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Lipids in Diabetes Study



Background

The number of people world wide with diabetes is predicted to double to 221 million by the year 2010. In industrialised countries, one in three people die from heart disease and one in six from strokes. In people with diabetes the risk is two to four times greater. Of the 5102 patients with newly diagnosed type 2 diabetes recruited into the UK Prospective Diabetes Study (UKPDS), 59% of deaths were from cardiovascular disease. Analysis showed that potentially modifiable risk factors for cardiovascular disease in these patients were a raised LDL cholesterol, a low HDL cholesterol, hyperglycaemia, hypertension and smoking. The results of the UKPDS glucose and blood pressure intervention arms, published in September 1998, showed conclusively that improved blood pressure control can reduce cardiovascular risk with a similar, non-significant,trend for improved blood glucose control.

Lipid lowering therapy has been shown to reduce the risk of cardiovascular events, in people without diabetes, in both primary and secondary prevention studies. However, no lipid lowering trials involving substantial numbers of people with diabetes have been reported and there was no lipid intervention arm in the UKPDS. Whilst people with diabetes usually have total cholesterol levels similar to those found in the general population, they tend to have higher LDL cholesterol (particularly small dense LDL) and lower HDL cholesterol levels with elevated triglyceride values.

The evidence available from the small numbers of people with diabetes included in the Helsinki Heart Study, AFCAPS/TexCAPS and WOSCOPS suggests that lipid-lowering therapy is worthwhile for secondary prevention and possibly primary prevention. The higher absolute risk for cardiovascular disease associated with diabetes suggest that lipid lowering therapy may be of greater benefit in diabetic individuals and should certainly be considered where the annual coronary event risk is greater than 3%. Given the characteristic dyslipidaemia seen in diabetes, fibrates would be a logical therapeutic choice although they must be used with caution if renal function is impaired. Nicotinic acid may affect glycaemic control whilst resins can exacerbate hypertriglyceridaemia. Statins are well tolerated and do not affect glycaemic control but may have less effect on triglyceride levels.

Subject Selection

Subjects will be recruited from hospital based diabetic clinics and via local general practitioner diabetic registers who:

Two-by-Two Factorial Randomisation

A minimum of 5000 eligible subjects will be randomised to double-blind, fixed-dose therapy with:

and, simultaneously, to:

Cerivastatin
Arm

Fenofibrate
Arm
1,250
cerivastatin
fenofibrate
1,250
placebo
fenofibrate
2,500
fenofibrate
1,250
cerivastatin
placebo
1,250
placebo
placebo
2,500
placebo

2,500
cerivastatin
2,500
placebo
5,000
subjects
in total

The factorial design makes for a more efficient study and allows for separate assessment of the cerivastatin and fenofibrate interventions, with minimal effects on non-drug study costs and sample size requirements. In addition, the possible additional benefits or risks of combined therapy can be investigated. Of those randomised, 25% will be allocated cerivastatin alone, 25% fenofibrate alone, 25% both cerivastatin and fenofibrate and 25% will receive only placebo therapy. The main analyses for the cerivastatin arm will be performed comparing the 2,500 subjects allocated cerivastatin with the 2,500 allocated matching placebo, irrespective of their fenofibrate allocation. Similarly, the fenofibrate arm analyses will compare fenofibrate with placebo, irrespective of cerivastatin allocation.

Study Medication

Cerivastatin (Lipobay), a third generation HMG-CoA reductase inhibitor, is 100 times more potent than fluvastatin and does not interact with digoxin, warfarin or erythromycin. It has been shown to reduce mean LDL cholesterol levels by circa 33% at a dose of 0.3 mg per day with a concomitant reduction in mean triglyceride levels of 9 to 14%. The LDS will use a dose of 0.4 mg per day.

Fenofibrate (Lipantil), a clofibrate analogue, can reduce mean total cholesterol levels by 20 to 25% and mean triglyceride levels by as much as 40 to 60% at a dose of 300 mg per day. The LDS will use micronised fibrate at a dose of 200 mg per day. The lipid changes to be expected using this dose are expected to equate to a circa 25% reduction in cardiovascular risk.

Side effects with either study drug are generally minor and adverse effects rare. Although data available suggest that the risks of myositis and rhabdomyolysis when cerivastatin and fenofibrate are given together are slight, all subjects will have four-monthly plasma creatine phosphokinase and alanine transaminase measurements.

Five Year Followup

Subjects will be treated for a minimum of five years and followed until closeout of their clinical centre i.e. maximum follow-up for any one subject will be 7.1 years. Subjects who discontinue study medication will continue to be followed up until study closeout if at all possible. Lipid profiles will be measured at each visit during the first year and annually thereafter. Additional annual measurements will include glycosylated haemoglobin, urinary albumin, blood pressure, full blood count and digital electrocardiography. Subject questionnaires will be used to collect quality of life and health economic resource utilisation data.

Study Management

The Lipids in Diabetes Study is an academic, investigator led trial designed, run and analysed by the University of Oxford Diabetes Trials Unit.

Funding

The trial is funded by an educational grant from Bayer.