8/12/2019 0000605-201211060-00016

1/2

Cardiovascular Effects of Diabetes Drugs: Emerging From theDark Ages

After the fall of the Roman Empire, the developedworld entered centuries of intellectual darknessmarked by minimal scientific progress, a period oftencalled the Dark Ages. After many centuries, progress re-sumed and eventually accelerated during the Renaissance.In a similar fashion, knowledge about the comparative ef-fectiveness of drugs to treat type 2 diabetes is finally begin-ning to emerge from 40 years of stagnation. This period ofdarkness and the current reawakening provide critically im-portant lessons for contemporary medicine about the useof surrogate end points in drug development, regulatoryoversight, and the hazards associated with reliance on com-mercial funding for pivotal clinical trials.

The diabetes Dark Ages began in 1961 with the initi-

ation of one of the first major randomized, controlled trials(RCTs) in modern medicine, the UGDP (UniversityGroup Diabetes Project) study. The design of this study

was complex, with patients randomly assigned to 5 treat-ment groups: variable-dose insulin, fixed-dose insulin, tol-butamide, phenformin, or diet alone. In 1970, the tolbu-tamide group discontinued therapy because of an increasein all-cause and cardiovascular (CV) mortality compared

with the other treatment groups (1). The makers of tol-butamide launched an aggressive campaign to discredit theUGDP study findings by using leading and well-remunerated academics (2). As Schwartz and Meinert (2)

described in 2004, The arguments became increasing adhominem, eventually challenging the honesty of theUGDP investigators.

The reaction of the broader pharmaceutical industryto the concern about the CV effects of sulfonylureas wasdecisive and sustained. For the next 40 years, industry sim-ply stopped performing RCTs comparing CV outcomesfor alternative diabetes treatment strategies. In 2007, a sys-tematic review catalogued this unfortunate state of affairs,describing the evidence for comparative effectiveness forCV outcomes with diabetes drugs as low to very low (3).

An anachronistic regulatory policy requiring only that newdiabetes drugs show that they lower blood glucose levels

without obvious safety problems, not that they improveclinical outcomes, allowed industry to avoid performingstudies on CV outcomes. Thoughtful academics have crit-icized the reliance on biochemical measures as a surrogatefor clinical benefit, because numerous surrogates havefailed to show a consistent link with actual clinical out-comes (4). However, regulatory policy for diabetes drugdevelopment remained essentially static for 50 years.

A series of traumatic shock waves ultimately was re-quired to shake the complacency of the diabetes commu-nity and the regulators. The first of these shocks occurredin 2005 after an advisory panel of the U.S. Food and Drug

Administration (FDA) recommended approval of muragli-tazar, the first dual ( and ) peroxisome proliferator

activated receptor modulator to reach an advanced stage ofdevelopment. The biochemical effects of muraglitazar, in-cluding robust reduction in hemoglobin A

1clevels, marked

increases in high-density lipoprotein cholesterol levels, andsubstantial decreases in triglyceride levels, were impressive.However, immediately after the panel recommendation,my colleagues and I used the FDA briefing documents toreanalyze the CV outcomes data from the muraglitazar de-velopment program and found a doubling of major CVmorbidity and mortality (5). The FDA quickly reassessedthe drug and declined approval. The makers of the drugsoon terminated the development program. Nonetheless, a

risky drug came very close to regulatory approval.The second shock wave occurred in 2007 when mycolleagues and I published a meta-analysis of CV outcomes

with rosiglitazone based on study-level data that becameavailable after a court settlement required the drug makerto disclose all clinical trial results (6). Thirty-five of the 42clinical trials used in the analysis were unpublished. Thestudy calculated an estimated 43% increase in the risk formyocardial infarction for rosiglitazone compared withother diabetes drugs or placebo.

The meta-analysis initially met with much controversy(7), but the FDA eventually confirmed the findings by

using patient-level data. A Senate investigation later re-vealed that the company had completed its own internalanalysis 2 years before our publication, confirming a sig-nificantly increased risk for myocardial infarction (8). By2010, the evidence for harm was so overwhelming thatEuropean authorities forced the company to withdrawrosiglitazone from the market and the FDA restricted itsuse to patients whose disease was refractory to all othertherapies. In 2012, the drug maker paid a record $3 billionfine for civil and criminal penalties, related in part to con-cealing safety data for rosiglitazone.

The third shock wave occurred in 2008, when theNational Institutes of Health terminated a trial designed tocompare more-intensive with less-intensive glucose lower-ing after observing an increase in CV mortality in the moreaggressively treated group (9).

These 3 successive shocks finally forced the FDA toreconsider its decades-old policy of approving diabetesdrugs primarily on the basis of glucose-lowering effects. Anadvisory panel, convened in 2008, endorsed an approachrecommendation that I presented with support from Dr.Thomas Fleming requiring a 2-stage approval process fordiabetes drugs.

