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Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysisDiabetes Medications as Monotherapy or Metformin-Based Combination Therapy

Nisa M. Maruthur, MD, MHS; Eva Tseng, MD, MPH; Susan Hutfless, PhD; Lisa M. Wilson, ScM; Catalina Suarez-Cuervo, MD; Zackary Berger, MD, PhD; Yue Chu, MSPH; Emmanuel Iyoha, MBChB, MPH; Jodi B. Segal, MD, MPH; and Shari Bolen, MD, MPH
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 19 April 2016.


From The Johns Hopkins University School of Medicine; The Johns Hopkins University Bloomberg School of Public Health; and Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, Maryland, and Center for Health Care Research and Policy, MetroHealth/Case Western Reserve University; MetroHealth Medical Center; and Case Western Reserve University, Cleveland, Ohio.

Disclaimer: The authors of this article are responsible for its content. Statements in the article should not be construed as endorsement by the AHRQ or the U.S. Department of Health and Human Services. The AHRQ retains a license to display, reproduce, and distribute the data and the report from which this article was derived under the terms of the Agency's contract with the author.

Acknowledgment: The authors thank their Task Order Officers at AHRQ, Drs. Karen Lee and Elisabeth Kato, and their Associate Editor at the RAND Corporation, Dr. Margaret A. Maglione, for their guidance on this review, as well as Jessica Gayleard for her help in reviewing articles.

Financial Support: This project was funded under contract 290-2012-00007-I from AHRQ, U.S. Department of Health and Human Services.

Disclosures: Dr. Maruthur reports a contract with AHRQ during the conduct of the study. Ms. Wilson reports a contract with AHRQ during the conduct of the study. Dr. Berger reports a contract with AHRQ during the conduct of the study. Dr. Segal reports a contract with AHRQ during the conduct of the study. Dr. Bolen reports a contract with AHRQ during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-2650.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.

Requests for Single Reprints: Nisa M. Maruthur, MD, MHS, Welch Center for Prevention, Epidemiology and Clinical Research, 2024 East Monument Street, Room 2-601, Baltimore, MD 21287; e-mail, maruthur@jhmi.edu.

Current Author Addresses: Dr. Maruthur: Welch Center for Prevention, Epidemiology and Clinical Research, 2024 East Monument Street, Room 2-601, Baltimore, MD 21287.

Dr. Tseng: Welch Center for Prevention, Epidemiology and Clinical Research, 2024 East Monument Street, Room 2-617, Baltimore, MD 21287.

Dr. Hutfless: Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins School of Medicine, 600 North Wolfe Street, Blalock 449, Baltimore, MD 21287.

Ms. Wilson and Drs. Suarez-Cuervo and Iyoha: Department of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, 624 North Broadway, Room 680, Baltimore, MD 21205.

Drs. Berger and Segal: Johns Hopkins Outpatient Center, 601 North Caroline Street, #7143, Baltimore, MD 21287.

Ms. Chu: The Johns Hopkins University, 615 North Wolfe Street, Room W5508, Baltimore, MD 21205.

Dr. Bolen: MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109.

Author Contributions: Conception and design: N.M. Maruthur, S. Hutfless, L.M. Wilson, Z. Berger, E. Iyoha, J.B. Segal, S. Bolen.

Analysis and interpretation of the data: N.M. Maruthur, E. Tseng, S. Hutfless, L.M. Wilson, C. Suarez-Cuervo, Z. Berger, Y. Chu, E. Iyoha, J.B. Segal, S. Bolen.

Drafting of the article: N.M. Maruthur, E. Tseng, L.M. Wilson, C. Suarez-Cuervo, Y. Chu, E. Iyoha, S. Bolen.

Critical revision of the article for important intellectual content: N.M. Maruthur, L.M. Wilson, C. Suarez-Cuervo, Z. Berger, J.B. Segal, S. Bolen.

Final approval of the article: N.M. Maruthur, E. Tseng, S. Hutfless, L.M. Wilson, C. Suarez-Cuervo, Z. Berger, Y. Chu, E. Iyoha, J.B. Segal, S. Bolen.

Provision of study materials or patients: L.M. Wilson.

Statistical expertise: N.M. Maruthur, L.M. Wilson, J.B. Segal, S. Bolen.

Obtaining of funding: N.M. Maruthur, S. Bolen.

Administrative, technical, or logistic support: L.M. Wilson, Y. Chu.

Collection and assembly of data: N.M. Maruthur, E. Tseng, S. Hutfless, L.M. Wilson, C. Suarez-Cuervo, Z. Berger, Y. Chu, E. Iyoha, J.B. Segal, S. Bolen.


Ann Intern Med. 2016;164(11):740-751. doi:10.7326/M15-2650
Text Size: A A A

Background: Clinicians and patients need updated evidence on the comparative effectiveness and safety of diabetes medications to make informed treatment choices.

Purpose: To evaluate the comparative effectiveness and safety of monotherapy (thiazolidinediones, metformin, sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium–glucose cotransporter 2 [SGLT-2] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists) and selected metformin-based combinations in adults with type 2 diabetes.

Data Sources: English-language studies from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, indexed from inception through March 2015 (MEDLINE search updated through December 2015).

Study Selection: Paired reviewers independently identified 179 trials and 25 observational studies of head-to-head monotherapy or metformin-based combinations.

Data Extraction: Two reviewers independently assessed study quality and serially extracted data and graded the strength of evidence.

Data Synthesis: Cardiovascular mortality was lower for metformin versus sulfonylureas; the evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or of low strength. Reductions in hemoglobin A1c values were similar across monotherapies and metformin-based combinations, except that DPP-4 inhibitors had smaller effects. Body weight was reduced or maintained with metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors and increased with sulfonylureas, thiazolidinediones, and insulin (between-group differences up to 5 kg). Hypoglycemia was more frequent with sulfonylureas. Gastrointestinal adverse events were highest with metformin and GLP-1 receptor agonists. Genital mycotic infections were increased with SGLT-2 inhibitors.

