Introduction 173
Glycaemic control 174
Dyslipidaemia 177
Hypertension 183
Non-pharmacological means of reducing blood pressure 186
Pharmacological treatment of cardiovascular disease 187
Obesity 188
Conclusion 189
References 189
Diabetes is now one of the most common non-communicable diseases and poses one of the most challenging health problems worldwide. Modernisation and Westernisation of lifestyles are the underlying cultural processes driving the escalating diabetes epidemic. In 2000 the estimated worldwide prevalence of type 2 diabetes was 151 million adults, compared to 135 million in 1995 and 30 million in 1985 (Harris et al 1998). It is estimated that this prevalence will increase to 300 million people worldwide in 2025, with the steepest increases in rates of diabetes being in developing countries due to their rapidly changing economies and lifestyles (King et al 1998).
The burden of macrovascular disease in people with diabetes has been recognised for many years. It is well established that people with type 1 and type 2 diabetes have an increased risk of atherosclerotic cardiovascular disease (CVD). People with diabetes have a higher incidence of morbidity and mortality from coronary heart disease (CHD), and there is also evidence suggesting an increased risk of stroke and peripheral vascular disease in these people.
Epidemiological studies from around the world have confirmed the excessive cardiovascular morbidity and mortality in people with diabetes compared to non-diabetic subjects in the same geographical area over the same time period. Data from the Framingham cohort, in the USA (Kannel & McGee 1979), which first examined this issue, demonstrated an increase in CVD in people with diabetes compared to people who did not have diabetes in the study population. There were higher rates of CHD, congestive cardiac failure, stroke, peripheral vascular disease and cardiovascular death within the subgroup of people with diabetes. Although this group was small, and there might have been discrepancies in the diagnostic criteria for diabetes, several other larger studies have mirrored these findings.
Another study from the USA (Wingard et al 1993) demonstrated the increased prevalence of coronary heart disease in different age groups. The rate of CHD was increased 14-fold in the 18–44-years age group, threefold in the 45–64-years age group and doubled in those people over the age of 65 years. Two further studies have also shown that whereas the absolute rates of CVD are higher in men with diabetes, the relative risk of CVD is higher in women with diabetes (Jousilahti et al 1999, Manson et al 1990), so it is sometimes stated that ‘women with diabetes lose the protection of their gender’.
The age-adjusted mortality has also been shown to be greater in diabetic populations. A meta-analysis of ten observational studies (Lee et al 2000) revealed a relative risk of death of 1.9 for men and 2.6 for women, when compared with their non-diabetic counterparts.
The South Tees Mortality Study (Roper et al 2002) looked at death rates in a cohort of 4842 people with type 2 diabetes and found that one-quarter was dead within 6 years, the majority from cardiovascular causes. Cardiovascular mortality was significantly increased in both sexes and all age groups, but it was particularly evident in middle-aged women with diabetes. Relative death rates for age band 40 to 59 years were 5.47 and 5.60 for men and women, respectively.
Despite the accumulation of this evidence over the past three decades, reducing the risk of cardiovascular disease in the person with diabetes remains a major challenge. This chapter examines a multifactorial approach to reducing cardiovascular morbidity and mortality in the person with diabetes and includes detailed examination of several recent studies that have helped provide evidence for this approach.
GLYCAEMIC CONTROL
Controversy remains regarding the extent to which hyperglycaemia contributes to the high prevalence of CVD in people with type 1 and type 2 diabetes and there is relatively little convincing evidence to suggest that aggressively managing hyperglycaemia reduces cardiovascular risk in people with diabetes mellitus. One study in 1971 even suggested that, far from being protective, lowering plasma glucose using the sulphonylurea, tolbutamide, had toxic effects on the myocardium (University Group Diabetes Program 1970). Although this study has subsequently been criticised for poor study design and the results of other studies have contradicted this evidence, other controversial issues arose in this field in the 1980s. The association between elevated plasma insulin levels and coronary heart disease in insulin-resistant people, for example, led some investigators to suggest that insulin itself might be atherogenic, given that insulin stimulates both smooth muscle proliferation and lipid synthesis. Over the past decade, however, more evidence has been published that has further increased our understanding about the relationship between CVD and glycaemic control.
UNITED KINGDOM PROSPECTIVE DIABETES STUDY
The long-awaited results from the United Kingdom Prospective Diabetes Study (UKPDS) were published in 1998 (UKPDS Study Group 1998a, 1998b, 1998c, 1998d). This randomised, controlled trial of people newly diagnosed with type 2 diabetes refuted the suggestion that treatment with either sulphonylureas or insulin therapy was associated with increased cardiovascular risk (UKPDS Study Group 1998a). Subjects in the main study were randomised either to conventional treatment with diet or to intensive treatment with either sulphonylurea or insulin therapy. There was a significant reduction in HbA1c in the intensive treatment group and a 25% risk reduction in microvascular endpoints (neuropathy, nephropathy and retinopathy and need for laser treatment). However, despite small reductions in macrovascular endpoints, such as myocardial infarction (MI), these results did not reach statistical significance. These people have been followed for a few years since the end of the UKPDS and the reduction in MI with intensive treatment based on sulphonylureas or insulin therapy is now statistically significant.
Interestingly, a substudy from the UKPDS group in overweight individuals indicated that treatment with metformin led to a reduction in cardiovascular events, including MIs and diabetes-related deaths (UKPDS Study Group 1998b). Because MI was such a common cause of death in these individuals, the reduction in MIs was also mirrored by a reduction in total mortality. This unexpected finding was not fully anticipated by the UKPDS investigators and the results remain difficult to explain. The number of people receiving metformin was small (n = 342) and this might have exaggerated the degree of benefit. The reductions in events could not be explained on the basis of reductions in HbA1c, suggesting that metformin might have extended benefits that were not directly related to glucose-lowering effects of the drug. Metformin has a relatively minor effect in reducing insulin resistance at the level of the liver, and this is one possible explanation.
