Deaths Hospitalizations Company. Takeda Pharmaceuticals. Takeda Pharmaceuticals. Takeda Pharmaceuticals. Janssen Pharmaceuticals

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1 Takeaways: Diabetes Drug Investigation From: Sent: Mon, Dec 22, 2014 at 10:51 am To: Cc: clip_image002.jpg (64.5 KB) clip_image004.jpg (78.1 KB) Download all 5 Takeaways from the Diabetes Drugs Investigation by Elbert Chu, Coulter Jones, and John Fauber MEDPAGE TODAY All 30 diabetes drugs reviewed for this series were approved by the U.S. Food and Drug Administration from based on surrogate measures of elevated blood sugar such as HbA1c, which can indicate risk for type 2 diabetes complications, but not always. Here are a few key points of what we learned in the course of our investigation. Read the full analysis, an examination of adverse events, or more about how we did it. 1. Diabetes drugs improve lab tests, but not much more, particularly in pre-diabetics. None of the 30 diabetes drugs approved by the FDA in the last decade have rigorous proof of reducing clinical outcomes such as heart attack, stroke, blindness, or amputations. 2. Physicians and drug makers have reported diabetes drugs as the "primary suspect" in thousands of deaths and hospitalizations. At least 3,300 deaths and 20,000 hospitalizations have been linked to new diabetes drugs in adverse event reports submitted by clinicians and pharmaceutical companies to the FDA since FDA's Adverse Events Reporting System (FAERS) collects case reports from healthcare providers, pharmaceutical companies and the general public. These are the reports that were used for the MedPage Today and the Milwaukee Journal Sentinel analysis. Although the FAERS database is known to be incomplete, it is one of the few tools to monitor risks for drugs already approved. (For full discussion of methodology, see howmedpage Today/Journal Sentinel conducted the analysis.) Reporters reached out to the drug makers. All who responded cited the limitations of the FDA's reporting system and said they monitor reported problems. Search: Generic (Brand Name), FDA Link Year First Approved for Diabetes Deaths Hospitalizations Company albiglutide (Tanzeum) GlaxoSmithKline alogliptin (Nesina) alogliptin + metformin (Kazano) alogliptin + pioglitazone (Oseni) bromocriptine (Cycloset) Salix canagliflozin (Invokana) Janssen 1 of 6 1/11/ :54 AM

2 2 of 6 1/11/ :54 AM Generic (Brand Name), FDA Link Year First Approved for Diabetes Deaths Hospitalizations Company colesevelam (Welchol) Daiichi Sankyo dapagliflozin (Farixga) AstraZeneca dulaglutide (Trulicity) Eli Lilly and Co. empagliflozin (Jardiance) Boehringer Ingelheim exenatide (Byetta) ,115 AstraZeneca exenatide extended-release (Bydureon) AstraZeneca insulin detemir (Levemir) ,198 Novo Nordisk insulin glulisine (Apidra) Sanofi linagliptin (Tradjenta) Boehringer-Ingelheim linagliptin + metformin (Jentadueto) Boehringer-Ingelheim liraglutide (Victoza) ,827 Novo Nordisk metformin (Fortamet) Shionogi, Inc. pioglitazone + glimepiride (Duetact) pioglitazone + metformin (Actoplus Met) pioglitazone + metformin extended-release (Actoplus Met XR) pramlintide acetate (Symlin) AstraZeneca repaglinide + metformin (Prandimet) Novo Nordisk rosiglitazone + glimepiride (Avandaryl) GlaxoSmithKline saxagliptin (Onglyza) AstraZeneca saxagliptin + metformin extended-release (Kombiglyze XR) AstraZeneca sitagliptin + metformin (Janumet) ,044 Merck sitagliptin + metformin extended-release (Janumet XR) Merck sitagliptin + simvastatin (Juvisync) Merck sitagliptin phosphate (Januvia) ,425 Merck Showing 1 to 30 of 30 entries Sources: FDA Adverse Events Reporting System (FAERS), FDA Drugs database 3. Diabetes drug makers paid physicians on influential panels millions of dollars. The physicians in the American Association of Clinical Endocrinologists and American Diabetes Association panels that have presided over changes in defining pre-diabetes and diabetes or patient treatment guidelines received more than $2 million for consulting and speaking activities for diabetes drug manufacturers: AACE panel members were paid for speaking and consulting: GlaxoSmithKline $494,513 Eli Lilly and Co. $650,099 Merck $735,367 Janssen, Inc* $145, Novo Nordisk Inc* $47, Other companies* $134,654.97

3 3 of 6 1/11/ :54 AM Total $2,208,011 ADA panel members were paid for speaking and consulting: Eli Lilly and Co. $312,754 Merck $229,882 Janssen, Inc* $32,550 Novo Nordisk Inc* $17, Other companies* $43, Total $636,095 Source: Only Eli Lilly, GlaxoSmithKlein, and Merck filed disclosures since All other disclosures came from Open Payments. That data only includes the last five months of Risk of a risk now equals disease. The seemingly small shifts in definition has meant that millions of Americans are now diagnosed with pre-diabetes -- that is, a risk for developing type 2 diabetes. Most endocrinologists and every FDA label indicate these diabetes drugs have never rigorously proven to prevent or reduce heart attacks or strokes. Yet the absolute lifetime risk for adverse clinical outcomes such as kidney failure and blindness in people with pre-diabetes remains very low in the single-digit percentiles.

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5 5 of 6 1/11/ :54 AM 5. The clinical threshold for diagnosing diabetes has crept lower and lower over the past decade. Over the years, a series of changes by the American Diabetes Association have increased the number of those considered diabetic or pre-diabetic. Before the changes, some 21.6 million American adults, or 9%, met the definition for diabetes. A look at the changes: 1997: The group lowers the threshold defining diabetes from a fasting blood glucose level of 140 mg/dl to 125 mg/dl. As a result, 3.9 million more American adults qualify as diabetics. That increases the total to 25.5 million, or 10.6% of the population. 2003: The group lowers the threshold for pre-diabetes from a fasting blood glucose level of mg/dl to a range of mg/dl. As a result, 46.1 million more meet the definition. Prior to the change, 16.8 million, or 7%, qualified. That increased to 62.9 million, or 26.2%. 2008: In a joint statement, the American Association of Clinical Endocrinologists and the American College of Endocrinology say that diabetes drugs can be used to treat pre-diabetes with careful judgment. 2009: Sales of diabetes drugs hit $15 billion 2010: American Diabetes Association says the hemoglobin A1C blood test can be used to diagnose pre-diabetes and sets the threshold at a range of 5.7% to 6.5%. As a result, some 34.1 million Americans, or 14.2%, qualify as pre-diabetics by this measure. When combined with the lower fasting glucose test definition, 77.3 million Americans, or 32.2%, now qualify as pre-diabetics.

6 6 of 6 1/11/ :54 AM 2013: The endocrinology groups issue another joint statement saying pre-diabetes can be treated with diabetes drugs if lifestyle changes diet and exercise don t work. 2013: Sales of diabetes drugs hit $23 billion. Source: Lisa Schwartz and Steven Woloshin, Dartmouth Institute for Health Policy and Clinical Practice; IMS Health; American Diabetes Association; American Association of Clinical Endocrinologists. Schwartz and Woloshin are co-founders of Informulary, a company that provides data on the benefits, harms and uncertainties of drugs. Footnote: Diabetes percentages are from National Health and Nutrition Examination survey data from 2009 to Census population estimates from 2012 were used to calculate the number of adult Americans affected by the conditions. Prediabetes percentages are estimated from NHANES data and use 2012 Census data to calculate the number of Americans.