Current Diabetes Reports

, 14:478 | Cite as

Systematic Reviews to Ascertain the Safety of Diabetes Medications

  • Michael R. Gionfriddo
  • Oscar L. Morey-Vargas
  • Juan P. Brito
  • Aaron L. Leppin
  • M. Hassan Murad
  • Victor M. Montori
Pharmacologic Treatment of Type 2 Diabetes (A Vella, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pharmacologic Treatment of Type 2 Diabetes


Clinicians and patients with type 2 diabetes enjoy an expanding list of medications to improve glycemic control. With this expansion has come a flurry of concerns about the safety of these antihyperglycemic agents, concerns that affect judgments about the risk/benefit balance of therapy. Some of these safety signals have been identified through the synthesis of existing research evidence. Thus, it has become important for clinicians and clinical policymakers to understand the strengths and limitations of systematic reviews and meta-analyses in determining the safety of diabetes medications. In this paper, we highlight key safety concerns with diabetes medications and discuss the role evidence synthesis plays in each, with special attention to its strengths and limitations.


Systematic review Meta-analysis Diabetes Safety Diabetes medications 



This publication was supported by CCaTS Grant Number TL1 TR000137 from the National Center for Advancing Translational Science (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Compliance with Ethics Guidelines

Conflict of Interest

Michael R. Gionfriddo declares that he has no conflict of interest. Oscar L. Morey-Vargas declares that he has no conflict of interest. Juan P. Brito declares that he has no conflict of interest. Aaron L. Leppin declares that he has no conflict of interest. M. Hassan Murad declares that he has no conflict of interest. Victor M. Montori declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Centers for Disease Control and Prevention. Increasing prevalence of diagnosed diabetes—United States and Puerto Rico, 1995–2010. Morb Mortal Wkly Rep. 2012;61:918–21.Google Scholar
  2. 2.
    Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010;4, CD002967. doi: 10.1002/14651858.CD002967.pub4.PubMedGoogle Scholar
  3. 3.
    Silagy CA, Middleton P, Hopewell S. Publishing protocols of systematic reviews: comparing what was done to what was planned. JAMA. 2002;287:2831–4.PubMedCrossRefGoogle Scholar
  4. 4.
    Green S, Higgins JPT, Alderson P, Clarke M, Mulrow CD, Oxman AD. Chapter 1: Introduction. In: Higgins JPT, Green S (editors), Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from
  5. 5.
    Lavis JN. How can we support the use of systematic reviews in policymaking? PLoS Med. 2009;6:e1000141. doi: 10.1371/journal.pmed.1000141.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    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. doi: 10.1001/jama.294.20.joc50147.PubMedCrossRefGoogle Scholar
  7. 7.
    Mehta SN, Goldfine AB, Abrahamson MJ, DiVincenzo R, Laffel LM. Changing prescribing patterns of type 2 diabetes medications from 2002–2010: an electronic health record-based evaluation. J Diabetes Sci Technol. 2013;7:119–22.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med. 2007;356:2522–4. doi: 10.1056/NEJMe078099.PubMedCrossRefGoogle Scholar
  9. 9.
    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. doi: 10.1056/NEJMoa072761.PubMedCrossRefGoogle Scholar
  10. 10.
    Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA. 2007;298:1189–95. doi: 10.1001/jama.298.10.1189.PubMedCrossRefGoogle Scholar
  11. 11.
    Hiatt WR, Kaul S, Smith RJ. The cardiovascular safety of diabetes drugs—insights from the rosiglitazone experience. N Engl J Med. 2014;369:1285–7. doi: 10.1056/NEJMp1309610.Google Scholar
  12. 12.
    •Nissen SE, Wolski K. Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med. 2010;170:1191–201. doi: 10.1001/archinternmed.2010.207. This meta-analysis included the largest trial of cardiovascular safety for rosiglitazone and confirmed an increased of myocardial infarction and heart failure associated with rosiglitazone use.PubMedCrossRefGoogle Scholar
  13. 13.
    •Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicenter, randomized, open-label trial. Lancet. 2009;373:2125–35. doi: 10.1016/s0140-6736(09)60953-3. This is the largest randomized trial looking at the cardiovascular safety of rosiglitazone and is at the center of the controversy surrounding the cardiovascular safety of rosiglitazone.PubMedCrossRefGoogle Scholar
  14. 14.
    Egger M, Smith GD, Altman D. Systematic reviews in health care: meta-analysis in context. London: BMJ books; 2008.Google Scholar
  15. 15.
    Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64:401–6. doi: 10.1016/j.jclinepi.2010.07.015.PubMedCrossRefGoogle Scholar
  16. 16.
    ••Department of Health and Human Services. Advisory committee meeting for NDA 21071 Avandia (rosiglitazone maleate) tablet July 13 and 14, 2010. This document details the 2010 FDA review of rosiglitazone, within which the limitations of the RECORD trial are highlighted.
  17. 17.
    Food and Drug Administration. FDA requires removal of certain restrictions on the diabetes drug Avandia. November 25, 2013.
  18. 18.