DIABETES CONTROL AND COMPLICATIONS TRIAL
The results of the Diabetes Control and Complications Trial (DCCT), a multicentre trial, which randomised 1141 people with type 1 diabetes to usual care or intensive insulin therapy, mirrored to some extent the findings from the UKPDS Study. There was a significant reduction in microvascular endpoints in the intensive treatment group compared to the conventionally treated group (DCCT Research Group 1995). Although there was a trend towards a reduction in cardiovascular disease in the intensive treated group, again this did not reach statistical significance. This might be due to the small number of events that actually occurred throughout the period of follow-up (40 in the control group; 23 in the treatment group), which is attributable to the young age of the population studied (13–39 years). A subsequent meta-analysis, including data from DCCT and several smaller studies, demonstrated a significant reduction in the number of macrovascular events, but no significant effect on the number of people developing macrovascular disease, or on macrovascular mortality (Lawson et al 1999).
Therefore, although the results from the UKPDS and DCCT trials were beneficial in so much as they proved that treatment with insulin or sulphonylureas reduced microvascular events and did not lead to an increase in cardiovascular disease, to date, no study has demonstrated that intensive management of hyperglycaemia reduces the risk of CHD. However, in addition to the evidence that metformin might reduce the incidence of macrovascular complications, the thiazolidinediones, a new group of oral agents, have also been shown to have extended benefits beyond glucose lowering, including favourable affects on blood pressure, lipids and microalbuminuria, as well as reductions in novel cardiovascular risk markers such as C-reactive protein (CRP) (Haffner et al 2002). Whether this translates into clinical benefit in terms of a reduction in cardiovascular events is currently being tested in large studies with rosiglitazone and pioglitazone, respectively.
Based on the results of the UKPDS, Alan should initially be treated with lifestyle measures. If, as is likely, he is unable to reach the target HbA1c with lifestyle measures alone, then metformin would be the drug of first choice. It would be helpful, however, to have an echocardiogram to be certain that he does not have cardiac failure, as this would be a contraindication to the use of metformin. An echocardiogram would also establish the best secondary preventive therapies. If significant left ventricular dysfunction is present, a thiazolidinedione is also contraindicated because of the side effect of fluid retention, so a sulphonylurea would be indicated.
DYSLIPIDAEMIA
Hyperlipidaemia is also a risk factor for atherosclerotic cardiovascular disease. In the general population, the Multiple Risk Factor Intervention Trial (MRFIT) demonstrated that the incidence of ischaemic events increases proportionally with elevations in serum low-density lipoprotein (LDL) cholesterol, and conversely with reductions in serum high-density lipoprotein (HDL) cholesterol concentrations (Stamler et al 1993). This study also showed that the absolute increase in risk of a cardiovascular event per unit rise in serum cholesterol was steeper in people with diabetes than in those without.
Well-controlled type 1 diabetes is associated with serum lipids similar to that of the general population. Poor glycaemic control, increasing age, obesity and the presence of nephropathy all lead to an increase in serum triglyceride and very low-density lipoprotein (VLDL) concentrations in type 1 diabetes. Type 2 diabetes is also associated with an unfavourable lipid profile; although the level of total and LDL cholesterol might be within normal limits, the HDL concentration tends to be low with elevated triglycerides. In addition, the distribution of LDL subfractions is altered so that small, dense LDL particles predominate and these are thought to be more atherogenic. This pattern of dyslipidaemia is also seen in those people without frank diabetes who have the ‘metabolic syndrome’ and who also have an increased risk of cardiovascular disease (see Chapter 4).
It is interesting to remember that as recently as 10 years ago lipid-lowering agents were thought to have few beneficial effects on cardiovascular mortality in the general population and the data from one meta-analysis even suggested that there was an increased risk of suicide and accidental death in people who were receiving lipid-lowering agents (Davey Smith & Pekkanen 1992). The advent of the HMG CoA reductase inhibitors (statins) revolutionised lipid-lowering therapy and the evidence that has emerged over the past decade for reducing serum total and LDL cholesterol is compelling and has dramatically changed clinical practice. This has included subgroup analysis of large studies containing many people with diabetes and, more recently, studies performed exclusively in people with diabetes.
Three major studies published in the 1990s, in which more than 15 000 people participated, looked at the issue of secondary prevention of atherosclerotic CVD using statin therapy: the Scandinavian Simvastatin Survival Study (4S) (Scandinavian Simvastatin Survival Study Group 1994), the Cholesterol and Recurrent Events (CARE) Trial (Sacks et al 1996) and the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study (LIPID Study Group 1998).
Data from the 4S and CARE, which were conducted in the US and Canada, and from the LIPID Study, which was carried out in Australia and New Zealand, were consistent. Reducing LDL and total cholesterol is associated with reductions in all-cause mortality, CHD-related deaths and major coronary events (first MI, unstable angina). As a result, statin therapy in people with a history of coronary heart disease is normal practice.
PRIMARY PREVENTION STUDIES
Also in the 1990s, two large studies also examined the issue of the role of statins in the primary prevention of coronary heart disease. Data from the West of Scotland Coronary Prevention Study (WOSCOPS) and the Airforce/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) suggested that statin therapy was also of benefit in people with no history of CVD (Shepherd et al 1995, Downs et al 1998). People with a wide range of cardiovascular risk were included in these studies and all people appeared to benefit. Few people with diabetes were included in these studies so no meaningful analysis could be made of the data from these small subgroups.
However, despite the large numbers of people in these five studies, relatively few individuals with diabetes were included. A total of 2000 people with diabetes were included in these five cohorts and, until recently, clinical practice was based on data from these small diabetic subgroups. Over the last few years, however, further studies have been published that have greatly enhanced our knowledge of the effects of lipid-lowering in the population of people with diabetes.
The Heart Protection Study
The Heart Protection Study (HPS) was a large randomised study designed to address the question of whether lowering LDL cholesterol below previously accepted thresholds in people at high risk of cardiovascular disease would confer added benefit (Heart Protection Society Collaborative Group 2002). In particular, its aim was to study the effects of lipid lowering within subgroups for which there was limited existing evidence including people with diabetes, women, the elderly and those with non-coronary occlusive arterial disease.
