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Clinician Article

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



  • Palmer SC
  • Mavridis D
  • Nicolucci A
  • Johnson DW
  • Tonelli M
  • Craig JC, et al.
JAMA. 2016 Jul 19;316(3):313-24. doi: 10.1001/jama.2016.9400. (Review)
PMID: 27434443
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Disciplines
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 5/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 5/7
  • Hospital Doctor/Hospitalists
    Relevance - 6/7
    Newsworthiness - 4/7
  • Internal Medicine
    Relevance - 6/7
    Newsworthiness - 4/7
  • Endocrine
    Relevance - 5/7
    Newsworthiness - 4/7

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 a-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.


Clinical Comments

Endocrine

This review provides an important clinical clue for selection of anti-diabetic drugs without any DI information from pharmaceutical companies.

Family Medicine (FM)/General Practice (GP)

I just don`t see important clinical information in this massive review of all RCTs of diabetic agents. We know that now 3 medications improve cardiovascular and mortality patient-oriented outcomes (metformin, empagliflozin, and liguratide), yet you`d never know from this systematic review that there are any special meds from among the many treatment options.

General Internal Medicine-Primary Care(US)

The meta-analysis reinforces what most clinicians probably already suspect: metformin should be the first-line agent for most patients with adult-onset diabetes. After that, there doesn't seem to be much of a difference in what agent is selected. Patient preference, cost, and side effect profiles should drive the decision. A more helpful comparison would be metformin + insulin versus metformin + second other agent. This article will not change my practice.

General Internal Medicine-Primary Care(US)

Despite this study's limitations, some findings are important. Limitations: small trials with few CV outcomes. 190 of 301 trials included trial sponsors in data management, authorship, or both. Baseline weight but not BMI was reported. The trial of adding a 3rd oral agent was added to metformin / sulfonylurea. Important findings: DPP-4 inhibitors fared poorly as single agents and as second or third agents. SGLT-2 and metformin had the lowest risk for hypoglycemia. Surprisingly, metformin / sulfonylurea / GLP-1 had the lowest 3-drug regimen risk for hypoglycemia. No difference in primary or secondary endpoints! Diabetes is best PREVENTED. A socio / medico / politico concerted effort is needed to address this major health crisis.

General Internal Medicine-Primary Care(US)

This is an important meta-analysis after much published data showing risks with various drug classes of diabetes medications. This shows none of the diabetes drug classes increase mortality when compared with metformin. I found that outcome surprising with regard to the sulfonylureas (smaller studies showed increased risk), but reassuring given the large numbers of individuals taking these medications.

Internal Medicine

Interesting article.

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