Time for Clinically Relevant Comparative Effectiveness Studies in Type 2 Diabetes

Editorials18 January 2011Time for Clinically Relevant Comparative Effectiveness Studies in Type 2 DiabetesFREEDavid M. Nathan, MDDavid M. Nathan, MDFrom Diabetes Center, Massachusetts General Hospital, Boston, MA 02114.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-154-2-201101180-00303 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The type 2 diabetes epidemic continues at great human and financial cost (1). Much of the expense that attends diabetes and its care is attributable to the development of long-term complications, such as retinopathy, nephropathy, and neuropathy, which cause more cases of blindness, renal failure, and amputations than any other disease (2). In addition, diabetes is associated with a 2- to 5-fold increase in cardiovascular disease (3), which contributes to premature mortality. Fortunately, diabetes-specific microvascular complications can be reduced substantially by lowering chronic glycemia (4, 5); whether similar reductions decrease cardiovascular disease in type 2 diabetes is not as clear (6, 7). A hemoglobin A1c (HbA1c) level less than 7%, approximately equal to a mean glucose level of 8.3 mmol/L (150 mg/dL) (8), has been widely adopted as a rational goal with the expectation, based on substantial clinical trial data, that microvascular complications will be reduced and health improved (9, 10).Although the most persuasive trial in type 2 diabetes, the UKPDS (United Kingdom Prospective Diabetes Study) (4–6), used drugs that are now all available in generic formulations and are relatively inexpensive, the need to achieve and maintain low HbA1c levels and the obvious increasing market for diabetes drugs worldwide have spurred the development of 7 new classes of drugs in the past 15 years (11) to complement the 3 older stalwarts: insulin, metformin, and sulfonylureas. Moreover, the progressive decline in β-cell function and accompanying worsening of glycemic control with longer-duration diabetes (12) have also made the development of new drugs attractive, if not necessary. The cost of these new drugs has become increasingly problematic. Between 2001 and 2007, the cost of diabetes medications in the United States almost doubled, from approximately $7 billion to almost $13 billion, largely owing to the use of new, more expensive medications (13).Given the magnitude of the diabetes epidemic, the need to control glycemia effectively over long periods, and the large number of therapeutic choices now available, it is critical to compare therapeutic agents and treatment strategies. The authors of the international consensus algorithm for the treatment of type 2 diabetes decried the paucity of head-to-head drug comparison studies (9). More recently, recognizing the potential public health importance of comparative effectiveness research (CER), the Patient Protection and Affordable Care Act established the Patient-Centered Outcomes Research Institute to assist patients, clinicians, purchasers, and policymakers in making informed health decisions based on CER. More than $1 billion of American Recovery and Reinvestment Act funding has been dedicated to CER, and Francis Collins, director of the National Institutes of Health, has highlighted the need for CER studies (14). The variable effects of the different classes of antidiabetic agents on long-term glycemia and cardiovascular risk factors and the differences in side effect profiles, safety, tolerability, and cost need to be examined and weighed.Unfortunately, the randomized, controlled clinical trial by Buse and colleagues (15) in this issue, which was designed in concert with and funded by the manufacturer of exenatide, does little to help us understand the relative role of the new drugs and nothing to advance CER. Like many industry-supported and designed trials, the design of this study is safe for the drug under study, the glucagon-like peptide 1 [7-36 amide] receptor agonist exenatide, by virtue of challenging its efficacy only against a placebo control and not using an active comparator (competitor). The investigators combine exenatide, the major effect of which is to stimulate insulin secretion, with insulin, presumably with the intent of positioning exenatide for a new indication to be used with insulin. The study is admirable in that it used a double-blind design and the same protocol for adjusting the insulin dose in both treatment groups. Whether the study could be effectively blind, however, considering the high (probably >50%) prevalence of gastrointestinal side effects with exenatide, is questionable. Moreover, although the higher insulin doses in the placebo group than the exenatide group seem to suggest that the goal-driven insulin algorithm was applied as designed in both groups, one wonders why the basal insulin dose was not adjusted even more aggressively in the placebo group to achieve the target fasting plasma glucose level less than 5.55 mmol/L (<100 mg/dL); the fasting plasma glucose levels achieved were 6.77 mmol/L (122 mg/dL) in the placebo group and 6.27 mmol/L (113 mg/dL) in the exenatide group.Buse and colleagues (15) note that the current standard of care for type 2 diabetes is to add preprandial insulin to basal insulin when glucose goals are not being achieved. Because they chose a placebo instead of an active comparator, one can only conclude that exenatide added to