In the first step, a CV outcomes trial must rule out anupper 95% CI for a hazard ratio of 1.8 for CV events,

Annals of Internal Medicine Editorial

2012 American College of Physicians 671

wnloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013

8/12/2019 0000605-201211060-00016

2/2

followed by a postapproval study to rule out an upper CIof 1.3 (10). Some critics predicted that this policy wouldhalt the development of diabetes drugs, but it has actuallydone the opposite. Dozens of new diabetes drugs are nowin development with ongoing CV outcomes trials under

way. The 40-year veil of darkness has finally begun to lift

after this pivotal policy shift.In this historical context, Roumie and colleagues arti-

cle (11) in this issue renews an old controversy. The find-ings of the UGDP trial were never refuted by a modernRCT. Instead, we have a series of post hoc analyses ofstudies never designed to resolve the CV safety concernabout sulfonylureas. Some but not all of these studies sug-gested that sulfonylureas were similar to other diabetesdrugs in their effects on CV outcomes.

Because sulfonylureas and metformin were approvedduring the legacy era in which CV outcomes trials were notrequired, the new FDA diabetes guidance is not applicable.

Accordingly, no financial incentives exist for industry toperform comparative effectiveness trials evaluating these 2commonly used therapies. We must therefore use observa-tional studies to answer a scientific question first asked in1961: Do sulfonylureas increase adverse CV events?

Roumie and colleagues study (11) is a laudable effort,and the findings have implications for millions of patients

worldwide. The authors used many of the best methodsavailable to analyze observational data, including carefuladjustment for known confounders, propensity matching,and multiple sensitivity analyses. Despite the recognizedlimitations of observational studies, the findings are credi-

ble and important. Sulfonylureas seem inferior to met-formin with respect to CV outcomes. However, in theabsence of a modern RCT confirming the findings, wemust view these data as hypothesis-generating rather thandefinitive. As such, the UGDP controversy remains unre-solved 51 years after the study was initiated.

How might sulfonylureas increase adverse CV out-comes? One theory focuses on their adverse effects on isch-emic preconditioning, an adaptive mechanism that allowsthe myocardium to resist necrosis after intermittent peri-ods of ischemia (12). Another hypothesis relates tosulfonylurea-induced hypoglycemia, which theoretically

may result in myocardial ischemia. Regardless of mecha-nism, this scientific question demands a definitive answer.In the absence of an industry-sponsored study, publichealth authorities should conduct such a clinical trial. Withmore than two thirds of diabetic patients dying of CVcauses and millions of patients currently receiving sulfonyl-

ureas, this question must be resolved with high-quality ev-idence. Continued darkness is not an acceptable option.

Steven E. Nissen, MD

Cleveland Clinic

Cleveland, OH 44195

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum M12-2295.

Requests for Single Reprints: Steven E. Nissen, MD, Department ofCardiology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH44195; e-mail, nissens@ccf.org.

Ann Intern Med. 2012;157:671-672.

References1.Goldner MG, Knatterud GL, Prout TE. Effects of hypoglycemic agents onvascular complications in patients with adult-onset diabetes. 3. Clinical implica-

tions of UGDP results. JAMA. 1971;218:1400-10. [PMID: 4941698]2.Schwartz TB, Meinert CL.The UGDP controversy: thirty-four years of con-tentious ambiguity laid to rest. Perspect Biol Med. 2004;47:564-74. [PMID:15467178]3.Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S, et al.Systematic review: comparative effectiveness and safety of oral medications fortype 2 diabetes mellitus. Ann Intern Med. 2007;147:386-99. [PMID: 17638715]4.Fleming TR, DeMets DL.Surrogate end points in clinical trials: are we beingmisled? Ann Intern Med. 1996;125:605-13. [PMID: 8815760]5.Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and majoradverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA.2005;294:2581-6. [PMID: 16239637]6.Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarc-tion and death from cardiovascular causes. N Engl J Med. 2007;356:2457-71.[PMID: 17517853]

7.Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk formyocardial infarction and cardiovascular death. Ann Intern Med. 2007;147:578-81. [PMID: 17679700]8. Grassley, Baucus release committee report on Avandia: senators expressconcern about FDAs role in protecting patients in ongoing Avandia study [pressrelease]. Washington, DC: U.S. Senate Committee on Finance; 10 February2010. Accessed at www.finance.senate.gov/newsroom/chairman/release/?idbc56b552-efc5-4706-968d-f7032d5cd2e4 on 28 September 2012.9.Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB,et al; Action to Control Cardiovascular Risk in Diabetes Study Group.Effectsof intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-59. [PMID: 18539917]10. U.S. Food and Drug Administration. Guidance for Industry: DiabetesMellitusEvaluating Cardiovascular Risk in New Antidiabetic Therapies toTreat Type 2 Diabetes. Silver Spring, MD: U.S. Food and Drug Administration;December 2008. Accessed at www.fda.gov/downloads/Drugs/GuidanceCompliance

RegulatoryInformation/Guidances/ucm071627.pdf on 28 September 2012.11.Roumie CL, Hung AM, Greevy RA, Grijalva CG, Liu X, Murff HJ, et al.Comparative effectiveness of sulfonylurea and metformin monotherapy on car-diovascular events in type 2 diabetes mellitus. A cohort study. Ann Intern Med.2012;157:601-10.12.Meier JJ, Gallwitz B, Schmidt WE, Mugge A, Nauck MA. Is impairment ofischaemic preconditioning by sulfonylurea drugs clinically important? Heart.2004;90:9-12. [PMID: 14676228]

Editorial Cardiovascular Effects of Diabetes Drugs

672 6 November 2012 Annals of Internal Medicine Volume 157 Number 9 www.annals.org

wnloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013