This is one of the biggest controversies medical science has seen in recent times. There have been reports that the popular Anti Diabetic Drug ‘Rosiglitazone’ increases the risk of Myocardial Infarction. Dr. Om Lakhani analyzes the background and the current status of this controversy.
Sources
- “The Rosiglitazone Controversy: Indian Perspective” : V Mohan, S. Joshi: Editorial JAPI Volume 55: July 2007
- Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-71.
- Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; June 5:[Epub ahead of print]
- Krall RD. Cardiovascular safety of rosiglitazone. Published online
- Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJV. For the RECORD Study Group. Rosiglitazone Evaluated for Cardiovascular Outcomes - An Interim Analysis. N Engl J Med 2007; June 5:[Epub ahead of print]
- Drazen JM, Morrissey S, Curfman GD. Rosiglitazone – Continued Uncertainty about safety. N Engl J Med 2007; June 5:[Epub ahead of print]
- Nathan DM. Rosiglitazone and cardiotoxicity – weighing the evidence. N Engl J Med 2007; June5:[Epub ahead of print].
Psaty BM, Furberg CD. The Record of rosiglitazone and the risk of myocardial infarction. N Engl J Med 2007; June 5:[Epub ahead of print].
Q. What are “Glitazones” or “Thiazolines” and why have they been always in the news ?
Ø “Glitazone” or “Thiazolidines” the popular anti diabetics have always been in the news for reasons right or wrong
Ø Glitazones are wonderful antidiabetic drugs because they reduce the Insulin Resistance. Insulin Resistance as we know is the main pathological factor in Type 2 Diabetes Mellitus.
Ø It was widely used after its introduction but then came the first big controversy.
Ø About 63 deaths were reported in US due to hepatotixicity caused by earlier products from this family. The US FDA withdrew the drug from the market.
Ø But popular demand made this group of drugs come back in newer safer versions as ‘Rosiglitazone’ and ‘Pioglitazone’
Ø Because of their history they were always viewed with suspicion and the FDA had asked the doctors to regularly monitor the hepatic functions of their patients who were prescribed these medications.
Ø But the drugs turned out to be safe and did not cause hepatotoxicty.
Ø Because of this new found safety this group of drugs widely rose in prominence.
Ø In recent time two trials DREAM and ADOPT have went on to suggest that it is time we start using them as first line agents.
Ø But then came the big storm after a meta analysis submitted in New England Journal of Medicine questioned the safety of Rosiglitazone once again. (more on in it is given below)
Q. What are the know side effects of Rosiglitazone ?
Rosiglitazone and Pioglitazone are known to cause the following side effects.
Pedal Odema
Weight gain
Reduced Hematocrit
Fluid Retention.
Q. What is the recent controversy about Rosiglitazone that created a storm in the medical circles ?
Ø The recent controversy about Roiglitazone came forward after a meta analysis published in New England Journal of Medicine by Nissen et al reported an increase risk of Coronary Artrey disease and Myocardial Infarction on usage of Rosiglitazone.
Ø They concluded on studying 42 trials that
Rosiglitazone Increases risk of MI by 42%
It increases the risk of Death due to Cardiovascular event by 64 %
Ø This study was widely reported in Lay press and hence created a lot of anxiety in patients already taking this drug.
Q. Why was this reported viewed with suspicion ?
Ø Meta-analysis by nature are two weak to conclude anything major
Ø Many question Meta-analysis per se and even those who do believe in them have questioned the way this one was carried out.
Ø Analyses of the 42 studies showed that 40 of them were small and all these put together did not yield statistically significant difference for myocardial infarction (MI) between groups.
Ø Responding quickly to the metaanalysis by Nissen et al , the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study investigators did an unplanned interim analysis of their results two years before the study was scheduled to conclude.
Ø The results indicated no statistically significant differences in the overall risk of hospitalization or death from cardiovascular causes between the study groups
Ø The results were (not surprisingly) inconclusive as this is an interim analysis after 3.75 years of median follow up and thus lacked adequate power as the original analysis was planned to be done after 6 years of median follow up.
Ø From a purely statistical perspective, these results would indicate a slight increase in risk for MI / coronary artery disease among subjects on rosiglitazone.
Ø However, a closer analysis of these data would indicate that the presently available data are not conclusive as none of the studies had cardiovascular disease (CVD) as primary end-points except RECORD.
Ø In the RECORD study, only an interim analysis was published which had inadequate power to assess CVD outcomes.
Ø Several Societies like the American Diabetes Association, Endocrine Society in the US, American Association of Clinical Endocrinologists have come out with statements urging physicians and patients not to panic and stop the medication but to undergo a reevaluation by their treating physicians and make decisions with them.
Ø Even the US FDA has not withdrawn the drug but asked for strict review and some changes have been made on the prescription label.
Ø The EU regulatory agencies have also not withdrawn the drug.
Q. So what should the conclusion and what should be done now ?
The Editorial in recent edition of JAPI advices the following for the Indian Physicians:
1. Reassure patients and physicians that there is nothing to panic.
2. Advise patients not to abruptly stop their medications but discuss it with their physician and under medical supervision of experts decide on case to case basis a plan which meets patient’s safety and therapy concerns.
3. Ensure that current glycemic control & non glycemic comorbid conditions are validated by not just fasting and postprandial blood glucose but do a glycosylated hemoglobin test, lipid profile,hematocrit and electrocardiogram(with or without an echocardiogram)
4. If they have established heart disease, it may be worthwhile to discuss with their physician / cardiologist about stopping the drug and appropriately adjusting their anti-diabetic medications.
5. If the physician is convinced about any concern then there are other options available in the same class, other class as well as Insulin. Both options need patient education and physician supervision to ensure patient safety risk as well as the glycemic control is well balanced as well as monitored periodically.
6. New patients with type 2 diabetes at risk of heart disease could probably be given alternate drug therapies until further evidence emerges with respect to the safety of this class of drugs.
7. Strict adherence to CVD risk reduction i.e. Aspirin (or Clopidrogel), Statin, ACE (or ARB) inhibitors, weight reduction, tighter glucose and BP control and stricter cardiac evaluation in all diabetic patients.
8. Individualized comprehensive evaluation and cardioprotective measures can be re-addressed and its an ideal opportunity for patient education to ensure that they are in control of their diabetes and vascular risk.
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