Evidence for the Treatment Effect of Dyslipidaemia

The term dyslipidaemia covers many patterns of lipid changes from the normal values. The most common pattern in type 2 diabetic patients is elevated serum triglyceride levels and decreased serum HDL cholesterol levels. Evidence for a positive treatment effect of dyslipidaemia in type 2 diabetes mellitus comes from post-hoc analyses of diabetic patients participating in larger secondary intervention studies comprising patients with known cardiovascular disease. Since the risk of a first myocardial infarction in patients with type 2 diabetes is the same as the risk for a re-infarction in a nondiabetic subject, it seems reasonable to extrapolate from the overall results from these studies.

The Scandinavian Simvastatin Survival Study (4S) included 4,444 patients with a recent myocardial infarction or angina pectoris and an increased fasting serum-cholesterol level in the range 5.5–8.0 mmol/l. Of these, 202 had diabetes. Patients were randomized to treatment with placebo or simvastatin. The me- dian follow-up time for the diabetic patients was 5.3 years. A significant risk reduction of 55% with lipid-lowering drug therapy was seen for major cardiovascular events, while no effect was seen on total and cardiovascular mortality. The number needed to treat to prevent one major cardiovascular event during a 5-year period was 4.8.

The Cholesterol and Recurrent Events (CARE) trial was also a secondary intervention study including 4,159 patients with a fasting serum-cholesterol level =6.2 mmol/l, thus examining the effect of cholesterol-lowering therapy in patients with cardiovascular disease and a fasting serum cholesterol level within the normal range. 586 diabetic patients participated in the study. A borderline significant risk reduction of 25% was found for major cardiovascular events (death from cardiovascular disease or nonfatal myocardial infarction, coronary artery bypass grafting, or percutaneous transluminal coronary angi- oplasty). No effect on mortality was found.

The Helsinki Heart Study was a primary intervention trial enrolling both nondiabetic and diabetic patients with high fasting serum non-HDL cholesterol levels. The overall result was a significant 34% reduction in the risk for cardiovascular disease with treatment with a fibrate (gemfibrozil), however the 38% risk reduction found in a subanalysis in the type 2 diabetic population was not significant.

Table 3. Various type of drug therapy of dyslipidaemia LDL cholesterol Triglyceride lowering

Combined lowering

dyslipidaemia Drug of choice Statins

Statins Combination

Fibrates

Resins Nicotinic acid or statins Fibrates

It is important to repeat that the evidence for a positive treatment effect of dyslipidaemia is based on post-hoc analyses from secondary intervention

studies in mixed populations. No primary intervention trials in type 2 diabetic patients have been published.

Treatment Approach for Dyslipidaemia Patients with dyslipidaemia should be examined in order to exclude sec-

ondary dyslipidaemia (e.g. renal disease, hypothyroidism), in which case the underlying cause should be treated.

Behaviour Modification Diet should be optimized with a reduction in dietary content of saturated

fatty acids. Weight loss and increased physical activity will lead to decreased serum triglyceride and increased fasting serum HDL cholesterol levels. Max- imal effect of this approach is a reduction in fasting serum LDL cholesterol of 0.4–0.6 mmol/l.

Pharmacological Therapy Glucose-lowering therapy reduces both serum levels of triglycerides and

to a lesser extent serum LDL cholesterol levels, thus optimizing glycaemic control is prior to treatment with specific dyslipidaemic drugs. The serum LDL cholesterol level for initiation of drug therapy is still debated, but the more risk factors the lower level. In high-risk patients the limit is 2.6 mmol/l. Various types of drug therapy for the different forms of dyslipidaemia are shown in table 3.

Evidence for theTreatment Effect of Microalbuminuria

Microalbuminuria (urinary albumin excretion rate in the range 30–300 mg/

24 h) is an important risk factor for the development of both micro- and macrovascular disease. It is known that both the treatment of hyperglycaemia 24 h) is an important risk factor for the development of both micro- and macrovascular disease. It is known that both the treatment of hyperglycaemia

19 in the placebo group developed diabetic nephropathy. This difference could not be attributed to differences in glycaemic control, body mass index, or blood pressure values, which were similar in both groups throughout the study period. Reciprocal plasma creatinine levels as a measure for renal function decreased significantly in the placebo group as a sign of deterioration of kidney function but remained stable in the enalapril group.

Treatment Approach for Microalbuminuria Since both the treatment of hyperglycaemia and hypertension decreases

urinary albumin excretion rate, these treatment modalities should be optimized. In case of increased albumin excretion rate despite sufficient antihyperten-

sive treatment without an ACE inhibitor, treatment with this drug should be initiated. Treatment with an ACE inhibitor should be started in a low dose and gradually increased, especially in patients with normotension because of the risk for orthostatic hypotension.

Evidence for the Treatment Effect of Aspirin

The beneficial effect of low-dose acetylsalicylic acid as secondary prevention of cardiovascular disease is well established in both the diabetic and

nondiabetic population. The previously described HOT trial also examined the effect of treatment with acetylsalicylic acid in patients with hypertension. Of the 18,790 patients, half were randomized to 75 mg aspirin daily and the other half to placebo. No specific data for the diabetic subgroup have been published. For the whole study population a significant 15% reduction in the risk for major cardiovascular events was seen, primarily due to a 36% reduction

in the risk for myocardial infarction. Fatal bleeds were equally common in the two groups, but nonfatal bleeds (primarily gastrointestinal) were significantly more frequent among patients receiving acetylsalicylic acid than in those receiving placebo.

The US Physicians Health Study was a primary prevention trial in which

a low-dose aspirin regimen (375 mg every other day) was compared with placebo in 22,071 male physicians. There was an overall significant 44% risk reduction for myocardial infarction in the acetylsalicylic acid-treated group, a low-dose aspirin regimen (375 mg every other day) was compared with placebo in 22,071 male physicians. There was an overall significant 44% risk reduction for myocardial infarction in the acetylsalicylic acid-treated group,

Who Should be Treated with Aspirin Primary prevention: Consider aspirin therapy as a primary prevention

strategy in type 2 diabetic subjects with at least one of the following criteria: family history of coronary artery disease; cigarette smoking; controlled hypertension; micro- or macroalbuminuria.

Secondary prevention: Aspirin should be used as a secondary prevention strategy in all diabetic patients with evidence of large vessel disease. People with aspirin allergy, bleeding tendency, anticoagulant therapy, on- going or recent gastrointestinal bleeding, and clinically active hepatic disease are not to be treated with aspirin. Therapy should be given as enteric-coated aspirin in doses of 75–325 mg/day.

Evidence for the Treatment Effect of Dyslipidaemia