There were 5963 people with diabetes within the study group and 90% of these were classified as having type 2 diabetes. There were highly significant reductions in serum total LDL cholesterol concentrations and a corresponding 22% reduction in first major vascular event in the simvastatin-treated group when compared to the placebo group. These figures are similar to the reductions seen with simvastatin in the non-diabetic, high-risk people studied.
An even greater reduction was seen in the group with diabetes but without previous coronary or occlusive vascular disease. A total of 2912 diabetic people had no cardiovascular disease and simvastatin reduced the primary endpoint of first major vascular event from 13.5% to 9.3%, and of first major coronary event from 6.5% to 3.7%. This effect was still seen regardless of age, sex, blood pressure, body mass index (BMI), HBA1c and, most importantly, initial LDL cholesterol, with similar levels of relative risk reduction in those with high serum cholesterol levels compared to those individuals with ‘normal’ cholesterol levels (Collins et al 2003).
ALLHAT-LLA and ASCOT-LLA
The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial–Lipid Lowering Arm (ALLHAT-LLA) was a non-blinded, randomised study with one arm examining the benefits of cholesterol lowering with 40 mg of pravastatin in modestly hypertensive people with one or more coronary heart disease risk factors. The other arm of the study compared the effects of two different antihypertensive regimes (The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group 2002a).
In this trial, the primary endpoint of all-cause mortality was not altered significantly by treatment with pravastatin, unlike other primary prevention trials. There was a non-statistically significant reduction in rates of CHD and stroke. These rather disappointing results were thought to be due to a lower than average compliance rate in the treatment group (70–75%) and high use of open-label statins in the placebo group, leading to a smaller reduction in both total and LDL cholesterol than observed in the other large intervention trials. In total, 3638 people with type 2 diabetes took part in the study (35% of the cohort) and there were no differences in the rates of the primary or secondary endpoints in this subgroup.
Published shortly after ALLHAT in 2003, the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA) was a similarly designed study, again with one arm, looking at cholesterol lowering, this time with 10 mg of atorvastatin in people with hypertension and who were at high risk, but had no previous history of CHD (Sever et al 2003). The results of this study revealed a 36% reduction in non-fatal MI and fatal CHD in the active treatment group. However, treatment with atorvastatin in the subgroup with diabetes (25% of the total cohort) did not lead to a statistically significant reduction in primary endpoint. This might have been due to the higher use of open-label statins within the placebo group with diabetes than among the group who did not have diabetes.
Collaborative Atorvastatin Diabetes Study (CARDS)
Until very recently, no study had shown the benefits of cholesterol lowering in a cohort containing only individuals with diabetes. This evidence has now been provided by the Collaborative Atorvastatin Diabetes Study (CARDS), a multicentre, double-blind trial that examined the effects of cholesterol lowering in 2838 people with type 2 diabetes and low LDL-cholesterol (median 3.1 mmol/L) randomised to atorvastatin 10 mg/day or placebo (Colhoun et al 2004).
CARDS also reinforces the long-term safety profile of statins. The study showed no significant differences in treatment-related events or liver enzyme abnormalities and no cases of muscle symptoms or rhabdomyolysis. Discontinuation rates associated with treatment-related events were low in both groups.
SHOULD EVERYONE WITH DIABETES RECEIVE A STATIN?
These more recent studies add weight to the argument for treating people with diabetes with statins to reduce cardiovascular risk. Before the availability of these data, it was necessary to extrapolate data from the older studies to the population of people with diabetes in order that they could enjoy the benefits of lipid-lowering therapy. However, the issue of whether or not all people with diabetes should receive statin therapy remains controversial.
Some believe that everyone with type 2 diabetes should be treated as if they had pre-existing CHD, and one large study based on data from Finland suggested that a person with diabetes was at greater risk of suffering from a coronary event than a person without diabetes who has previously had a similar event (Haffner et al 1998). A similar study carried out in Tayside, however, has suggested that, while certainly at higher risk of CHD than the general population, people with diabetes without known cardiovascular disease are not more likely to suffer an event than a person who has pre-existing cardiovascular disease (Evans et al 2002). Several recent guidelines suggest that all people with diabetes are treated as a CHD equivalent, and so should be given a statin. Although all people with diabetes would gain from the widespread use of statins, the issues of cost and compliance need to be considered carefully before adopting such a ‘blanket’ prescribing policy.
A further issue that remains unresolved is the use of statins in people with type 1 diabetes. This group has a much higher incidence of CHD than their counterparts who do not have diabetes. Despite this, however, diabetes is usually diagnosed at a young age when the absolute incidence of CHD is negligible. The benefit of statin therapy in type 1 diabetes has not been proven given the very small numbers of these people included in statin trials. The timing of initiation of therapy also remains unresolved in people with type 1 diabetes, and there is still a need for further information regarding the benefits of statins in people with diabetes but who do not have CHD, particularly people with type 1 diabetes and younger people with type 2 diabetes.
A further cloudy issue in the management of dyslipidaemia is how far cholesterol should be lowered. Although the Heart Protection Study provided some indication as to target levels of cholesterol it was not specifically designed to identify this. A recent novel analysis of the reduction of CHD events with all forms of lipid-lowering therapy (Brady & Betteridge 2003) has shown that the lower the cholesterol the greater the reduction in CHD events, and the same is true for an analysis of the reduction of CHD events in people with diabetes. The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) Study (Cannon et al 2004) has demonstrated that high-dose atorvastatin is better than a less efficacious dose of pravastatin in reducing major cardiovascular events or death in patients with acute coronary syndromes; 18% of the cohort had diabetes but the reduction in diabetic subjects did not reach statistical significance.
OTHER DRUGS
Fibrates are also available as lipid-lowering therapy. They cause a reduction in serum triglycerides and elevations in HDL cholesterol with little impact on LDL cholesterol. Given that the major lipid abnormalities seen in people with diabetes are a reduction in HDL cholesterol and elevated serum triglycerides, it would seem likely that fibrates would be a more reasonable choice of lipid-lowering therapy in the person with diabetes. A randomised double-blind placebo-controlled trial has studied the effect of fibrates on progression of coronary artery disease in people with type 2 diabetes (Diabetes Atherosclerosis Intervention Study Investigators 2001) and demonstrated a 28% reduction in triglycerides and 6% increase in HDL cholesterol, with no significant change in LDL cholesterol. There was a significant reduction in coronary artery plaque progression in the fenofibrate-treated group compared to the placebo group. There was also a reduction in clinical endpoints in the treated group, although the study did not have statistical power to analyse these data. This is currently being examined in a larger randomised, prospective study of fenofibrate in people with diabetes examining harder cardiovascular end points.
