide financial incentives for improved performance, not necessarily to reflect evidence-based best practice.
The JBS 2 authors admit this will be difficult to achieve, especially in older people, and that it ‘is not based on extensive clinical trial evidence.’ However, they offer two persuasive justifications.
- Trial data show that the greater the blood pressure lowering the greater the benefit, and observational data show no blood pressure threshold below which risk declines no further.
- Blood pressure lowering is the most important factor in the prevention of diabetic nephropathy and end-stage renal failure.
The best evidence for blood pressure lowering in type 2 diabetes is still that from the UKPDS (UKPDS Group, 1998c). Participants were randomised to either intensive blood pressure-lowering therapy, which achieved 144/82 mmHg, or less intensive therapy, which achieved 154/87 mmHg. In the former group, microvascular end points, heart failure, stroke and death were reduced by 30–40%. There were also 21% fewer myocardial infarctions in the former group, which is encouraging, although the reduction was not statistically significant.
The jury is still out whether newer antihypertensive agents, in particular angiontensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, have advantages over older ones, although there is now a suspicion that the use of beta-blockers should be restricted to those with established coronary heart disease (Beevers, 2005). Beta-blockers can also ‘interfere with metabolic and autonomic responses to hypoglycaemia’ (British Medical Association and Royal Pharmaceutical Society of Great Britain, 2006) and thus mask the warning signs for hypoglycaemic episodes.
The evidence for renin–angiotensin system blockade is best in terms of nephroprotection. The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT; ALLHAT Collaborative Research Group, 2002) detected no significant differences in cardiovascular outcomes between treatment regimens based on chlorthalidone, amlodipine or lisinopril.
Few people will respond adequately to monotherapy (Brown et al, 2003) and we believe that it makes clinical sense to start with an ACE inhibitor or a diuretic, and then add in the other agent, followed by a calcium-channel blocker if needed. Probably what matters most is that the blood pressure is lowered, not how it is lowered.
Aim for normal glucose
The Diabetes Control and Complications Trial (DCCT; DCCT Research Group, 1993) first made us aware of the importance of good glycaemic control in the prevention of microvascular complications in type 1 diabetes, and the UKPDS (UKPDS Group, 1998b) confirmed the same for type 2. In the UKPDS, hyperglycaemia was also a cardiovascular risk factor: every 1% increase in HbA1c was associated with 14% more deaths, 14% more myocardial infarctions and 12% more strokes (Stratton et al, 2000). However, the effect of treatment was not large. The intensively treated group, who achieved an HbA1c of 7.0%, had 16% fewer myocardial infarctions than the conventionally treated group, who achieved an HbA1c of 7.9%, but the reduction in myocardial infarctions failed to reach statistical significance.
The DCCT was not powered to detect a beneficial effect on cardiovascular disease over its original 10-year duration; nor was it designed to be. However, follow-up of the participants several years later revealed a 57% reduction in the risk of non-fatal myocardial infarction, stroke or cardiovascular death in the previously intensively treated group (Nathan et al, 2005).
Since good glycaemic control definitely prevents microvascular complications and may prevent cardiovascular events, the only acceptable target is normoglycaemia. Unfortunately, in many of the people with diabetes we see, we will fail; and even the revised QOF indicator of HbA1c less than 7.5% (Kenny, 2006) can be daunting, especially in those with diabetes of long duration and people on insulin treatment. However, it is necessary that we do everything we can.
As with blood pressure, probably what matters most is that blood glucose is brought within the normal range, not how that is done. However, the JBS 2 authors remind us that a retrospective analysis of the UKPDS showed better outcomes in overweight people treated with metformin (UKPDS Group, 1998a). This drug lowers glucose equally effectively in those of normal weight, it is cheap, and, provided the contraindications are observed, it is safe. Consequently, it is the drug of choice in type 2 diabetes when lifestyle modifications are no longer sufficient.
There are interesting suggestions that glitazones may have a beneficial effect on macrovascular disease. The only large-scale outcome trial to date, the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive), demonstrated a relatively small but significant benefit, but at the cost of an increase in heart failure (Dormandy et al, 2005).
Benefits of aspirin
Although the use of low-dose aspirin is widely advocated, the evidence for its benefit in primary prevention in individuals with diabetes is limited. Hopefully, the issue will be resolved by A Study of Cardiovascular Events iN Diabetes (ASCEND; http://www.ctsu.ox.ac.uk/ascend/index.htm [accessed 16.06.06]), which will compare aspirin and omega-3 fatty acids, both in combination and individually, with placebo in primary prevention in 10 000 people with diabetes.
In the meantime, the best evidence is from the Hypertension Optimal Treatment (HOT) trial (Hansson et al, 1998). This investigated both aggressive blood pressure lowering and aspirin use in almost 19 000 individuals with hypertension. The latter reduced myocardial infarction by 36% with no effect on stroke. Eight per cent of participants in the study had diabetes; in this sub-group, aggressive blood pressure lowering (diastolic blood pressure 80 mmHg, compared with 90 mmHg) reduced major cardiovascular events by half.
