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Backgrounder on Diabetes Drug Avandia Controversy

I’ve been tracking the various developments and commentaries on the controversy surrounding diabetes drug Avandia (rosiglitazone, manufactured by GlaxoSmithKline). For those of you interested in background information and commentaries relating to the use of Avandia and increased risk for heart disease, as well as the affordability of chronic medications like diabetes drugs, I’ve compiled a short reading list including abstracts to the original research articles to help you get started. Please read my conflict of interest disclosure at the end of this article.

“Older and cheaper pills just fine for diabetes” Mon Jul 16, 2007 5:30PM EDT
Older and cheaper pills are just as effective for treating diabetes as some of the more expensive new drugs, U.S. researchers reported on Monday.

This related to a review published in the Annals of Internal Medicine; I’ve included the abstract below – you may access the full review article online here:

Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus
Shari Bolen, MD, MPH; Leonard Feldman, MD; Jason Vassy, MD, MPH; Lisa Wilson, BS, ScM; Hsin-Chieh Yeh, PhD; Spyridon Marinopoulos, MD, MBA; Crystal Wiley, MD, MPH; Elizabeth Selvin, PhD; Renee Wilson, MS; Eric B. Bass, MD, MPH; and Frederick L. Brancati, MD, MHS

18 September 2007 | Volume 147 Issue 6

Background: As newer oral diabetes agents continue to emerge on the market, comparative evidence is urgently required to guide appropriate therapy.

Purpose: To summarize the English-language literature on the benefits and harms of oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and {alpha}-glucosidase inhibitors) in the treatment of adults with type 2 diabetes mellitus.

Data Sources: The MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception through January 2006 for original articles and through November 2005 for systematic reviews. Unpublished U.S. Food and Drug Administration and industry data were also searched.

Study Selection: 216 controlled trials and cohort studies and 2 systematic reviews that addressed benefits and harms of oral diabetes drug classes available in the United States were identified.

Data Extraction: Using standardized protocols, 2 reviewers serially abstracted data for each article.

Data Synthesis: Evidence from clinical trials was inconclusive on major clinical end points, such as cardiovascular mortality. Therefore, the review was limited mainly to studies of intermediate end points. Most oral agents (thiazolidinediones, metformin, and repaglinide) improved glycemic control to the same degree as sulfonylureas (absolute decrease in hemoglobin A1c level of about 1 percentage point. Nateglinide and {alpha}-glucosidase inhibitors may have slightly weaker effects, on the basis of indirect comparisons of placebo-controlled trials. Thiazolidinediones were the only class that had a beneficial effect on high-density lipoprotein cholesterol levels (mean relative increase, 0.08 to 0.13 mmol/L [3 to 5 mg/dL]) but a harmful effect on low-density lipoprotein (LDL) cholesterol levels (mean relative increase, 0.26 mmol/L [10 mg/dL]) compared with other oral agents. Metformin decreased LDL cholesterol levels by about 0.26 mmol/L (10 mg/dL), whereas other oral agents had no obvious effects on LDL cholesterol levels. Most agents other than metformin increased body weight by 1 to 5 kg. Sulfonylureas and repaglinide were associated with greater risk for hypoglycemia, thiazolidinediones with greater risk for heart failure, and metformin with greater risk for gastrointestinal problems compared with other oral agents. Lactic acidosis was no more common in metformin recipients without comorbid conditions than in recipients of other oral diabetes agents.

Limitations: Data on major clinical end points were limited. Studies inconsistently reported adverse events other than hypoglycemia, and definitions of adverse events varied across studies. Some harms not assessed in trials or observational studies may have been overlooked.

Conclusions: Compared with newer, more expensive agents (thiazolidinediones, {alpha}-glucosidase inhibitors, and meglitinides), older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points.

“Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults With Type 2 Diabetes” Executive Summary published 16 Jul 2007 by the U.S. Department of Health and Human Services.
This above was a report published by the Agency of Healthcare Research and Quality. Table of Contents include: 1. Background 2. Conclusions 3. Comparisons of effects 4. Differences in effectiveness 5. Remaining issues 6. Synopsis 7. Addendum 8. Full Report 9. For More Copies 10. Summary Tables

“Diabetes drug tied to increased cancer prevalence” Wed Jul 18, 2007 5:27PM EDT
“Patients with diabetes, especially women, who take thiazolidinediones, which include commonly prescribed drugs such as Avandia and Actos, may have an increased risk of developing cancer, according to a new report.” The abstract of the original medical journal is below, and the full article is available via open access here:

Association between cancer prevalence and use of thiazolidinediones: results from the Vermont Diabetes Information System
Maria E Ramos-Nino, Charles D MacLean, and Benjamin Littenberg

Background Peroxisome proliferator-activated receptors (PPARs) have emerged as important drug targets for diabetes. Drugs that activate PPARγ, such as the thiazolidinediones (TZDs), are widely used for treatment of Type 2 diabetes mellitus. PPARγ signaling could also play an anti-neoplastic role in several in vitro models, although conflicting results are reported from in vivo models. The effects of TZDs on cancer risk in humans needs to be resolved as these drugs are prescribed for long periods of time in patients with diabetes.