The Veterans Affairs High-density lipoprotein cholesterol Intervention Trial (VA-HIT) Study Group carried out a randomised double-blind placebo controlled trial looking at the effect of treatment with gemfibrozil in 2500 men with established CHD and reduced HDL cholesterol and normal levels of LDL cholesterol (Rubins et al 1999). This cohort had a large diabetes subgroup. The study demonstrated that HDL cholesterol increased and triglycerides were significantly reduced in the gemfibrozil treated group. There was also a 22% relative risk reduction in primary endpoints in the treatment group and a 41% relative risk reduction in CHD related death in the subgroup of people with diabetes.
Although these studies look promising, larger studies looking at the effects of fibrates on clinical endpoints are necessary. No large study has looked at the combined effect of a fibrate and a statin and, although this might seem like the ideal combination in the person with diabetes, given the typical lipid profile, there are concerns regarding the safety of these agents in combination in terms of rhabdomyolysis.
Ezetimibe is a novel lipid-lowering agent that acts by selectively inhibiting cholesterol absorption without disrupting the absorption of fat soluble vitamins. It reduces LDL cholesterol by 15–20% and is mainly used in people who are intolerant of statins (especially at higher doses), or as combination therapy in people who are failing to reach target serum cholesterol levels despite high dose statins.
PRACTICAL ASPECTS OF LIPID-LOWERING THERAPY IN PEOPLE WITH DIABETES
Based on the evidence described above, all people with diabetes with existing cardiovascular disease (coronary heart disease, cerebrovascular or peripheral vascular disease) should be treated with either simvastatin 40 mg or pravastatin 40 mg as a starting dose. People with diabetes without known cardiovascular disease should be treated with either simvastatin 40 mg or atorvastatin 10 mg if they are at high risk, and this will include nearly everyone over 40 years of age. Cholesterol targets should be at least less than 5.0 mmol/L in both situations, and can be lowered with time. The dose can be increased if the target cholesterol is not reached or the person’s medication can be switched to rosuvastatin, which is a newer, more potent statin, a fibrate or ezetimibe can be added. Fibrates can also be added if raised triglycerides or a low HDL cholesterol is part of the problem, but the use of these drugs combined with a statin will usually be following advice from secondary care.
In our earlier case study, Alan has a history of MI and is already on simvastatin. His total cholesterol is not to target and the dose of simvastatin that was used in the most recent studies was higher. The first step would be to increase the simvastatin to 40 mg. If a repeat cholesterol is still not less than 5.0 mmol/L there are three treatment options: increase the simvastatin to 80 mg with possible side effects, switch to a more potent statin such as atorvastatin or rosuvastatin, or add ezetimibe.
Hypertension is commonly associated with both types 1 and 2 diabetes. It is estimated that 10–30% of people with type 1 diabetes and over 50% of people with type 2 diabetes are hypertensive, which is double the prevalence than in the general population. It is estimated that 40% of people with type 2 diabetes are hypertensive by the age of 45, this figure rising to 60% at 75 years (Hypertension in Diabetes Study (HDS) 1993a).
The pathophysiology of hypertension in diabetes is multifactorial, with issues such as alterations in vascular reactivity to pressor agents and changes in the renin–angiotensin system being thought to be responsible in type 1 diabetes. Although all these factors can also operate in type 2 diabetes, additional factors are at play, such as central obesity, renovascular disease and insulin resistance.
It is well known that there is an additive effect of coexistent hypertension on CHD outcomes in people with diabetes. Data from the Framingham Study suggested that people with type 2 diabetes and hypertension had a higher incidence of CHD than those with diabetes alone (Garcia et al 1974). This has been confirmed by two larger studies.
In the UKPDS cohort, 35% of men and 46% of women were hypertensive at the start of the study (although this is likely to be an underestimation given that hypertension was defined as a mean blood pressure of > 160/90 mmHg). It was noted that people with hypertension were three times more likely to have had a previous cardiovascular event (Hypertension in Diabetes Study (HDS) 1993a) and had a much greater prevalence of ECG features of coronary heart disease at entry to the study. Also, over 4.6 years of follow-up, the presence of hypertension predicted an increase in the incidence of cardiovascular events (Hypertension in Diabetes Study (HDS) 1993b).
The MRFIT Study (Stamler et al 1993) also demonstrated the synergistic effect of hypertension and diabetes on cardiovascular risk. Over 5000 men with diabetes participated in the study and were noted to have a mortality rate three times higher than their counterparts without diabetes. The presence of hypertension predicted CHD and stroke mortality, especially in those people who had hypercholesterolaemia or were smokers.
REDUCING BLOOD PRESSURE: THE EFFECT ON CARDIOVASCULAR DISEASE
A large number of studies dating back to the 1970s have looked at the issue of treating blood pressure in the context of reducing cardiovascular risk. Most of these studies were published in the late 1980s and confirmed that blood pressure reduction in the general population did indeed reduce the risk of coronary heart disease and stroke. Men and women of all ages were shown to benefit from blood-pressure reduction. The majority of these early studies used thiazide diuretics and beta-blockers.
Over the past few years, however, further studies have examined other issues in the treatment of hypertension. Two major trials looked at the effect of blood-pressure lowering on intensive targets. The Hypertension Optimal Treatment (HOT) Trial was designed to address the question of how far blood pressure should be lowered to achieve the most benefit in terms of cardiovascular disease, i.e. are there additional benefits or risks in lowering blood pressure to fully normotensive levels or is there little benefit in lowering diastolic blood pressure to below 90 mmHg (Hansson et al 1998)? Interestingly, although the study showed that reducing blood pressure to within normotensive limits did not confer any additional benefit in terms of cardiovascular morbidity in people without diabetes, this was not true for the subgroup of people who had diabetes, in whom additional benefit was seen (Hansson et al 1998). Indeed, it was observed in the subgroup of people with diabetes that active lowering to within normal limits conferred additional benefits. These results have formed the basis for most guidelines in treatment of hypertension in diabetes.
