Back in 2007, a paper published in the New England Journal of Medicine based on the observations of Steven Nissen, MD, Cleveland Clinic, identified a significant increase in the risk of myocardial infarction (MI) in patients administered rosiglitazone (Avandia), a thiazolidinedione made by GlaxoSmithKline (GSK) that was then widely used to treat patients with type 2 diabetes mellitus (T2DM).1 The study also observed a slightly increased risk of death from cardiovascular events.
Avandia, originally approved by the FDA in 1999,2 was a top-selling drug in 2006 with net sales of nearly $3 billion, before the risks were identified.3 In 2010, regulatory agencies in the United States as well as Europe announced the limited availability of Avandia for use in treating diabetes. While the European Medicines Agency (EMA) completely banned the sales of the drug,4 the FDA limited its use by requiring GSK to develop a restricted access program under a Risk Evaluation and Mitigation Strategy, whereby Avandia would only be available to T2DM patients as a last resort when all other drugs have failed to regulate their glycemic levels.5
Following the FDA decision, Nissen expressed relief that the decision brought an end to “one of the worst drug safety tragedies in our lifetime.”6 He believes the drug is far too dangerous to use in diabetes treatment based on more than 50 studies that have linked Avandia to an elevated risk of heart attack.3 However, in a surprising move last year, the FDA convened a 26-member panel to loosen restrictions on prescription of Avandia. The result: half of the advisory committee voted in favor of softening the restrictions, and GSK vowed to work with the FDA to implement potential changes.7
In an article that was published in the September 2013 issue of Evidence-Based Diabetes Management on the roller coaster treatment of Avandia by the FDA, G. Alexander Fleming, MD, president and CEO of the healthcare consulting firm Kinexum and a former FDA regulator, recalled Nissen’s evaluation, stating: “While the medical community was given the impression with his metaanalysis that the drug was dangerous, to be fair, the meta-analysis was incomplete and heavily criticized by statisticians, but that didn’t matter in the ensuing public controversy. Things became politicized and the debate was no longer based on science.”8
In a press release late in 2013, the FDA announced that it had removed certain restrictions on prescribing the drug based on newer meta-analysis that showed a lower risk of heart attack or death in patients taking Avandia versus patients taking standard diabetes medications. Although the FDA requires GSK to work with physicians and train them on the current knowledge on the associated CV risks, GSK is no longer required to conduct a postmarketing clinical trial comparing Avandia with Actos (the only other approved thiazolidinedione, manufactured by Takeda) and other standard diabetes drugs.9
Avandia though, seems to have lost the battle. In an e-mail response, Heidi Siegel, director of external communications at GSK, said about the company’s plans to “relaunch” the drug, “We are not planning to promote Avandia in the United States. We believe it is important for patients and their healthcare providers to have a range of options to treat diabetes, and Avandia (rosiglitazone) will continue to be an option for physicians.”
Heart Failure in Patients With Diabetes
Hospital admission for heart failure is a very common complication of diabetes, since glycemic exposure has been found to be strongly associated with the risk of developing microvascular and macrovascular complications.10 Arterial damage, which can lead to a heart attack or stroke, is a major threat among individuals with diabetes. High blood sugar levels can increase blood pressure, body weight, and cholesterol levels. Together, these factors promote arterial disease.11
According to the American Heart Association, heart disease and stroke are the primary causes of death and disability among patients with T2DM, and 60% of patients with diabetes die from some form of heart disease or stroke. Patients with T2DM are also 2 to 4 times more likely to suffer from heart disease or stroke than those without diabetes (Figure).12 Improved glycemic control could substantially reduce the risk of CV events, assuming that lowering of glucose levels would, in the long term, result in fewer microvascular and macrovascular events.
Considering these preexisting complications in patients with diabetes, the added risk of a blood glucose—lowering drug causing CV events would be a big no-no. Following the initial rosiglitazone debacle, both the FDA and EMA issued new guidance to ensure CV safety of newer therapeutic options for diabetes under development. A consequence of these guidelines was the inclusion of the major adverse cardiovascular events (MACEs) as the primary outcome of a number of safety trials. MACE has been defined as a composite of cardiovascular death, myocardial infarction, or stroke, along with other end points, such as hospital admission for acute coronary syndrome. Additionally, experts in the field recommend including hospital admission for heart failure as a prespecified component of MACE.10
Markers for Increased CV Risk
A recently published study identified serum markers as strong predictors of an increased risk of CV events. This trial, which enrolled 352 South Asian patients with T2DM, found that the levels of a serum immunoglobulin (cFLC) were significantly elevated in 8% of patients with CV disease events over a 2-year follow-up period. Results indicate that cFLC could be used as a marker for adverse CV events.13
A recent study of 12,000 patients with T2DM from the SAVOR-TIMI 53 trial was presented at the 63rd annual meeting of the American College of Cardiology held in Washington, DC (complete coverage on pages SP245-SP250). The trial found that, regardless of baseline risk, a substantial share of stable patients with this disease have signs of ongoing myocardial damage or hemodynamic stress. These conditions were strongly associated with later risk of death from MI. For enrolled patients, biomarkers measured in the study were high-sensitivity troponin, NT-proBNP, and hsCRP. Researchers found a stepwise increase in rates of CV death and MI with higher quartiles of each biomarker.14
Recent Trends With the Newer Therapies
According to the Lancet paper, heart failure, stroke, and MI were quite common among patients participating in the recent large-scale clinical trials that evaluated Actos and Onglyza (a DPP-4 inhibitor by BMS/AstraZeneca). Another trial that evaluated Nesina (Takeda Pharmaceuticals) also found a trend toward increased CV risk.10 With this knowledge, physicians should monitor their diabetic patients for CV events, especially those with a preexisting risk, who are administered these drugs.
