The authors suggested that the potential mechanism for increased MI in the rosiglitazone group could be its known effects on increasing low-density lipoproteins (LDL), precipitating congestive heart failure and reducing hemoglobin levels.
Rosiglitazone is one of two peroxisome proliferation activated receptor y (PPAR-y) agonists licensed for use in the United States; the other is pioglitazone. The third drug was troglitazone; it was taken off the market in March of 2000 due to hepatotoxicity.
The PPAR-y agonists decrease plasma glycemia by increasing insulin sensitivity in the peripheral tissues. These drugs have complex physiologic effects in activating and suppressing multiple genes, with most target genes being unknown. The observed side effects with rosiglitazone are not necessarily a class effect. Pioglitazone showed a trend toward reducing triglycerides and cardiovascular events, including MI and CVA, in a prospective, randomized trial called Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE).
This meta-analysis precipitated an interim analysis of the ongoing Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial.3 The RECORD trial is a randomized, open-label, multicenter, non-inferiority trial of 4,427 patients; 2,220 received add-on rosiglitazone, and 2,227 received a combination of metformin plus sulfonylurea (control group). The primary end point was hospitalization or death from cardiovascular causes. Interim findings were inconclusive for the rosiglitazone group. There was also no evidence of any increase in death from cardiovascular causes or all causes. However, rosiglitazone was found to be associated with an increased risk of congestive heart failure. The data were insufficient to determine whether the drug was associated with increased MI risk.
This important meta-analysis raises concerns about the association of rosiglitazone with cardiovascular events—but do not consider it definitive. For now, patients with comparable alternatives to rosiglitazone (indeed all patients on this medication) should be advised of the undetermined safety concerns. For those who consider rosiglitazone a compelling choice, abrupt discontinuation on the basis of this study may be premature.
Finally, we need to remain cognizant of the proven negative side effects of rosiglitazone—it increases fracture risks in women, precipitates congestive heart failure, increases LDL, and decreases hemoglobin levels. We should consider alternative anti-hyperglycemic agents in selected patients at risk until there are solid data from large randomized control trials with rosiglitazone that pre-empt its use altogether.
References
- Gerstein HC, Yusuf S, Bosch J, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet 2006 Sep 23; 368(9547):1096-1105.
- Kahn SE, Haffner SM, Heise MA, et al; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006 Dec 7;355(23):2427-2443.
- Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiac outcomes and regulation of glycemia in diabetes (RECORD): study design and protocol. Diabetologia. 2005;48:1726-1735.
Statins and Sepsis in Dialysis Patients
Gupta R, Plantinga LC, Fink NE, et al. Statin use and hospitalization for sepsis in patients with chronic kidney disease. JAMA. 2007 Apr 4;297(13):1455-1464.
Epidemiological data has revealed an increase in the rate of sepsis in the U.S. during the past two decades.1 In individuals with chronic kidney disease who are on dialysis, sepsis is a significant cause of morbidity and mortality. Various studies have looked at risk factors associated with septicemia in patients with chronic kidney disease; however, no preventive treatments have been identified.