A further randomised controlled trial from the UKPDS Study, also published in 1998, randomised 1148 people with type 2 diabetes and hypertension to either tight or less tight blood pressure control. Data from this study (the Hypertension in Diabetes Study) confirmed the beneficial effects of tight blood pressure control on cardiovascular disease in people with type 2 diabetes (UKPDS Study Group 1998a).
The Losartan Intervention For Endpoint reduction in hypertension (LIFE) Trial (Dahlof et al 2002) compared losartan- and atenolol-based therapy in 9193 people with hypertension and left ventricular hypertrophy. The primary composite endpoint was cardiovascular death, MI and stroke. Losartan reduced the primary endpoint significantly, with significant reductions in stroke but not in MI or cardiovascular death. In all, 1195 people with pre-existing diabetes were included in the study, and the results were published separately (Lindholm et al 2002). In people with diabetes, losartan caused significant reductions in the composite endpoint and in cardiovascular and total mortality compared to atenolol, but the reduction in strokes and MI was not significant.
The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) also set out to establish the relative benefit of various drugs in certain high-risk groups such as the elderly, black people and people with diabetes. A total of 33 357 participants (12 062 with type 2 diabetes) from North America, all of whom had at least one other risk factor for CVD, were randomly assigned to chlorthalidone, lisinopril, amlodipine or doxazosin (The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group 2002b). The doxazosin arm of the trial was discontinued early because there was a clear benefit of chlorthalidone over doxazosin. The main study revealed no significant differences between the groups in terms of the primary outcome measures of death due to CHD or non-fatal MI, with chlorthalidone being superior to lisinopril and amlodipine in terms of reduction in stroke, combined CHD and CVD.
CURRENT GUIDELINES AND LIMITATIONS
A large number of studies have therefore proved the efficacy and safety of all antihypertensive classes in people with diabetes (Table 8.1). A number of guidelines have been published in response to these data (Krans et al 1995, Ramsay et al 1999, The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure 1997). The majority of these suggest that clinicians aim for a target blood pressure of < 140/80 mmHg (some even lower) in people with diabetes. Although the evidence overwhelmingly suggests that this is the correct course of action, these targets are often very difficult to achieve. This was well demonstrated in the UKPDS/HDS studies in which, despite regular visits and intensive treatment with at least three agents in 29% of situations, only 56% of hypertensive individuals reached a target blood pressure of < 150/85 mmHg.
| Drug | Study | |
|---|---|---|
| Of proven macrovascular benefit | ||
| ACE inhibitors |
captopril
enalapril
fosinopril
lisinopril
|
CAPP
Syst-EUR
FACET
GISSI-3
|
| Angiotensin receptor blockers | losartan | LIFE |
| Beta-blockers | atenolol | HDS |
| Calcium channel blockers |
amlodipine
felodipine
nitrendipine
|
FACET
HOT
Syst-EURO
|
| Diuretics |
chlorthalidone
hydrochlorothiazide
|
ALLHAT
MIDAS
|
| Of uncertain macrovascular benefit | ||
| Alpha-blockers | doxazosin | ALLHAT |
| Calcium channel blockers |
isradipine
nisoldipine
|
MIDAS
ABCD
|
The UKPDS also examined the efficacy of different antihypertensive agents in reducing macrovascular and microvascular complications in type 2 diabetes (UKPDS Study Group 1998b). In this study, both captopril and atenolol were equally effective in reducing blood pressure and rates of macrovascular endpoints. It was previously perceived that beta-blockers might reduce hypoglycaemic awareness, although in practice this has not proved problematic. In both groups, however, approximately one-third of people required three or more antihypertensive agents. This highlights the fact that first choice of antihypertensive agent in this group is often academic, given that many agents have to be prescribed in a stepwise fashion, often leading to issues with adherence and polypharmacy. However, following the results of the ALLHAT Study, many clinicians would advocate using a thiazide diuretic as a first-line agent in treating hypertension in people with diabetes. Angiotensin-converting enzyme (ACE) inhibitors are also useful in people with diabetes because of their reno- and cardioprotective effects (see below). Calcium channel antagonists were thought to be unsafe in people with diabetes but the results of the HOT Trial, the Systolic Hypertension in Europe (SYST-EUR) Trial and from A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system (ACTION) do not support this hypothesis (Poole-Wilson et al 2004).
PRACTICAL ASPECTS OF BLOOD PRESSURE LOWERING THERAPY IN PEOPLE WITH DIABETES
Based on the evidence described above, everyone with diabetes should have their blood pressure estimated at least once a year. People with a raised systolic blood pressure over 140 mmHg or a raised diastolic blood pressure over 90 mmHg should initially be offered lifestyle measures, but this is unlikely to be adequate by itself and often multiple hypotensive agents will be required. The early use of diuretics and either ACE inhibitors or angiotensin receptor antagonists is suggested; and calcium channel blockers, beta-blockers or alpha-blockers can be added at a later stage if targets are not reached or if patients cannot tolerate other agents.
Alan, presented earlier in case study 8.1 (p. 176), has treated hypertension that is not to target on a combination of a diuretic and a beta-blocker. The beta-blocker should be continued because Alan has established coronary heart disease. An ACE inhibitor should be added both to reduce blood pressure and for maximum cardioprotection (see below). Mumazza (case study 8.2, p. 182) has two blood pressure readings that are raised. If hypertension is confirmed on subsequent readings, an ACE inhibitor would be the drug of first choice, with the addition of a diuretic if targets were not reached.