    Ioannidis JP, Trikalinos TA. Early extreme contradictory estimates may appear in published research: the Proteus phenomenon in molecular genetics research and randomized trials. J Clin Epidemiol. 2005;58:543–9. doi: 10.1016/j.jclinepi.2004.10.019.PubMedCrossRefGoogle Scholar
  19. 19.
    Ioannidis JP. Evolution and translation of research findings: from bench to where? PLoS Clin Trials. 2006;1:e36. doi: 10.1371/journal.pctr.0010036.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    •Murad M, Montori VM. Synthesizing evidence: shifting the focus from individual studies to the body of evidence. JAMA. 2013;309:2217–8. doi: 10.1001/jama.2013.5616. This paper expounds the reasons why clinicians should examine the body of evidence rather than individuals studies.PubMedCrossRefGoogle Scholar
  21. 21.
    Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180–8. doi: 10.1001/jama.298.10.1180.PubMedCrossRefGoogle Scholar
  22. 22.
    Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427–43. doi: 10.1056/NEJMoa066224.PubMedCrossRefGoogle Scholar
  23. 23.
    Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ. 2009;180:32–9. doi: 10.1503/cmaj.080486.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Felson DT. Bias in meta-analytic research. J Clin Epidemiol. 1992;45:885–92.PubMedCrossRefGoogle Scholar
  25. 25.
    Savoie I, Helmer D, Green CJ, Kazanjian A. Beyond Medline: reducing bias through extended systematic review search. Int J Technol Assess Health Care. 2003;19:168–78.PubMedCrossRefGoogle Scholar
  26. 26.
    Sampson M, McGowan J. Errors in search strategies were identified by type and frequency. J Clin Epidemiol. 2006;59:1057–63. doi: 10.1016/j.jclinepi.2006.01.007.PubMedCrossRefGoogle Scholar
  27. 27.
    Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomized controlled trial. Lancet. 2005;366:1279–89. doi: 10.1016/s0140-6736(05)67528-9.PubMedCrossRefGoogle Scholar
  28. 28.
    Lewis JD, Ferrara A, Peng T, Hedderson M, Bilker WB, Quesenberry Jr CP, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. 2011;34:916–22. doi: 10.2337/dc10-1068.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Piccinni C, Motola D, Marchesini G, Poluzzi E. Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care. 2011;34:1369–71. doi: 10.2337/dc10-2412.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Colmers IN, Bowker SL, Majumdar SR, Johnson JA. Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: a meta-analysis. CMAJ. 2012;184:E675–83. doi: 10.1503/cmaj.112102.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Ferwana M, Firwana B, Hasan R, Al-Mallah MH, Kim S, Montori VM, et al. Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies. Diabetes Med. 2013;30:1026–32. doi: 10.1111/dme.12144.CrossRefGoogle Scholar
  32. 32.
    Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013;173:534–9. doi: 10.1001/jamainternmed.2013.2720.PubMedCrossRefGoogle Scholar
  33. 33.
    Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141:150–6. doi: 10.1053/j.gastro.2011.02.018.PubMedCrossRefGoogle Scholar
  34. 34.
    Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and pancreatitis risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;16:48–56. doi: 10.1111/dom.12176.PubMedCrossRefGoogle Scholar
  35. 35.
    ••Cohen D. Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed? BMJ. 2013;346:f3680. doi: 10.1136/bmj.f3680. This is an investigative report written by an editor from the BMJ that highlights the concerns around the safety of glucagon supressing drugs.
  36. 36.
    Murad MH, Coto-Yglesias F, Wang AT, Sheidaee N, Mullan RJ, Elamin MB, et al. Clinical review: drug-induced hypoglycemia: a systematic review. J Clin Endocrinol Metab. 2009;94:741–5. doi: 10.1210/jc.2008-1416.PubMedCrossRefGoogle Scholar
  37. 37.
    Meinert CL. Clinical trials: design, conduct and analysis. New York, New York: Oxford University Press; 2012.Google Scholar
  38. 38.
    Duijnhoven RG, Straus SM, Raine JM, de Boer A, Hoes AW, De Bruin ML. Number of patients studied prior to approval of new medicines: a database analysis. PLoS Med. 2013;10:e1001407. doi: 10.1371/journal.pmed.1001407.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Meinert CL. Clinical Trials Dictionary: Terminology and usage recommendations. Hoboken, NJ: John Wiley & Sons, Inc.; 2012.Google Scholar
  40. 40.
    U.S. Food and Drug Administration. FDA’s Sentinel Initiative. 2013. Accessed 19 Sept 2013.
  41. 41.
    Heeley E, Riley J, Layton D, Wilton LV, Shakir SAW. Prescription-event monitoring and reporting of adverse drug reactions. Lancet. 2001;358:1872–3. doi: 10.1016/S0140-6736(01)06898-2.PubMedCrossRefGoogle Scholar
  42. 42.
    Hazell L, Shakir SAW. Under-reporting of adverse drug reactions: a systematic review. Drug Saf. 2006;29:385.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Michael R. Gionfriddo
    • 1
    • 2
  • Oscar L. Morey-Vargas
    • 1
    • 3
  • Juan P. Brito
    • 1
    • 3
  • Aaron L. Leppin
    • 1
  • M. Hassan Murad
    • 1
    • 4
  • Victor M. Montori
    • 1
    • 3
  1. 1.Knowledge and Evaluation Research UnitMayo ClinicRochesterUSA
  2. 2.Mayo Graduate SchoolMayo ClinicRochesterUSA
  3. 3.Division of Endocrinology, Diabetes, Metabolism, and NutritionMayo ClinicRochesterUSA
  4. 4.Division of Preventive, Occupational and Aerospace Medicine, Division of Health Care Policy and ResearchMayo ClinicRochesterUSA

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