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Editorials |

Cardiovascular Effects of Diabetes Drugs: Emerging From the Dark Ages FREE

Steven E. Nissen, MD
[+] Article and Author Information

From 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 of Cardiology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail, nissens@ccf.org.


Ann Intern Med. 2012;157(9):671-672. doi:10.7326/0003-4819-157-9-201211060-00016
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After the fall of the Roman Empire, the developed world entered centuries of intellectual darkness marked by minimal scientific progress, a period often called the “Dark Ages.” After many centuries, progress resumed and eventually accelerated during the Renaissance. In a similar fashion, knowledge about the comparative effectiveness of drugs to treat type 2 diabetes is finally beginning to emerge from 40 years of stagnation. This period of darkness and the current reawakening provide critically important lessons for contemporary medicine about the use of surrogate end points in drug development, regulatory oversight, and the hazards associated with reliance on commercial funding for pivotal clinical trials.

The diabetes Dark Ages began in 1961 with the initiation of one of the first major randomized, controlled trials (RCTs) in modern medicine, the UGDP (University Group Diabetes Project) study. The design of this study was complex, with patients randomly assigned to 5 treatment groups: variable-dose insulin, fixed-dose insulin, tolbutamide, phenformin, or diet alone. In 1970, the tolbutamide group discontinued therapy because of an increase in all-cause and cardiovascular (CV) mortality compared with the other treatment groups (1). The makers of tolbutamide launched an aggressive campaign to discredit the UGDP study findings by using leading and well-remunerated academics (2). As Schwartz and Meinert (2) described in 2004, “The arguments became increasing ad hominem, eventually challenging the honesty of the UGDP investigators.”

The reaction of the broader pharmaceutical industry to the concern about the CV effects of sulfonylureas was decisive and sustained. For the next 40 years, industry simply stopped performing RCTs comparing CV outcomes for alternative diabetes treatment strategies. In 2007, a systematic review catalogued this unfortunate state of affairs, describing the evidence for comparative effectiveness for CV outcomes with diabetes drugs as “low to very low” (3). An anachronistic regulatory policy requiring only that new diabetes drugs show that they lower blood glucose levels without obvious safety problems, not that they improve clinical outcomes, allowed industry to avoid performing studies on CV outcomes. Thoughtful academics have criticized the reliance on biochemical measures as a surrogate for clinical benefit, because numerous surrogates have failed to show a consistent link with actual clinical outcomes (4). However, regulatory policy for diabetes drug development remained essentially static for 50 years.

A series of traumatic shock waves ultimately was required to shake the complacency of the diabetes community and the regulators. The first of these shocks occurred in 2005 after an advisory panel of the U.S. Food and Drug Administration (FDA) recommended approval of muraglitazar, the first dual (α and γ) peroxisome proliferator–activated receptor modulator to reach an advanced stage of development. The biochemical effects of muraglitazar, including robust reduction in hemoglobin A1c levels, marked increases in high-density lipoprotein cholesterol levels, and substantial decreases in triglyceride levels, were impressive. However, immediately after the panel recommendation, my colleagues and I used the FDA briefing documents to reanalyze the CV outcomes data from the muraglitazar development program and found a doubling of major CV morbidity and mortality (5). The FDA quickly reassessed the drug and declined approval. The makers of the drug soon terminated the development program. Nonetheless, a risky drug came very close to regulatory approval.

The second shock wave occurred in 2007 when my colleagues and I published a meta-analysis of CV outcomes with rosiglitazone based on study-level data that became available after a court settlement required the drug maker to disclose all clinical trial results (6). Thirty-five of the 42 clinical trials used in the analysis were unpublished. The study calculated an estimated 43% increase in the risk for myocardial infarction for rosiglitazone compared with other 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 revealed that the company had completed its own internal analysis 2 years before our publication, confirming a significantly increased risk for myocardial infarction (8). By 2010, the evidence for harm was so overwhelming that European authorities forced the company to withdraw rosiglitazone from the market and the FDA restricted its use to patients whose disease was refractory to all other therapies. In 2012, the drug maker paid a record $3 billion fine for civil and criminal penalties, related in part to concealing safety data for rosiglitazone.

The third shock wave occurred in 2008, when the National Institutes of Health terminated a trial designed to compare more-intensive with less-intensive glucose lowering after observing an increase in CV mortality in the more aggressively treated group (9).

These 3 successive shocks finally forced the FDA to reconsider its decades-old policy of approving diabetes drugs primarily on the basis of glucose-lowering effects. An advisory panel, convened in 2008, endorsed an approach recommendation that I presented with support from Dr. Thomas Fleming requiring a 2-stage approval process for diabetes drugs.

