Rationale and design of a trial improving outcome of type 2 diabetics on hemodialysis

Rationale and design of a trial improving outcome of type 2 diabetics on hemodialysis. Background Non–insulin-dependent diabetes mellitus dialysis patients have the highest cardiovascular mortality known in any group of patients. Mixed dyslipidemia with moderately elevated low-density lipoprotein (LDL) cholesterol and high levels of triglyceride-rich lipoproteins is common in this condition. It is not known, however, whether patients with type 2 diabetes on dialysis with this form of dyslipidemia derive benefit from lipid-lowering therapy. Recently, drugs have become available that potently lower triglyceride-rich, apoB-containing lipoproteins and thus permit testing of this issue. This is the first trial to address specifically the issue of whether the excessive cardiovascular mortality of patients with type 2 diabetes on dialysis can be lowered by statins. Methods The Die Deutsche Diabetes Dialyse Studie is a prospective randomized placebo-controlled trial that tests the hypothesis that atorvastatin, a hydroxymethyl-glutaryl coenzyme A reductase inhibitor, decreases the rate of cardiovascular mortality and of nonfatal myocardial infarction in patients with type 2 diabetes who have been on hemodialysis treatment for no more than two years. The primary endpoint, cardiovascular mortality, includes fatal myocardial infarction, sudden death, death during coronary intervention, death from heart failure, and other coronary causes. Secondary endpoints comprise overall mortality, nonfatal cardiovascular events, fatal and nonfatal cerebrovascular disease, and the mean percentage change in lipid profile from baseline. The trial enrolls 1200 men and women on hemodialysis for less than two years and with type 2 diabetes at 150 centers throughout Germany. Inclusion criteria are age of 18 to 80 years, low-density cholesterol of 80 to 190 mg/dl (2.1 to 4.9 mmol/liter), and triglyceride levels of less than 1000 mg/dl (11.4 mmol/liter). Patients are randomized to either inactive (placebo) or active (atorvastatin, 20 mg/day) drug therapy. The average duration of follow-up is more than 2.5 years. To protect against a lower than expected rate of events, the trial will be continued until a predetermined fixed number of endpoints occurs in the entire cohort so that the predefined power of the trial will be guaranteed. Conclusions This trial was designed to demonstrate that lipid lowering with atorvastatin will improve life expectancy and quality of life in type 2 diabetics on hemodialysis. The resolution of this question is important because the genesis of vascular lesions in this condition is multifactorial and the precise role of dyslipidemia has not been defined.

[1]  C. Wanner,et al.  Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. , 1999, Kidney international.

[2]  C. Wanner,et al.  Non-insulin-dependent diabetes mellitus and hypertriglyceridemia impair lipoprotein metabolism in chronic hemodialysis patients. , 1999, Journal of the American Society of Nephrology : JASN.

[3]  A. Collins,et al.  Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. , 1998, The New England journal of medicine.

[4]  T. Shoji,et al.  Intermediate-density lipoprotein as an independent risk factor for aortic atherosclerosis in hemodialysis patients. , 1998, Journal of the American Society of Nephrology : JASN.

[5]  D. Serur,et al.  Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients. , 1998, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[6]  F. Kronenberg Homocysteine, lipoprotein(a) and fibrinogen: metabolic risk factors for cardiovascular complications of chronic renal disease , 1998, Current opinion in nephrology and hypertension.

[7]  E. Ritz,et al.  Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients: a prospective study in 412 subjects. , 1997, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[8]  F. Kronenberg,et al.  Apolipoprotein B, fibrinogen, HDL cholesterol, and apolipoprotein(a) phenotypes predict coronary artery disease in hemodialysis patients. , 1997, Journal of the American Society of Nephrology : JASN.

[9]  Mai-Szu Wu,et al.  Poor pre-dialysis glycaemic control is a predictor of mortality in type II diabetic patients on maintenance haemodialysis. , 1997, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[10]  S. Olson,et al.  Renal Dysfunction Does Not Alter the Pharmacokinetics or LDL‐Cholesterol Reduction of Atorvastatin , 1997, Journal of clinical pharmacology.

[11]  Terje R Pedersen,et al.  Cholesterol Lowering With Simvastatin Improves Prognosis of Diabetic Patients With Coronary Heart Disease: A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S) , 1997, Diabetes Care.

[12]  J. Himmelfarb,et al.  Reassessing the cardiac risk profile in chronic hemodialysis patients: a hypothesis on the role of oxidant stress and other non-traditional cardiac risk factors. , 1997, Journal of the American Society of Nephrology : JASN.

[13]  M Nauck,et al.  Quantitative determination of high-, low-, and very-low-density lipoproteins and lipoprotein(a) by agarose gel electrophoresis and enzymatic cholesterol staining. , 1995, Clinical chemistry.

[14]  D. Sprecher,et al.  Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[15]  R. Heyka,et al.  Lipoprotein(a) Is an Independent Risk Factor for Cardiovascular Disease in Hemodialysis Patients , 1992, Circulation.

[16]  L. Niskanen,et al.  5-year incidence of atherosclerotic vascular disease in relation to general risk factors, insulin level, and abnormalities in lipoprotein composition in non-insulin-dependent diabetic and nondiabetic subjects. , 1990, Circulation.

[17]  P. Attman,et al.  Serum apolipoprotein profile of patients with chronic renal failure. , 1987, Kidney international.

[18]  E. Ritz,et al.  Serum lipids predict cardiac death in diabetic patients on maintenance hemodialysis. Results of a prospective study. The German Study Group Diabetes and Uremia. , 1993, Nephron.