Case study 8.1
Alan attends his GP’s surgery for routine review. He is 52 years old, works as a taxi driver and takes no regular exercise. He is known to have hypertension and coronary heart disease, having suffered a myocardial infarct 2 years earlier. He is overweight, with a body mass index of 28, and he has hyperlipidaemia with elevation of triglycerides and total cholesterol, discovered when screened following his heart attack. His lipid profile results 18 months previously were: triglycerides 3.7 mmol/L, total cholesterol 7.9 mmol/L and HDL cholesterol 0.6 mmol/L. He has symptoms of peripheral vascular disease, with claudication after walking about 500 yards. Despite advice from his GP, Alan continues to eat a diet high in fat and he smokes 30 cigarettes per day. He drinks less than 10 units of alcohol per week.
Alan’s present medications are: glyceryl trinitrate spray, isosorbide mononitrate, and atenolol for his angina along with bendroflumethiazide for hypertension control, aspirin 75 mg and simvastatin 20 mg.
At this GP attendance, Alan reports that he has noticed increasing tiredness over the past few months and more recently he has been more thirsty. His GP checks a urine sample, which confirms the presence of glycosuria, and a random blood glucose is measured at 18.2 mmol/L. Alan’s blood pressure is measured at 166/94 mmHg. His HbA1c comes back at 8.8%, and his lipid profile shows a total cholesterol of 5.9 mmol/L and HDL cholesterol 0.8 mmol/L.
Case study 8.2
Mumazza, an Asian woman aged 58, has presented to her GP with symptoms of thirst, polyuria and polydipsia. Her body mass index is 28 and blood pressure is 144/92 mmHg. She has no past medical history of note and takes no medications. Her mother had died at the age of 74, diabetes had been diagnosed in the months before her death. Mumazza is a non-smoker and takes no alcohol. Investigations confirmed the clinical suspicion of type 2 diabetes with a random blood glucose of 14.4 mmol/L and an HbA1c of 8.2%. Total cholesterol was 6.1 mmol/L with an HDL cholesterol of 0.9 mmol/L and triglycerides of 4.3 mmol/L. Mumazza was given dietary advice by a dietician, instruction in urine testing and reviewed 8 weeks later. At this review, she had lost weight and home urine testing was all negative. Her HbA1c was down to 6.8% and her blood pressure was 142/92 mmHg. Lipid estimation showed a total cholesterol of 5.2 mmol/L, HDL cholesterol of 1.0 mmol/L and triglycerides were 2.8 mmol/L. Mumazza has no known heart disease and her total cholesterol is only modestly increased. Nonetheless, her cardiovascular risk would be substantially reduced with either atorvastatin 10 mg or simvastatin 40 mg.
NON-PHARMACOLOGICAL MEANS OF REDUCING BLOOD PRESSURE
It seems likely that, although there is no direct evidence that reducing blood pressure through lifestyle measures reduces the risk of CVD, these should be the first line of management in hypertension both in the general population and in people who have diabetes.
Excess body fat is the most important factor causing a predisposition to hypertension (Stamler 1991). Weight loss has been proven in a population with diabetes to reduce both insulin resistance and blood pressure (Su et al 1995) and should be encouraged in people with type 2 diabetes.
There is also a clear linear relationship between alcohol consumption, blood pressure levels and the prevalence of hypertension in populations, and people with diabetes and hypertension should be advised to limit their alcohol intake. In addition, lowering dietary salt intake has been shown to reduce the need for antihypertensive therapy (Whelton et al 1998), and such dietary advice should be offered.
ACE INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS
ACE inhibitors were initially introduced for the treatment of hypertension, including people with diabetes. Subsequent studies demonstrated that ACE inhibitors had additional benefit in reducing the deterioration in renal function in people with type 1 diabetes with diabetic nephropathy. In the field of cardiology, they are now well established as treatment for congestive cardiac failure, improving both morbidity and mortality. An unexpected finding in several of the heart failure studies was that the use of ACE inhibitors was associated in a reduction in acute vascular events, including MIs. This subgroup analysis formed the rationale for the HOPE (Heart Outcomes Protection Evaluation) Study, in which people with existing cardiovascular disease, or people with diabetes with a high cardiovascular risk, were treated with ramipril or placebo (Heart Outcomes Prevention Evaluation (HOPE) Study Investigators 2000). At the end of 5 years, there were significant reductions in stroke, MI and cardiovascular death in the active treatment group.
However, the HOPE study has been severely criticised. Significant differences were seen when blood pressures in the ramipril and control groups were compared, leading some commentators to suggest that the benefit was due to aggressive blood-pressure lowering, similar to levels attained in HOT and UKPDS, in a high-risk group of individuals. Similar results were seen in the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) study (EUROPA Investigators 2003). The blood-pressure differences between perindopril and placebo in the EUROPA Study were if anything greater than those seen in HOPE Study. The EUROPA study thus confirms a cardioprotective and vasculoprotective effect of ACE inhibitors in high-risk individuals, including people with diabetes, but does not exclude blood-pressure lowering as a possible mechanism.
Similar benefits in terms of reductions in cardiovascular outcomes have not been shown using angiotensin receptor antagonists (ARAs). Two studies have examined these drugs in people with type 2 diabetes and established diabetic nephropathy (Brenner et al 2001, Lewis et al 2001). Neither of these studies showed an effect on cardiovascular deaths, although both showed that irbesartan and losartan slowed the rate of renal impairment in type 2 diabetes. Should we therefore treat people with type 2 diabetes with ACE inhibitors for cardioprotection and probable renal protection, or should we treat them with ARAs for renal protection and possible cardioprotection? Until well-designed studies have compared ACE inhibitors with ARAs for cardiovascular outcomes, this cannot be answered. From a practical point of view, however, all people with diabetes with existing cardiovascular disease should be treated with an ACE inhibitor, and ACE inhibitors or ARAs provide a firm base for the treatment of hypertension in people with diabetes without existing cardiovascular disease, as described above.
The role of aspirin in the secondary prevention of cardiovascular disease is well established, as in Alan’s case presented above. There is much evidence to suggest that treatment with low-dose aspirin in people with or without diabetes with angina reduces the risk of vascular events.