In the first step, a CV outcomes trial must rule out an upper 95% CI for a hazard ratio of 1.8 for CV events, followed by a postapproval study to rule out an upper CI of 1.3 (10). Some critics predicted that this policy would halt the development of diabetes drugs, but it has actually done the opposite. Dozens of new diabetes drugs are now in 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' article (11) in this issue renews an old controversy. The findings of the UGDP trial were never refuted by a modern RCT. Instead, we have a series of post hoc analyses of studies never designed to resolve the CV safety concern about sulfonylureas. Some but not all of these studies suggested that sulfonylureas were similar to other diabetes drugs in their effects on CV outcomes.

Because sulfonylureas and metformin were approved during the legacy era in which CV outcomes trials were not required, the new FDA diabetes guidance is not applicable. Accordingly, no financial incentives exist for industry to perform comparative effectiveness trials evaluating these 2 commonly used therapies. We must therefore use observational studies to answer a scientific question first asked in 1961: 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 methods available to analyze observational data, including careful adjustment for known confounders, propensity matching, and multiple sensitivity analyses. Despite the recognized limitations of observational studies, the findings are credible and important. Sulfonylureas seem inferior to metformin with respect to CV outcomes. However, in the absence of a modern RCT confirming the findings, we must view these data as hypothesis-generating rather than definitive. As such, the UGDP controversy remains unresolved 51 years after the study was initiated.

How might sulfonylureas increase adverse CV outcomes? One theory focuses on their adverse effects on ischemic preconditioning, an adaptive mechanism that allows the myocardium to resist necrosis after intermittent periods of ischemia (12). Another hypothesis relates to sulfonylurea-induced hypoglycemia, which theoretically may result in myocardial ischemia. Regardless of mechanism, this scientific question demands a definitive answer. In the absence of an industry-sponsored study, public health authorities should conduct such a clinical trial. With more than two thirds of diabetic patients dying of CV causes and millions of patients currently receiving sulfonylureas, this question must be resolved with high-quality evidence. Continued darkness is not an acceptable option.

References

Goldner MG, Knatterud GL, Prout TE. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. 3. Clinical implications of UGDP results. JAMA. 1971; 218:1400-10.
PubMed
CrossRef
 
Schwartz TB, Meinert CL. The UGDP controversy: thirty-four years of contentious ambiguity laid to rest. Perspect Biol Med. 2004; 47:564-74.
PubMed
CrossRef
 
Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007; 147:386-99.
PubMed
 
Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996; 125:605-13.
PubMed
 
Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005; 294:2581-6.
PubMed
CrossRef
 
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.
PubMed
 
Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med. 2007; 147:578-81.
PubMed
 
Grassley, Baucus release committee report on Avandia: senators express concern about FDA's role in protecting patients in ongoing Avandia study [press release]. Washington, DC: U.S. Senate Committee on Finance; 10 February 2010. Accessed at www.finance.senate.gov/newsroom/chairman/release/?id=bc56b552-efc5-4706-968d-f7032d5cd2e4 on 28 September 2012.
 
Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, et al, Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358:2545-59.
PubMed
 
U.S. Food and Drug Administration.  Guidance for Industry: Diabetes Mellitus—Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Silver Spring, MD: U.S. Food and Drug Administration; December 2008. Accessed at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf on 28 September 2012.
 
Roumie CL, Hung AM, Greevy RA, Grijalva CG, Liu X, Murff HJ, et al. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus. A cohort study. Ann Intern Med. 2012; 157:601-10.
 
Meier JJ, Gallwitz B, Schmidt WE, Mügge A, Nauck MA. Is impairment of ischaemic preconditioning by sulfonylurea drugs clinically important? Heart. 2004; 90:9-12.
PubMed
 

Figures

Tables

References

Goldner MG, Knatterud GL, Prout TE. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. 3. Clinical implications of UGDP results. JAMA. 1971; 218:1400-10.
PubMed
CrossRef
 
Schwartz TB, Meinert CL. The UGDP controversy: thirty-four years of contentious ambiguity laid to rest. Perspect Biol Med. 2004; 47:564-74.
PubMed
CrossRef
 
Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007; 147:386-99.
PubMed
 
Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996; 125:605-13.
PubMed
 
Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005; 294:2581-6.
PubMed
CrossRef
 
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.
PubMed
 
Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med. 2007; 147:578-81.
PubMed
 
Grassley, Baucus release committee report on Avandia: senators express concern about FDA's role in protecting patients in ongoing Avandia study [press release]. Washington, DC: U.S. Senate Committee on Finance; 10 February 2010. Accessed at www.finance.senate.gov/newsroom/chairman/release/?id=bc56b552-efc5-4706-968d-f7032d5cd2e4 on 28 September 2012.
 
Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, et al, Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358:2545-59.
PubMed
 
U.S. Food and Drug Administration.  Guidance for Industry: Diabetes Mellitus—Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Silver Spring, MD: U.S. Food and Drug Administration; December 2008. Accessed at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf on 28 September 2012.
 
Roumie CL, Hung AM, Greevy RA, Grijalva CG, Liu X, Murff HJ, et al. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus. A cohort study. Ann Intern Med. 2012; 157:601-10.
 
Meier JJ, Gallwitz B, Schmidt WE, Mügge A, Nauck MA. Is impairment of ischaemic preconditioning by sulfonylurea drugs clinically important? Heart. 2004; 90:9-12.
PubMed
 

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Making The Dark Ages Brighter With CAROLINA– a Dedicated Randomized Controlled Trial to Address the SU Controversy
Posted on November 12, 2012
Julio Rosenstock1, Nikolaus Marx2, Odd Erik Johansen3, Hans-Jürgen Wörle3 on behalf of the CAROLINA Steering Committee
1: Dallas Diabetes & Endocrine Ctr at Medical City, Dallas, TX 2: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany 3: Boehringer Ingelheim, Ingelheim, Germany
Conflict of Interest: All authors are involved in the CAROLINA steering committee. Julio Rosenstock has also served on scientific advisory boards and received honorarium or consulting fees from Pfizer, Roche, Sanofi, Novo Nordisk, Eli Lilly, MannKind, GlaxoSmithKline, Takeda, Daiichi Sankyo, Johnson & Johnson, Novartis, Boehringer Ingelheim, and Lexicon. He has also received grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Roche, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Amylin, Johnson & Johnson, Daiichi Sankyo, MannKind, Lexicon and Boehringer Ingelheim. Nikolaus Marx served as a speaker for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Cordis, GlaxoSmithKline, Lilly, MSD, Novartis, NovoNordisk, Pfizer, Roche, Sanofi, as well as Takeda and as a consultant for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Genfit, GlaxoSmithKline, MSD, NovoNordisk, Roche, Sanofi and Takeda. Furthermore he received unrestricted research grants from: Boehringer Ingelheim, GSK, MSD as well as Takeda and also participated in clinical trials sponsored by: Boehringer Ingelheim and Roche. Odd Erik Johansen and Hans-Jürgen Wörle are employed by Boehringer Ingelheim.

Dear Editor,

We read with great interest Dr. Nissen’s recent editorial [1] regarding the observational study published in your journal comparing sulfonylureas with metformin [2]. We agree entirely with his comment that the evidence-base to guide clinical decision making in type 2 diabetes mellitus currently suffers from the absence of a rigorous, randomized, controlled trial (RCT) addressing the sulfonylurea controversy. Not only are there conflicting results between older and more recent trials using sulfonylureas, but in addition observational studies are not concordant [2,3]. Indeed, no epidemiologic, observational retrospective or prospective cohort study even with the best of biostatistics and methodology can replace a properly conducted RCT.

In the editorial, Dr. Nissen rightfully called for the need of a RCT evaluating the effect of sulfonylureas on cardiovascular disease outcomes. We welcome his call and are pleased to inform that currently there is an ongoing RCT specifically designed and properly powered to address the SU controversy. The “Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes” (CAROLINA; NCT01243424) is such a trial. This study is a double-blind, double dummy, RCT that began in November 2010 and recently completed recruitment of the target number of 6000 patients with relatively early type 2 diabetes mellitus who are at high risk of or already have evidence of cardiovascular complications. Since this study will explore potential differing effects on cardiovascular outcomes of linagliptin therapy versus glimepiride, predominantly as add-on to metformin, its results may provide firm evidence to aid in the future clinical decision-making when selecting second line therapy in type 2 diabetes mellitus. CAROLINA is addressing an important piece of the large data gap of comparative effectiveness studies in diabetes, as recognized by Nissen [1] and others [4,5], and hopefully will help us move towards the “Age of Enlightenment” for selecting therapeutic strategies in the high risk population of patients with diabetes.

References:

1. Nissen S. Cardiovascular effects of diabetes drugs: emerging from the Dark Ages. Ann Int Med 2012;157:671-672.

2. Roumie CL, Hung AM, Greevy RA, Grijalva CG, Liu X, Murff HJ, et al. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus. A cohort study. Ann Intern Med 2012;157:601-610.

3. Zeller M, Danchin N, Simon D, et al. Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction. J Clin Endocrinol Metab 2010;95:4993-5002.

4. Nathan D. Time for clinically relevant comparative effectiveness studies in type 2 diabetes. Ann Intern Med 2011;154:131-132.

5. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations Ann Intern Med. 2011;154:602-613.

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