Limitation: Most studies were short, with limited ability to assess rare safety and long-term clinical outcomes.

Conclusion: The evidence supports metformin as first-line therapy for type 2 diabetes, given its relative safety and beneficial effects on hemoglobin A1c, weight, and cardiovascular mortality (compared with sulfonylureas). On the basis of less evidence, results for add-on therapies to metformin were similar to those for monotherapies.

Primary Funding Source: Agency for Healthcare Research and Quality.

Figures

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Appendix Figure.

Summary of evidence search and selection.

FDA = U.S. Food and Drug Administration; RCT = randomized, controlled trial.

* Total may exceed the number in the corresponding box because articles could be excluded for >1 reason at this level.

† Comorbid condition restrictions were end-stage renal disease, end-stage liver disease, cancer, new-onset diabetes after transplant, or a cardiovascular event within 3 mo (such as acute coronary syndrome, acute myocardial infarction, post–coronary artery bypass graft surgery, or drug-eluting stents).

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Figure 1.

Pooled between-group differences in the change in HbA1c for comparisons of monotherapies and metformin-based combination therapies.

All differences for HbA1c are absolute percentage-point differences. BL = baseline; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; HbA1c = hemoglobin A1c; Met = metformin; PLE = profile likelihood estimate; SGLT-2 = sodium–glucose cotransporter 2; SU = sulfonylurea; TZD = thiazolidinedione.

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Figure 2.

Pooled between-group differences in the change in weight for comparisons of monotherapies and metformin-based combination therapies.

BL = baseline; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; Met = metformin; PLE = profile likelihood estimate; SGLT-2 = sodium–glucose cotransporter 2; SU = sulfonylurea; TZD = thiazolidinedione; wt = weight.

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Figure 3.

Pooled odds ratios for mild and moderate hypoglycemia for comparisons of monotherapies and metformin-based combination therapies.

Relative risk for hypoglycemia shown by ranges in absolute RDs across study groups and as pooled odds ratios. DPP-4 = dipeptidyl peptidase-4; Met = metformin; PLE = profile likelihood estimate; RD = risk difference; SGLT-2 = sodium–glucose cotransporter 2; SU = sulfonylurea; TZD = thiazolidinedione.

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Figure 4.

Pooled odds ratios for GI side effects for monotherapies and metformin-based combination therapies.

DPP-4 = dipeptidyl peptidase-4; GI = gastrointestinal; GLP-1 = glucagon-like peptide-1; Met = metformin; RD = risk difference; SGLT-2 = sodium–glucose cotransporter 2; SU = sulfonylurea; TZD = thiazolidinedione.

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Response
Posted on June 20, 2016
Michaela B Rehman, Benoit V Tudrej, Rémy Boussageon
CHU de Poitiers & Poitiers University
Conflict of Interest: None Declared

It is surprising that Metformin is considered to be the first-line treatment in type 2 diabetes1, even though this status is only based on a small number of overweight patients (342 vs. 411) in the UKPDS34 trial2. Moreover, this trial had many biases: it was not double blinded, the endpoints changed during the study, there were multiple statistical analyses, etc..3. When all the trials analyzing metformin’s specific efficacy are analyzed together, there is no proof of efficacy on any micro or macrovascular endpoint4. It is a selection bias, to conclude that metformin is effective based on the UKPDS34 trial2 only. Why is the medical community persuaded that metformin is effective?
Metformin has not shown any efficacy on the prevention of microvascular complications, nor in the UKPDS34 trial2, nor in meta-analysis4. This is, however, the primary objective of any treatment in type 2 diabetes.
Metformin’s superiority over sulfonylureas is also questionable. To begin, sulfonylureas’ specific efficacy (vs. placebo) on micro and macrovascular complications is not established5. Secondly, there are data that suggest that they could be harmful with an increased risk of stroke and mortality6. Metformin could have a greater “efficacy” than sulfonylureas on cardiovascular endpoints, simply because the latter are more harmful. It is not because metformin is more effective than sulfonylureas that metformin is truly effective. Without a placebo group, it is not possible to conclude.
It is high time to look at the facts (or their absence!) and to admit that there is no real proof that metformin is effective. It is also important to remember that no treatment has shown any clinically pertinent efficacy (insulin included)5, apart from empagliflozin8 and liraglutide9 whose spectacular results on global mortality need to be confirmed and reproduced.

1. Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, et al. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Ann Intern Med 2016 ; 164:740-51
2. UK prospective diabetes study (UKPDS) group. Effect of Intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998; 352: 854-865
3. Boussageon R, Gueyffier F, Cornu C. Metformin as firstline treatment for type 2 diabetes: are we sure? BMJ. 2016 Jan 8;352:h6748. doi: 10.1136/bmj.h6748
4. Boussageon R, Supper I, Bejan-Angoulvant T, Kellou N, Cucherat M, Boissel JP, et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes : a meta-analysis of randomized controlled trials. Plos Med 2012 ;9(4):e1001204. doi: 10.1371/journal.pmed.1001204
5. Boussageon R, Gueyffier F, Cornu C. Effects of pharmacological treatments on micro- and macrovascular complications of type 2 diabetes: what is the level of evidence? Diabetes Metab 2014; 40:169-75
6. Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013 ; 15: 938-53
7. Montori VM, Fernández-Balsells M. Glycemic control in type 2 diabetes: time for an evidence-based about-face? Ann Intern Med 2009 ; 150 :803-8
8. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015 ; 373 :2117-28
9. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016 ; Jun 13. [Epub ahead of print]

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