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Lessons learnt from the 4D trial
Insights
In type 2 diabetes patients on hemodialysis, atorvastatin did not significantly reduce cardiovascular events. Statin therapy is not recommended for this high-risk group at this time.
Area of Science:
- Nephrology
- Cardiology
- Clinical Trials
Background:
- Renal dysfunction significantly increases cardiovascular disease (CVD) risk.
- Type 2 diabetes mellitus (T2DM) patients on maintenance hemodialysis represent a particularly high-risk population for CVD.
- Current CVD management strategies are being investigated in this vulnerable group.
Purpose of the Study:
- To evaluate the efficacy of atorvastatin in reducing cardiovascular outcomes in T2DM patients undergoing maintenance hemodialysis.
- To investigate the role of factors beyond atherogenic lipoprotein phenotype in CVD risk in this patient population.
Main Methods:
- The 4D study was a randomized, placebo-controlled trial.
- 1255 T2DM patients on maintenance hemodialysis received either atorvastatin (20 mg/d) or a placebo.
- Cardiovascular outcomes were monitored over a median follow-up of 4 years.
Main Results:
- Atorvastatin showed an 8% relative risk reduction in cardiovascular events, which was not statistically significant (95% CI, 0.77-1.10; P=0.37).
- The study observed a high incidence of cardiovascular events and a 24% overall cardiovascular mortality.
- A higher rate of fatal strokes was noted in the atorvastatin group, and the drug's effect on the primary endpoint was non-significant.
Conclusions:
- Initiating statin therapy with atorvastatin in T2DM patients on hemodialysis is not recommended currently due to non-significant efficacy and safety concerns.
- The high CVD risk in this population likely stems from factors other than solely an atherogenic lipoprotein phenotype.
- Statin therapy may be more beneficial if implemented earlier in the course of vascular damage progression.
Abstract:
Renal dysfunction alters the pathogenesis of cardiovascular disease (CVD) profoundly conferring a very high-risk to the patients. Currently strategies are developed to combat CVD and clinical studies test a number of hypothesis. In this setting the results of the 4D study, comparing atorvastatin with placebo on cardiovascular outcomes in 1255 type 2 diabetic patients on maintenance hemodialysis, came as a great and unsuspected surprise. After a median follow-up of 4 years atorvastatin (20 mg/d) decreased the relative risk by 8% (95% confidence interval, 0.77-1.10; P=0.37) despite a high number of cardiovascular events and an overall 24% cardiovascular mortality. This indicates, that the risk in type 2 diabetic patients on hemodialysis origins from factors other than an atherogenic lipoprotein phenotype alone. Due to non-significant effects of atorvastatin on the primary endpoint and the different quality of such endpoints in dialysis patients as well as an unexplained higher rate of fatal strokes in atorvastatin treated patients we do not recommend to initiate statin treatment in patients with type 2 diabetes mellitus undergoing hemodialysis therapy at the present time. Statin therapy should be implemented earlier during the course of progressive vascular damage.
