Steven E. Nissen, MD
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-2295.
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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
November 12, 2012
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.
Making The Dark Ages Brighter With CAROLINA– a Dedicated Randomized Controlled Trial to Address the SU Controversy
We read with great interest Dr. Nissen’s recent editorial  regarding the observational study published in your journal comparing sulfonylureas with metformin . 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  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.
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.
Nissen SE. Cardiovascular Effects of Diabetes Drugs: Emerging From the Dark Ages. Ann Intern Med. 2012;157:671–672. doi: 10.7326/0003-4819-157-9-201211060-00016
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Published: Ann Intern Med. 2012;157(9):671-672.
Cardiology, Coronary Risk Factors, Diabetes, Endocrine and Metabolism.
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