insulin decreases HbA1c levels by about 0.7% (similar to the effect of exenatide in other combination drug studies [16]) when compared with substandard therapy—and at the expense of 2 additional injections per day, very common gastrointestinal side effects, and an estimated additional cost of $3500 per year (17). The study did demonstrate a differential, albeit small, effect on weight: Exenatide was associated with a 1.8-kg weight loss and insulin with a 1.0-kg weight gain, similar to previous studies (18). The study was only 30 weeks in duration, however, limiting its applicability to a chronic disease in which drug effects are important over decades, not months.The welcome addition of new agents to treat type 2 diabetes must be tempered by a clear understanding of the relative long-term benefits and risks of the new agents and their combinations. The oldest medications—metformin, sulfonylureas, and insulin—which have been recommended as the first tier of care (10), remain more effective in lowering glycemia and are substantially less expensive than the newer agents. Sulfonylurea and insulin are associated with weight gain, albeit modest, and relatively rare severe hypoglycemia. Such studies as the one by Buse and colleagues are not adequate for comparing the effectiveness and cost-effectiveness of the increasingly complex array of medications at our disposal. Long-term comparative effectiveness studies are needed to determine the best treatment approaches for the ongoing epidemic of type 2 diabetes, which shows no sign of relenting.David M. Nathan, MDDiabetes Center, Massachusetts General HospitalBoston, MA 02114References1. CDC National Diabetes Fact Sheet, 2007. Accessed at www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf on 29 November 2010. Google Scholar2. Nathan DM. Long-term complications of diabetes mellitus. N Engl J Med. 1993;328:1676-85. [PMID: 8487827] CrossrefMedlineGoogle Scholar3. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241:2035-8. [PMID: 430798] CrossrefMedlineGoogle Scholar4. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65. [PMID: 9742977] CrossrefMedlineGoogle Scholar5. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-53. [PMID: 9742976] CrossrefMedlineGoogle Scholar6. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-89. [PMID: 18784090] CrossrefMedlineGoogle Scholar7. 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. [PMID: 18539917] CrossrefMedlineGoogle Scholar8. Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ; A1c-Derived Average Glucose Study Group. Translating the A1C assay into estimated average glucose values. Diabetes Care. 2008;31:1473-8. [PMID: 18540046] CrossrefMedlineGoogle Scholar9. American Diabetes Association. Standards of medical care in diabetes—2010. Diabetes Care. 2010;33 Suppl 1 S11-61. [PMID: 20042772] CrossrefMedlineGoogle Scholar10. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al; American Diabetes Association. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2009;52:17-30. [PMID: 18941734] CrossrefMedlineGoogle Scholar11. Nathan DM. Finding new treatments for diabetes—how many, how fast ... how good? N Engl J Med. 2007;356:437-40. [PMID: 17267901] CrossrefMedlineGoogle Scholar12. U.K. Prospective Diabetes Study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes. 1995;44:1249-58. [PMID: 7589820] CrossrefMedlineGoogle Scholar13. Alexander GC, Sehgal NL, Moloney RM, Stafford RS. National trends in treatment of type 2 diabetes mellitus, 1994-2007. Arch Intern Med. 2008;168:2088-94. [PMID: 18955637] CrossrefMedlineGoogle Scholar14. Collins F. Oral presentation. Comparative Effectiveness and Personalized Medicine: An Essential Interface Conference, National Institutes of Health, Bethesda, Maryland, 19–21 October 2010. Google Scholar15. Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY, et al. Use of twice-daily exenatide in basal insulin–treated patients with type 2 diabetes. A randomized, controlled trial. Ann Intern Med. 2011;154:103-12. LinkGoogle Scholar16. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092-100. [PMID: 15855572] CrossrefMedlineGoogle Scholar17. Byetta 10mcg pen. Accessed at www.drugstore.com/byetta-10-mcg-pen/2-4ml-pen-10mcg0-04ml-solution/qxn66780021201 on 29 November 2010. Google Scholar18. Heine RJ, VanGaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG; GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143:559-69. [PMID: 16230722] LinkGoogle Scholar Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From Diabetes Center, Massachusetts General Hospital, Boston, MA 02114.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-2754.Corresponding Author: David M. Nathan, MD, Diabetes Center, Massachusetts General Hospital, 50 Staniford Street, Boston, MA 02114; e-mail, [email protected]org. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoUse of Twice-Daily Exenatide in Basal Insulin–Treated Patients With Type 2 Diabetes John B. Buse , Richard M. Bergenstal , Leonard C. Glass , Cory R. Heilmann , Michelle S. Lewis , Anita Y.M. Kwan , Byron J. 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Situación actual 18 January 2011Volume 154, Issue 2Page: 131-132KeywordsDrug regulationDrugsGlucoseHbA1cHemoglobinInsulinInsulin secretionRenal failureType 2 diabetesWeight gain ePublished: 18 January 2011 Issue Published: 18 January 2011 Copyright & PermissionsCopyright © 2011 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...