Electronic ISSN 2287-0237

VOLUME

DRUG INDUCED CARDIO-VASCULAR EVENTS

FEBRUARY 2011 - VOL.1 | CLINICAL PRACTICE

Before drugs are launched on the market, studies should have already proven that these drugs are efficient in treatment of specific conditions, by trials in vivo, on experimental animals and then finally on humans.

However, premarketing clinical trials are limited and not neces- sarily homogenous. Limitations, such as the short period of drug administration, or emphasis only in the efficiency of the drug may have caused less attention to be paid towards patient safety or potentially undesirable side effects, such as water retention or worsening of patients’ cardiovascular condition. These drugs have been popularly prescribed to many patients, especially in the premarketing period. However, sometimes, unexpected and undesirable symptoms arise, and increase in number, to the point where the drug may be disapproved by the FDA or  similar  agency. Some studies illustrate the undesirable side effects of drugs, whereby increased numbers of cardiovascular complications are occurring to people taking the drug. This report will collate some of the data relating to two drugs which are facing controversy in the market recently, namely Sibutramine and Rosiglitazone.

Sibutramine, an anti-obesity agent, has a dual effect, inhibiting norepinephrine and serotonin reuptake. These reduce appetite and promote weight loss. Sibutramine improves insulin resistance, glucose metabolism, dyslipidemia, and inflammatory markers. Moreover, Sibutramine exerts a favorable effect on some surro- gate cardiovascular endpoints, such as reduction of left ventricular hypertrophy and improvement of endothelial dysfunction. In some studies, Sibutramine has been shown to decrease uric acid level and reduce high- sensitivity C-reactive protein (hs-CRP).

A good cardiovascular safety profile was shown in controlled trials over 1-2 years as well as in several observation studies. However, since 2002, several cardiovascular adverse effects have been reported. Sibutramine Cardiovascular and Diabetes Outcome Study (SCOUT) was a randomized, double-blind, placebo-controlled, multicenter trial that was conducted from 2003 through 2009. The objective of this study was to evaluate the long-term effects of Sibutramine treatment, combined with diet and exercise on the rates of cardiovascular events and cardiovascular death among subjects who were at high cardiovascular risk.

All the subjects received Sibutramine during a 6-week, single-blind, lead- in period, then underwent random  assignment  in  a  double-blind  to  Sibutramine or placebo. Subjects who were enrolled in the study were classified into their appropriate cardiovascular risk groups: diabetes only (DM- only group), cardiovascular disease only (CV- only group), or both (CV-DM group). The primary outcome was the time from randomization to the first occurrence of a primary outcome event. The primary outcome events were nonfatal myocardial infarction, nonfatal stroke, cardiac arrest, and cardiovascular death.

The result showed that Sibutramine group had a 16% increased risk, relative to the placebo group (HR=1.16; 95% CI 1.03, 1.31; p=0.02). The individual rates of nonfatal myocardial infarction and stroke were also increased in the Sibutramine group (HR for nonfatal MI,  1.28;  95%  CI,  1.04  to  1.57;  p=0.02,  HR  for nonfatal stroke, 1.36; 95% CI, 1.04 to 1.77; p=0.03). The rates of cardiovascular death and death from any cause were not significantly different. An analysis of the three cardiovascular- risk groups showed the increases in nonfatal primary outcome events were seen inthe CV- only and CV-DM groups but not in the DM-only group. The result of this and other studies study encouraged the man- ufacturer to voluntarily withdraw Sibutramine from the Australia, Canada and the U.S. market in October 2010.

Rosiglitazone is an oral antidiabetic agent and a member of the group of drugs known as thiazolidinedio- nes. Rosiglitazone specifically targets insulin resistance, which is thought to be central to the development of type 2 diabetes as well as dyslipidemia and hyperten- sion in patients with diabetes mellitus. The first indica- tions that of rosiglitazone increased the risk of myocar- dial infarction and cardiovascular death were published in 2007. The trials were divided between 3 categories. The first group included five of the studies submitted to the US FDA for the March 22, 1999. The second group included 35 studies, primarily identified from the GlaxoSmithKline clinical trial registry. And the last group included two studies from large, recently published trials, namely the Diabetes Outcome Prevention trial (ADOPT) and Diabetes Reduction Assessment with Ramipiril and Rosiglitazone Medi- cation (DREAM). The results showed that the odds ratio for myocardial infarction was 1.43 (95% CI1.03, 1.98; p=0.03) and the odds ratio for cardiovascular death was 1.64 (95% CI0.98, 2.74; p=0.06). The result of this study raised questions concerning the safety of thiazoli- dinedione group of drugs, especially rosiglitazone.

Later rosiglitazone was evaluated for Cardiac Outcome and Regulation of Glycemia in Diabetes (RECORD which was an open-label, randomized nonin- feriority trial. The primary endpoint was unconventional, cardiovascular hospitalization or cardiovascular death. That study was limited by low event rates, which resulted in insufficient statistical powers of detection The majority of results were concordant with the first meta-analysis study; the rosiglitazone group demonstrated increased risk for myocardial infarction but not cardiovascular or all-cause mortality. The US FDA did not withdraw rosi- glitazone from the market but it has cancelled ongoing phase clinical IV trials of Thiazolidinedione Intervention (00879970) at the present time. The phase II and phase III study indicated increased cardiovascular mortality, myocardial infarction and stroke including hospitaliza- tion for acute coronary syndrome and urgent revascular- ization procedures as a result of taking the drug. The US FDA ordered the manufacturer to demonstrate that the antidiabetic drugs therapy to treat type 2 diabetes will not increase cardiovascular risk. The European Union recommended that rosiglitazone be withdrawn  from  the EU market in September 2010.

Nowadays, we have many new drugs in the market; despite their apparent efficacy in treatment management, however, side effects have not necessarily been seriously investigated during premarketing. Serious reactions to the drug appear later on, which sometimes results in the drugs being withdrawn. Sibutramine was available for prescription since more than 10 years and has now been withdrawn in Western markets by the manufacturer; unlike the European Medicines Agency, the US FDA has not yet withdrawn Rosiglitazone from the market but the present clinical applications have shown it to increase the risk of cardiovascular events.

New antidiabetic agents need to be demonstrably free of causing patients increased risk of cardiovascular events.