The most convincing evidence of the benefits of aspirin in secondary prevention is the large meta-analysis performed by the Antiplatelet Trialists’ Collaboration. This included 29 trials in high-risk people with separate information on diabetes status (Antiplatelet Trialists’ Collaboration 1994). The rate of cardiovascular events, including MI, was reduced from 22% to 18% in people with diabetes, and from 16% to 13% in those without diabetes. Similarly, 20% of the people in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) Study of clopidogrel had prior diabetes, and the benefit if anything was greater in those individuals with diabetes (CAPRIE Steering Committee 1996).
The evidence for the use of aspirin in the primary prevention of cardiovascular disease is not as clear as in Mumazza’s situation (case study 8.2). Two trials published in the 1980s had conflicting results, one suggesting that aspirin was very effective in reducing the risk of first MI, the other demonstrating no benefit (Peto et al 1988, Steering Committee of the Physicians’ Health Study Research Group 1989). In the HOT Trial, people were also treated with 75 mg of aspirin or a placebo in addition to their hypotensive therapy. People who received aspirin had a significant reduction in cardiovascular events. It was reported that the relative benefit was similar in people with diabetes, although the specific data for those with diabetes were not provided.
Again from a practical point of view, all people with diabetes and existing cardiovascular disease should be treated with aspirin or clopidogrel; in a small number of individuals both will be used together following an acute coronary syndrome. Most current guidelines suggest the use of aspirin for primary prevention based on risk-table estimations. However, it is unclear how accurate these charts are at calculating the coronary risk in people with diabetes, given that the tables were based on the Framingham data, in which people with diabetes were underrepresented. New tables are being devised also taking into account novel risk factors, such as presence of microalbuminuria, which were not previously accounted for.
OBESITY
It is clear that abdominal obesity is closely related with diabetes mellitus. The risk of developing type 2 diabetes increases exponentially with increasing BMI. Individuals with a BMI of 21 are at least risk of developing the condition, whereas the relative risk of those with a BMI > 35 is approximately 100 (Bjorntorp 1991).
Obesity has always been associated with coronary heart disease. Until recently, the role of obesity as an independent risk factor remained controversial because of its co-existence with other traditional risk factors such as diabetes, hypertension and dyslipidaemia. However, several long-term studies have demonstrated that obesity should be considered as an independent risk factor for CVD, and these findings have led to the American Heart Association reclassifying obesity as a modifiable risk factor for coronary heart disease (Jousilahti et al 1999, Manson et al 1990).
As well as reducing the risk of developing diabetes, there is now observational evidence that significant weight loss (approximately 10 kg) in an obese individual is associated with dramatic risk reductions in morbidity and mortality and weight loss in people with diabetes has been shown to increase life expectancy. This approach is now being formally tested in a large, prospective study in the US that is projected to last for at least 10 years.
CONCLUSION
Atherosclerotic cardiovascular disease is a major cause of premature morbidity and mortality in people with diabetes. Appropriate treatment with hypoglycaemic agents, antihypertensive therapy including ACE inhibitors, lipid-lowering therapy, and antiplatelet therapy can reduce or delay the onset of macrovascular disease in people with diabetes.
REFERENCES
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, Major outcomes in moderately hypercholesterolaemic, hypertensive patients randomized to pravastatin vs usual care. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT), Journal of the American Medical Association 288 (2002) 2998–3007.
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), Journal of the American Medical Association 283 (2002) 2981–2997.
Antiplatelet Trialists’ Collaboration, Collaborative overview of randomised trials of antiplatelet therapy-I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients, British Medical Journal 308 (1994) 81–106.
P Bjorntorp, Metabolic implications of body fat distribution, Diabetes Care 14 (1991) 1132–1143.
AJB Brady, DJ Betteridge, Prevalence and risks of undertreatment with statins, British Journal of Cardiology 10 (2003) 218–219 .
BM Brenner, ME Cooper, D de Zeeuw, et al. for the RENAAL Study Investigators, Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy, New England Journal of Medicine 345 (2001) 861–869.
CP Cannon, E Braunwald, CH McCabe, et al. for the Pravastatin or Atorvastatin Evaluation and Infection Therapy — Thrombolysis in Myocardial Infaction (22 investigators), Intensive versus moderate lipid lowering with statins after acute coronary syndromes, New England Journal of Medicine 350 (2004) 1495–1504.
CAPRIE Steering Committee, A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE), Lancet 348 (1996) 1329–1339.
HM Colhoun, DJ Betteridge, PN Durrington, et al. on behalf of the CARDS investigators, Primary prevention of cardiovascular disease with atrovastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial, Lancet 364 (2004) 685–696.
R Collins, J Armitage, S Parish, et al., for the Heart Protection Study Collaborative Group, MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial, Lancet 361 (2003) 2005–2016.
B Dahlof, RB Devereux, SE Kjeldsen, et al. for the LIFE Study Group, Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol, Lancet 359 (2002) 995–1003.
G Davey Smith, J Pekkanen, Should there be a moratorium on the use of cholesterol lowering drugs? British Medical Journal 304 (6842) (1992) 431–434.
Diabetes Atherosclerosis Intervention Study Investigators, Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Athersclerosis Intervention Study, a randomised study, Lancet 357 (2001) 905–910.
Diabetes Control and Complications Trial (DCCT) Research Group, Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial, American Journal of Cardiology 75 (1995) 894–903.
JR Downs, M Clearfield, S Weiss, et al., Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of the AFCAPS/TexCAPS Air Force/Texas Coronary Atherosclerosis Prevention Study, Journal of the American Medical Association 279 (1998) 1615–1622.
European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) Investigators, Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease, Lancet 362 (2003) 782–788.
JM Evans, J Wang, AD Morris, Comparison of cardiovascular risk between patients with type 2 diabetes and those who had had a myocardial infarction: cross sectional and cohort studies, British Medical Journal 324 (2002) 939–942.
MJ Garcia, PM McNamara, T Gordon, WB Kannel, Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study, Diabetes 23 (2) (1974) 105–111.
SM Haffner, AS Greenberg, WM Weston, et al., Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus, Circulation 106 (2002) 679–684.
SM Haffner, S Lehto, T Ronnemaa, et al., Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction, New England Journal of Medicine 339 (1998) 229–234.
