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JAMA. 2016 Jul 19;316(3):313-24. doi: 10.1001/jama.2016.9400.

Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis.

Author information

1
Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
2
Department of Primary Education, School of Education, University of Ioannina, University Campus, Dourouti, Ioannina, Greece3Department of Hygiene and Epidemiology, School of Health Sciences, University of Ioannina, University Campus, Dourouti, Ioannina, G.
3
Center for Outcomes Research and Clinical Epidemiology (CORESEARCH), Pescara, Italy.
4
Division of Medicine, Department of Renal Medicine, University of Queensland at the Princess Alexandra Hospital, Woolloongabba, Australia6Translational Research Institute, University of Queensland, Woolloongabba, Australia.
5
Cumming School of Medicine, Health Sciences Centre, University of Calgary, Foothills Campus, Calgary, Alberta, Canada.
6
Sydney School of Public Health, University of Sydney, Sydney, Australia.
7
Division of Nephrology and Transplantation, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy10Diaverum Medical Scientific Office, Lund, Sweden.
8
Diaverum Medical Scientific Office, Lund, Sweden.
9
Division of Medicine, Department of Renal Medicine, University of Queensland at the Princess Alexandra Hospital, Woolloongabba, Australia11The George Institute for Global Health, Sydney, Australia.
10
Division of Medicine, Department of Renal Medicine, University of Queensland at the Princess Alexandra Hospital, Woolloongabba, Australia.
11
Nephrology Division, Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
12
Department of Medicine, Royal Alexandra Hospital, Edmonton, Alberta, Canada.
13
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
14
Sydney School of Public Health, University of Sydney, Sydney, Australia10Diaverum Medical Scientific Office, Lund, Sweden15Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Abstract

IMPORTANCE:

Numerous glucose-lowering drugs are used to treat type 2 diabetes.

OBJECTIVE:

To estimate the relative efficacy and safety associated with glucose-lowering drugs including insulin.

DATA SOURCES:

Cochrane Library Central Register of Controlled Trials, MEDLINE, and EMBASE databases through March 21, 2016.

STUDY SELECTION:

Randomized clinical trials of 24 weeks' or longer duration.

DATA EXTRACTION AND SYNTHESIS:

Random-effects network meta-analysis.

MAIN OUTCOMES AND MEASURES:

The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, serious adverse events, myocardial infarction, stroke, hemoglobin A1c (HbA1C) level, treatment failure (rescue treatment or lack of efficacy), hypoglycemia, and body weight.

RESULTS:

A total of 301 clinical trials (1,417,367 patient-months) were included; 177 trials (56,598 patients) of drugs given as monotherapy; 109 trials (53,030 patients) of drugs added to metformin (dual therapy); and 29 trials (10,598 patients) of drugs added to metformin and sulfonylurea (triple therapy). There were no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with odds of cardiovascular or all-cause mortality. Compared with metformin, sulfonylurea (standardized mean difference [SMD], 0.18 [95% CI, 0.01 to 0.34]), thiazolidinedione (SMD, 0.16 [95% CI, 0.00 to 0.31]), DPP-4 inhibitor (SMD, 0.33 [95% CI, 0.13 to 0.52]), and α-glucosidase inhibitor (SMD, 0.35 [95% CI, 0.12 to 0.58]) monotherapy were associated with higher HbA1C levels. Sulfonylurea (odds ratio [OR], 3.13 [95% CI, 2.39 to 4.12]; risk difference [RD], 10% [95% CI, 7% to 13%]) and basal insulin (OR, 17.9 [95% CI, 1.97 to 162]; RD, 10% [95% CI, 0.08% to 20%]) were associated with greatest odds of hypoglycemia. When added to metformin, drugs were associated with similar HbA1C levels, while SGLT-2 inhibitors offered the lowest odds of hypoglycemia (OR, 0.12 [95% CI, 0.08 to 0.18]; RD, -22% [-27% to -18%]). When added to metformin and sulfonylurea, GLP-1 receptor agonists were associated with the lowest odds of hypoglycemia (OR, 0.60 [95% CI, 0.39 to 0.94]; RD, -10% [95% CI, -18% to -2%]).

CONCLUSIONS AND RELEVANCE:

Among adults with type 2 diabetes, there were no significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality. Metformin was associated with lower or no significant difference in HbA1C levels compared with any other drug classes. All drugs were estimated to be effective when added to metformin. These findings are consistent with American Diabetes Association recommendations for using metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations.

PMID:
27434443
DOI:
10.1001/jama.2016.9400
[Indexed for MEDLINE]

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