Methods A total of 1003 subjects in community practice settings were interviewed at home at the time of enrolment into the Vermont Diabetes Information System, a clinical decision support program. Patients self-reported their personal and clinical characteristics, including any history of malignancy. Laboratory data were obtained directly from the clinical laboratory and current medications were obtained by direct observation of medication containers. We performed a cross-sectional analysis of the interviewed subjects to assess a possible association between cancer diagnosis and the use of TZDs.

Results In a multivariate logistic regression model, a diagnosis of cancer was significantly associated with TZD use, even after correcting for potential confounders including other oral anti-diabetic agents (sulfonylureas and biguanides), age, glycosylated hemoglobin A1C, body mass index, cigarette smoking, high comorbidity, and number of prescription medications (odds ratio = 1.59, P = 0.04). This association was particularly strong among patients using rosiglitazone (OR = 1.89, P = 0.02), and among women (OR = 2.07, P = 0.01).

Conclusion These data suggest an association between TZD use and cancer in patients with diabetes. Further studies are required to determine if this association is causal.

“New study slams safety of Glaxo’s Avandia drug” Wed Jul 18, 2007 9:51AM EDT
“German researchers… found little evidence that Avandia improved the quality or length of diabetics’ lives and concluded it could actually worsen complications of the disease, after studying pooled data from 18 past trials involving 8,000 patients.”

“Another Avandia Mystery: Actos Data” July 30, 2007, 8:15 am
“This June, when the medical journal Pharmacoepidemiology and Drug Safety published a study on the heart safety of GlaxoSmithKline’s diabetes drug Avandia, or rosiglitazone, there was something missing. People taking Avandia’s rival Actos, or pioglitazone, from Japan’s Takeda Pharmaceutical, didn’t show up in the analysis. Today a group of experts will convene outside Washington to advise FDA what to do with Avandia in light of the possible risk it carries for heart attacks. The availability of Actos, an alternative that so far hasn’t been fingered for the same side effect, may play a role in the committee’s and the agency’s calculations.”

Abstract is published below – full medical article requires a subscription (which I don’t have).

Coronary heart disease outcomes in patients receiving antidiabetic agents
Andrew T. McAfee, MD, MSc 1 2 *, Carol Koro, PhD 3 4, Joan Landon, MPH 1, Najat Ziyadeh, MA, MPH 1, Alexander M. Walker, MD, DrPH 1

Background There is conflicting evidence on the reduction of cardiovascular risk in diabetic patients treated with oral antidiabetic agents.

Objectives To compare the risk of myocardial infarction (MI) and coronary revascularization (CR) in type 2 diabetic patients treated with rosiglitazone, metformin, or sulfonylurea.

Methods Using data from a large US insurer, we created propensity-matched cohorts. We identified hospitalizations for MI or CR. We calculated incidence rates and 95% confidence intervals for the outcomes and estimated risks from Cox proportional hazards models.

Results We identified 26,931 initiators of monotherapy, 4,086 initiators of dual-therapy, and 2,346 initiators of combination with insulin therapy. There was no difference between the risk of the composite outcome with rosiglitazone monotherapy compared to metformin monotherapy (HR 1.07, 95% CI: 0.85, 1.34), and similarly with rosiglitazone monotherapy compared to sulfonylurea monotherapy (HR 0.82, 95% CI: 0.67, 1.02). There was no difference in the risk of outcome with rosiglitazone in combination with insulin therapy compared to other oral antidiabetic agents in combination with insulin (HR 0.88, 95% CI: 0.59, 1.32). Overall, there was little difference in the risk of the composite outcome or of the individual outcomes of MI and CR comparing rosiglitazone therapies to non-rosiglitazone therapies (HR for composite outcome 0.93, 95% CI: 0.80, 1.10).

Conclusions The results from the monotherapy and the dual-therapy comparisons, though not individually significant, are consistent in suggesting that the risk of cardiovascular outcome events in patients using rosiglitazone may lie between the risks associated with sulfonylureas (higher incidence) and metformin (lower incidence). Copyright © 2007 John Wiley & Sons, Ltd.

“FDA Official Calls for Avandia’s Withdrawal” July 30, 2007, 9:06 am
“FDA drug-safety reviewer David Graham, a high-profile critic of his own agency’s handling of some issues, will call for Avandia to be pulled from the market at today’s FDA committee hearing on GlaxoSmithKline’s diabetes drug.”

“Glaxo diabetes drug should stay on market: U.S. panel” Mon Jul 30, 2007 6:31PM EDT
“Avandia should stay on the U.S. market, even though data suggest it may increase the risk of a heart attack for some patients, an advisory panel said on Monday in a 22-1 vote. Several panel members said the Food and Drug Administration should consider asking for strong new warnings on Avandia, but that evidence was not strong enough to justify halting sales.”

Conflict of Interest Disclosure: I used to work as a medical science liaison for Takeda (year 2001-2002), the manufacturer of Actos (pioglitazone), which is a diabetes medication in the same drug class (the glitazones) as Avandia. My role as a MSL for Takeda was to interact with clinicians and research endocrinologists to facilitate research collaborations, as well as give clinical presentations relating to the disease state of diabetes and clinical data relating to Actos to managed care organizations.

Updated: June 30, 2013 — 8:07 am

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