L Hansson, A Zanchetti, SG Carruthers, et al. for the HOT Study Group, Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial, Lancet 351 (1998) 1755–1762 .
MI Harris, KM Flegal, CC Cowie, et al., Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults: the Third National Health and Nutrition Survey, 1988–1994, Diabetes Care 21 (1998) 518–524.
Heart Outcomes Prevention Evaluation (HOPE) study investigators, Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy, Lancet 355 (2000) 253–259.
Heart Protection Study Collaborative Group, MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial, The Lancet 360 (2002) 7–22.
Hypertension in Diabetes Study (HDS), Hypertension in diabetes study (HDS) I. Prevalence of hypertension in newly presenting type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic complications, Journal of Hypertension 11 (3) (1993) 309–317.
Hypertension in Diabetes Study (HDS), Hypertension in diabetes study (HDS) II. Increased risk of cardiovascular complications in hypertensive type 2 diabetic patients, Journal of Hypertension 11 (3) (1993) 319–325.
Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, The sixth report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure, Archives of Internal Medicine 157 (1997) 2413–2446.
P Jousilahti, E Vartiainen, S Tuomilehto, P Puska, Sex, age, cardiovascular risk factors, and coronary heart disease: a prospective follow-up study of 14 786 middle-aged men and women in Finland, Circulation 99 (9) (1999) 1165–1172.
WB Kannel, DL McGee, Diabetes and cardiovascular disease. The Framingham study, Journal of the American Medical Association 241 (1979) 2035–2038.
H King, RE Aubert, WH Herman, Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections, Diabetes Care 21 (1998) 1414–1431.
In: (Editors: HMJ Krans, M Porta, H Keen, K Staehr Johansen) Diabetes care and research in Europe: the St Vincent declaration action programme. Implementation document, 2nd edn. Guidelines on cardiovascular disease and stroke (1995) World Health Organisation, Copenhagen.
ML Lawson, HC Gerstein, E Tsui, B Zinman, Effect of intensive therapy on early macrovascular disease in young individuals with type 1 diabetes. A systematic review and meta-analysis, Diabetes Care 22 (suppl 2) (1999) B35–B39.
WL Lee, AM Cheung, D Cape, B Zinman, Impact of diabetes on coronary artery disease in women and men: a meta-analysis of prospective studies, Diabetes Care 23 (2000) 962–968.
EJ Lewis, LG Hunsicker, WR Clarke, et al., for the Collaborative Study Group, Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes, New England Journal of Medicine 345 (2001) 851–860.
LH Lindholm, H Ibsen, B Dahlof, et al. for the LIFE study group, Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol, Lancet 359 (2002) 1004–1010.
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group, Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels, New England Journal of Medicine 339 (1998) 1349–1357 .
JE Manson, GA Colditz, MJ Stampfer, et al., A prospective study of obesity and risk of coronary heart disease in women, New England Journal of Medicine 322 (1990) 882–889.
R Peto, R Gray, R Collins, et al., Randomised trial of prophylactic daily aspirin in British male doctors, British Medical Journal 296 (1988) 313–316.
PA Poole-Wilson, J Lubsen, BA Kirwan, et al. on behalf of the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system) investigators, Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial, Lancet 364 (2004) 849–857.
LE Ramsay, B Williams, GD Johnson, et al., Guidelines for management of hypertension: report of the third working party of the British Hypertension Society, Journal of Human Hypertension 13 (1999) 569–592.
NA Roper, RW Bilous, WF Kelly, et al., Cause-specific mortality in a population with diabetes. South Tees Diabetes Mortality Study, Diabetes Care 25 (2002) 43–48.
HB Rubins, SJ Robins, D Collins, et al. for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group, Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol, New England Journal of Medicine 341 (1999) 410–418.
FM Sacks, MA Pfeffer, LA Moye, et al. for the Cholesterol and Recurrent Events Trial investigators, The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels, New England Journal of Medicine 335 (1996) 1001–1009.
Scandinavian Simvastatin Survival Study Group, Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Lancet 344 (1994) 1383–1389.
PS Sever, B Dahlöf, NR Poulter, et al. for the ASCOT investigators, Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial ASCOT-LLA, Lancet 361 (2003) 1149–1158.
J Shepherd, SM Cobbe, I Ford, et al. for the West of Scotland Coronary Prevention Study Group (WOSCOPS), Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia, New England Journal of Medicine 333 (1995) 1301–1307.
J Stamler, Epidemiologic findings on body mass and blood pressure in adults, Annals of Epidemiology 1 (4) (1991) 347–632.
J Stamler, O Vaccaro, JD Neaton, D Wentworth, Diabetes, other risk factors and 12-year cardiovascular mortality for men in the Multiple Risk Factors Intervention Trial (MRFIT), Diabetes Care 16 (1993) 434–444.
Steering Committee of The Physicians’ Health Study Research Group, Final report on the aspirin component of the ongoing Physicians’ Health Study, New England Journal of Medicine 321 (1989) 129–135.
HY Su, WH Sheu, HM Chin, et al., Effect of weight loss on blood pressure and insulin resistance in normotensive and hypertensive obese individuals, American Journal of Hypertension 8 (11) (1995) 1067–1071.
UK Prospective Diabetes Study (UKPDS) Study Group, Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38), British Medical Journal 317 (1998) 703–713.
UK Prospective Diabetes Study (UKPDS) Study Group, Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 39), British Medical Journal 317 (1998) 713–720 .
UK Prospective Diabetes Study (UKPDS) Study Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet 352 (1998) 837–853.
UK Prospective Diabetes Study (UKPDS) Study Group, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34), Lancet 352 (1998) 854–865.
University Group Diabetes Program, A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes mellitus II. Mortality results, Diabetes 19 (suppl 2) (1970) 789–830.
PK Whelton, LJ Appel, MA Espeland, et al., Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). TONE Collaborative Research Group, Journal of the American Medical Association 279 (11) (1998) 839–846.
DL Wingard, EL Barret-Connor, et al., Prevalence of cardiovascular and renal complications in older adults with normal or impaired glucose tolerance or NIDDM. A population-based study, Diabetes Care 16 (7) (1993) 1022–1025.
