Treatment with pioglitazone might help lower the risk of cardiovascular events in patients with chronic kidney disease, the results of a large study suggest.
“CKD, as defined by a glomerular filtration rate of less than 60 mL/min per 1.73 m
The study, by Dr. Christian A. Schneider of the University of Cologne (Germany), and his associates, was funded by Takeda Pharmaceutical Co., which makes Actos (pioglitazone). All of the authors had potential conflicts of interest involving several pharmaceutical companies.
They assessed the effect of CKD on cardiovascular outcomes using data from the Prospective Pioglitazone Clinical Trial in Macrovascular Events, which compared the effects of the thiazolidinedione pioglitazone with placebo on cardiovascular outcomes in patients with diabetes and a history of macrovascular disease. A total of 5,238 patients aged 35–75 years with type 2 diabetes and documented evidence of macrovascular disease were enrolled in the trial.
Patients were randomly assigned to receive pioglitazone (2,605) or placebo (2,633), in addition to their existing glucose-lowering and cardiovascular medications. Pioglitazone was administered at 15 mg/day for the first month, 30 mg/day for the second month, and 45 mg/day for the third month. At baseline, serum creatinine was measured. Urinary albumin concentration was measured locally at the beginning and end of the study. Blood samples were collected for creatinine measurement to observe the natural history of renal disease.
The primary end point was time from randomization to the composite end point of all-cause mortality, nonfatal myocardial infarction (including silent MI), stroke, acute coronary syndrome, coronary/carotid arterial intervention, leg revascularization, or amputation above the ankle. The secondary end point was time to the first event of all-cause mortality, MI (excluding silent MI), and stroke (J. Am. Soc. Nephrol. 2008;19[1]:182–7).
Glomerular filtration rate data were available for 5,154 patients. CKD was defined as a GFR less than 60 mL/min per 1.73 m
In patients with CKD, the incidence of the primary end point was 28%, compared with 20% in patients without the disease. The incidence of the secondary end point was 18% in patients with CKD, compared with 12% in those without. More patients with CKD died of any cause (11%) than did those without the disease (6%).
“Multivariate analysis showed the presence of CKD was an independent risk factor for the primary composite end point,” the researchers wrote.
Among patients with CKD, 24% of those on pioglitazone met the primary end point, compared with 31% of the placebo group. Likewise, fewer patients on pioglitazone (15%) met the secondary end point, compared with those on placebo (21%). All-cause mortality rates were 8% for the pioglitazone group, compared with 14% for the placebo group. Overall, in the group with CKD, “there was a nonsignificant 25% risk reduction for pioglitazone relative to placebo for the primary end point and a significant 34% relative risk reduction for the secondary end point,” the investigators wrote.
In comparison, in patients without CKD, 19% on pioglitazone met the primary end point, compared with 20% in the placebo group. Similar results were seen for the secondary end point—11% of those on pioglitazone versus 12% of those on placebo. All-cause mortality was 6.0% for those on pioglitazone, compared with 5.7% for placebo.
In addition, during the mean 3-year treatment period, GFR for patients with CKD declined by 5.4 and 2.7 mL/min per 1.73 m
The authors offered possible mechanisms for the increased risk of cardiovascular events with CKD. First, CKD often coexists with other cardiovascular risk factors. Second, “impaired kidney function is associated with elevated markers of inflammation” and other cardiovascular risk factors. Third, patients with renal disease are less likely to receive efficacious therapies to prevent cardiovascular disease.
But Dr. David M. Nathan, director of the Diabetes Center at Massachusetts General Hospital, in Boston, and professor of medicine at Harvard Medical School, criticized the analysis, noting that the PROactive study on which it was based was controversial. One of the criticisms of that study is that undue emphasis was given to a secondary end point, which contrasted with the results of the prespecified primary end point (BMJ 2005;331:836–8). He said GFR declined by a greater degree in patients on pioglitazone than in those on placebo and that more patients in the pioglitazone group who did not have CKD at baseline went on to develop CKD, compared with their placebo counterparts.
The authors noted study limitations: Data were collected prospectively, but the analysis was done retrospectively; and treatment randomization was not stratified by CKD.
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