Current ADA guidelines (2006) recommend aspirin in people aged over 40 years and in those aged 30–40 years with additional cardiovascular risk factors. The JBS 2 guidelines take a slightly more cautious approach, suggesting its use in individuals with established macrovascular disease, in those aged over 50 years, in those with long-standing diabetes, and – in the light of the HOT trial – in those with treated hypertension (see Table 3). As with lipid-lowering therapy, the guidelines see no need to make a distinction between type 1 and type 2 diabetes.
Provided the contraindications are observed, low-dose aspirin is reasonably safe: in the HOT trial it produced twice as many bleeds as placebo but no increase in fatal bleeds.
Lessons from Steno-2
The message so far is that statin treatment reduces macrovascular events, glycaemic control reduces microvascular events, and blood pressure lowering reduces both. The question is: what is the aggregate benefit if all these interventions are delivered together? The answer is provided by the landmark Steno-2 study (Gaede et al, 2003).
In this trial, 160 people with type 2 diabetes and microalbuminuria were randomised to conventional treatment, according to Danish national guidelines, or intensive treatment with lifestyle modification and pharmacological interventions. The latter targeted hyperglycaemia, hypertension, dyslipidaemia, microalbuminuria and prevention of cardiovascular disease with aspirin. The targets were very similar to those advocated by the JBS 2 guidelines (Table 4) and the Alphabet Strategy.
Over the average 7.8 years of follow-up, it was found that intensive, multifactorial, target-driven intervention resulted in significant improvements in HbA1c, blood pressure, serum cholesterol and triglyceride levels, and urine albumin excretion. There were 85 cardiovascular events in 35 of 80 participants (44%) in the conventional therapy group but only 33 events in 19 of 80 participants (24%) in the intensive therapy group. Non-fatal myocardial infarction was reduced by 70%, non-fatal stroke by 85% and amputations by 50%.
This was not a comparison of good versus poor diabetes care: management of the conventionally treated group was in no way sub-standard. Raising the standard from very good to excellent doubles the benefit to people with diabetes (Gaede et al, 2003).
Screening for dysglycaemia
One possible reason for the rather disappointing results of trials like PROactive is that the intervention was simply too late to be of much benefit. In that trial, all participants had established macrovascular disease and over 40% had a history of diabetes of 10 years or more. Indeed, delaying intervention until diabetes is actually diagnosed results in many lost opportunities. In the UKPDS, 50% of participants showed evidence of complications at the time of diagnosis of type 2 diabetes (UKPDS Group, 1990).
The ‘prediabetic’ states of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) increase the risk not only of diabetes but also of cardiovascular disease. Randomised controlled trials have shown the benefit of lifestyle and pharmaceutical interventions in IGT to postpone or even prevent diabetes. The Diabetes Prevention Program (Knowler et al, 2002) demonstrated reductions in the development of diabetes of 58% by lifestyle change and 31% by metformin. The benefit of combining the two is not yet known.
The notion of an incremental, step-wise progression from ‘normal’ glucose tolerance through IGT to diabetes is itself misleading. The relationship between glycaemia and cardiovascular risk extends well below the diabetes threshold. All-cause, cardiovascular and coronary heart disease mortalities rise with HbA1c, with the lowest rates being seen in individuals with an HbA1c less than 5% (Khaw et al, 2001). Glycaemia in the healthy population, like blood pressure and cholesterol, appears to be continuously related to cardiovascular risk (Coutinho et al, 1999).
Simply waiting for individuals to present with diabetes is not an acceptable strategy. The most accurate instrument to detect dysglycaemia is the oral glucose tolerance test (OGTT), but routine use of this is not practicable. People who definitely should have an OGTT are those admitted to the coronary care unit: previously undiagnosed diabetes and IGT are extremely common in those with acute myocardial infarction (Norhammar et al, 2002).
For those without diagnosed cardiovascular disease, the JBS 2 guidelines propose a pragmatic approach. The JBS 2 authors suggest that all adults aged over 40 years should have random (non-fasting) blood glucose measured as part of a cardiovascular risk assessment in primary care. Those found to be at low risk and with a glucose of 6 mmol/l or less should be reassessed in 5 years. However, if the random blood glucose is 6.1 mmol/l or more then further testing should be undertaken with a view to the detection of IFG, IGT or diabetes. At-risk individuals can be offered lifestyle and pharmaceutical interventions to achieve risk factor targets including those for glycaemia. The recommended algorithm in the JBS 2 guidelines is shown in Figure 1.
The first targets for primary care teams may well be the indicators in the QOF. However, the evidence casts doubt on some of these: in particular, the indicator for a total cholesterol level of 5 mmol/l or less appears distinctly lax. In this area, the JBS 2 guidelines, in fact, simplify the decision whether to start treatment by focusing on the clinical situation rather than on biochemical targets or calculated cardiovascular risk. The blood pressure and HbA1c targets advocated by JBS 2 are also far more demanding than the indicators in the QOF. Meeting these will be formidable tasks but the evidence for benefit is now incontrovertible and the therapeutic options are improving.
The biggest challenge of all, we feel, will be the early detection of dysglycaemia. Fortunately this fits well into the health promotion strategies already widely undertaken in primary care. At least in the short term, the workload and resource implications will be considerable. But rising to this challenge will be greatly rewarded by the prevention of many cardiovascular events and deaths consequent upon diabetes.