Hypoglycemia and Heart Rhythm
Contradicting the preexisting knowledge about the relation between diabetes and heart health, scientists found that hypoglycemia in patients with diabetes could result in irregular heart rhythms. The study conducted among patients in the United Kingdom continuously monitored glucose levels and electrocardiograms for a week in older T2DM patients with a history of CV disease. This was more commonly observed as patients slept at night, when glucose levels dropped to low levels for several hours, during which period a markedly slower heart rate and abnormal heartbeats were observed.15
Complementing this observation about CV risks is a recent editorial published in the American Family Physician, highlighting the hierarchical importance of various interventions for improved control of CV risks. The editorial points out that smoking cessation, blood pressure control, metformin treatment, and lipid level reduction (in that order) would be more beneficial than glycemic control in patients with CV risk, specifically noting recent evidence that tight glucose control can be harmful. “It’s not to say that blood sugar is not important at all, but there are other much more important interventions,” according to the lead author on the editorial, Deborah R. Erlich, MD, of the Tufts University School of Medicine.16
1. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457-2471.
2. Drugs@FDA: FDA approved drug products. FDA website. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed April 29, 2014.
3. Thomas K, Tavernise S. F.D.A. to reconsider restrictions on diabetes drug. The New York Times. June 2, 2013. http://www.nytimes.com/2013/06/03/business/second-thoughts-on-safetyofavandia-stir-a-dispute.html?pagewanted=all&_r=0.
4. European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim [press release]. London, UK: European Medicines Agency; September 23, 2010. http://www.ema
5. FDA significantly restricts access to the diabetes drug Avandia [press release]. Silver Spring, MD: FDA; September 23, 2010. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm226975.htm.
6. Harris G. F.D.A. to restrict Avandia, citing heart risk. The New York Times. September 30, 2010. http://www.nytimes.com/2010/09/24/ health/policy/24avandia.html.
7. Tavernise S, Thomas K. F.D.A. vote is minor victory for troubled diabetes drug. The New York Times. June 6, 2013. http://www.nytimes.com/2013/06/07/business/fda-advisers-voteto-
8. Regan TL. FDA “Mea Culpa” part of a cautionary tale. Am J Manag Care. 2013;19(SP7):SP242-SP243.
9. FDA requires removal of certain restrictions on the diabetes drug Avandia [press release]. Silver Spring, MD: FDA; November 25, 2013. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376516.htm.
10. McMurray JJV, Gerstein HC, Holman RR, Pfeffer MA. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored [published online March 13, 2014]. Lancet Diabetes Endocrinol. doi:10.1016/S2213-8587(14)70031-2.
11. Diabetes and your risk of heart disease. InteliHealth website. http://www.intelihealth.com/article/diabetes-and-your-risk-of-heart-disease. Accessed April 30, 2014.
12. Cardiovascular disease & diabetes. American Heart Association website. http://www.heart.org/HEARTORG/Conditions/Diabetes/WhyDiabetesMatters/Cardiovascular-Disease-Diabetes_UCM_313865_Article.jsp. Accessed April 30, 2014.
13. Bellary S, Faint JM, Assi LK, et al. Elevated serum free light chains predict cardiovascular events in type 2 diabetes [published online April 17, 2014]. Diabetes Care. doi:10.2337/dc13- 2227.
14. Scirica B, Bhatt D, Braunwald E. Prognostic implications of simultaneous biomarker assessments in patients with type 2 diabetes mellitus: observations from the SAVOR-TIMI 53 trial. JACC.
2014;63(12, suppl A):Abstract 1121-1337.
15. Hypos at night linked to heart rhythm problems in type 2 diabetes patients. Diabetes.co.uk. website. http://www.diabetes.co.uk/news/2014/apr/hypos-at-night-linked-toheart-rhythm-problems-in-type-2-diabetes-patients-93716304.html. Published April 23, 2014. Accessed April 28, 2014.
16. Busko M. Give us a hand! focus first on CVD risk in diabetes. Medscape website. http://www.medscape.com/viewarticle/822132. Published March 18, 2014. Accessed April 30, 2014.
17. Aetna announces new metabolic syndrome risk-reduction pilot program with Newtopia [press release]. Hartford, CT: Aetna; October 10, 2013. http://newshub.aetna.com/press-release/products-and-services/aetna-announces-newmetabolic-syndrome-risk-reduction-pilot-prog.
Meanwhile, preventive wellness programs abound. Aetna, in collaboration with a Toronto-based company called Newtopia, has launched a metabolic syndrome (a condition that increases the chances of developing diabetes, stroke, or coronary artery disease) reduction program as part of its overall wellness program to help its employees develop personalized lifestyle plans (see page SP260). Newtopia is a personalized health company that employs next-generation approaches such as developing individualized lifestyle plans based on genetic testing and behavioral science, as well as assigning personal coaches. The pilot program will initially be delivered to 500 Aetna employees who will be monitored for 1 year.17