Original article:
Bezafibrate and simvastatin combination therapy for diabetic dyslipidaemia: efficacy and safety. Gavish D, Leibovitz E, Shapira I, Rubinstein A. J Intern Med 2000; 247: 563–9.

Summary
The authors determined the efficacy and safety of a statin-fibrate combination in an open 21-month trial in which 148 Type 2 diabetic patients first received a single drug for 6 months and then a combination of the two for 1 year. The drugs used were slow-release bezafibrate (400 mg/day) and simvastatin (20 mg/day). The study was performed in three clinics.
The combination treatment resulted in a pronounced fall in plasma triglycerides (42%), total cholesterol (23%), LDL cholesterol (29%), lipoprotein(a) levels (19%) and fibrinogen (10%), whilst HDL cholesterol increased by 25% (Fig. 1). The cardiovascular event rate was significantly reduced from 9.5% during the first 6 months of the study to less than 2% during the last year of the study when the patients were receiving both drugs. Two patients developed myopathy when on the combined regimen. Plasma creatinine phosphokinase levels doubled (but remained within the normal range) in most of the patients on combination therapy, compared with only a mild increase in patients receiving single medication.

Fig. 1: Percentage change from baseline in risk factors: triglycerides (TG), total cholesterol (Chol), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C) and creatinine phosphokinase (CPK).

Comment
This is an interesting study performed on dyslipidaemic Type 2 diabetic patients. The main finding was that the combination of simvastatin and bezafibrate was more efficacious than as a single medication for the treatment of diabetic dyslipidaemia. As the authors state, ‘information on the effect of combination medication in patients with diabetic dyslipidaemia together with high triglycerides and total cholesterol levels is sparse’. Therefore, their study was justified and necessary, especially since diabetes mellitus represents a major risk for cardiovascular disease. Their finding that the combination therapy resulted in a greater reduction in increased lipids in comparison with each single medication is important. Even more important is the fact that the cardiovascular event rate was significantly reduced from 9.5% during the first 6 months to less than 2% during the last year of the study when the patients were receiving both medications. Although this finding might well be due to the combination treatment itself, there is another possible explanation. It could be that these diabetic hyperlipidaemic patients presented an early and accelerated rate of atherosclerosis which may by itself have led to an increased rate of cardiovascular events. Thus, it could be that the patients were practically all affected by the atherosclerotic process during the first 6 months of observation, irrespective of the type of treatment. In this case, the remaining patients would be relatively ‘resistant’ to the atherosclerotic process and this might explain the reduced rate of cardiovascular events at this stage. It would therefore give the impression that the reduced rate resulted from the change of treatment from a single to a combination of antilipidaemic medications and not the result of the natural course of the disease per se.
As regards the study design, it would have been better, to avoid any bias due to different doctors at the different clinics, if the patients in the three participating clinics had been divided into two subgroups in each clinic (one subgroup starting with bezafibrate and the other with simvastatin) instead of the patients of one clinic starting with bezafibrate and the patients of the other two clinics with simvastatin.
It is also worth noting that although the percentage of myopathy during the combined treatment was very small, we must nevertheless acknowledge the seriousness of this side effect. It must also be emphasized that these drugs should be avoided in the presence of even a slight degree of renal failure.
Some further points concerning drug treatment of diabetic hyperlipidaemia are also worth noting in relation to this interesting article. One point of interest is a recent paper showing that bezafibrate reduces blood glucose in Type 2 diabetes [1]. It has also been shown that bezafibrate administration to Type 2 diabetic subjects results in a reduction in postprandial triglyceride-rich lipoprotein concentrations [2]. These lipoproteins are considered to be highly atherogenic. On the other hand, simvastatin by itself reduced the rate of coronary events in patients with diabetes or impaired fasting glucose levels [3]. This improvement, which also included a reduction in coronary mortality, was generally clear after an average 5.4 years of treatment. Thus, it could be expected that the rate of improvement after a combination of bezafibrate and simvastatin (as Gavish et al. suggest) might be even more pronounced after a substantially longer period of administration. Finally, it would have been interesting if in the present study other fibrinogen coagulation function tests had been included, especially those indicating activation of the coagulation cascade (F1 and F2 and thrombin-antithrombin complex) or tests indicating reduced fibrinolytic activity (plasminogen activator inhibitor-1), since it has been shown that 6 months’ therapy with bezafibrate resulted in a reduction in fluorogenic prothrombin time (a useful test for detecting hypercoagulability) [4].

References
1. Ogawa S, Takeuchi K, Sugimura K et al. Bezafibrate reduces blood glucose in type 2 diabetes mellitus. Metabolism 2000; 49: 331–4.
2. Attia N, Durlach V, Roche D et al. Post-prandial metabolism of triglyceride-rich lipoproteins in non-insulin-dependent diabetic patients before and after bezafibrate treatment. Eur J Clin Invest 1997; 27: 55–63.
3. Haffner SM, Alexander CM, Cook TJ et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1999; 159: 2661–7.
4. Yoshinari M, Yamamoto M, Waklsaka M et al. Effect of bezafibrate on hypercoagulability assessed by fluorogenic prothrombin time in hyperlipidemic patients with non-insulin-dependent diabetes mellitus. Thromb Res 1997; 86: 443–51.

Summary and Comment:
N. Katsilambros, Athens, Greece