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Cited by 300Diabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and LipoproteinsCardiovascular Function and Risk Factors

Cardiovascular Outcomes in Trials of Oral Diabetes Medications: A Systematic Review

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Selvin, Elizabeth, Bolen, Shari, Yeh, Hsin-Chieh, Wiley, Crystal, Wilson, Lisa M., Marinopoulos, Spyridon S., Feldman, Leonard, Vassy, Jason +3 more·2008·Archives of Internal Medicine
DOI 10.1001/archinte.168.19.2070PMC PMC2765722
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Abstract

BACKGROUND: A wide variety of oral diabetes medications are currently available for the treatment of type 2 diabetes mellitus, but it is unclear how these agents compare with respect to long-term cardiovascular risk. Our objective was to systematically examine the peer-reviewed literature on the cardiovascular risk associated with oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, and meglitinides) for treating adults with type 2 diabetes. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, from inception through January 19, 2006. Forty publications of controlled trials that reported information on cardiovascular events (primarily myocardial infarction and stroke) met our inclusion criteria. Using standardized protocols, 2 reviewers serially abstracted data from each article. Trials were first described qualitatively. For comparisons with 4 or more independent trials, results were pooled quantitatively using the Mantel-Haenszel method. Results are presented as odds ratios (ORs) and corresponding 95% confidence intervals (CIs). RESULTS: Treatment with metformin hydrochloride was associated with a decreased risk of cardiovascular mortality (pooled OR, 0.74; 95% CI, 0.62-0.89) compared with any other oral diabetes agent or placebo; the results for cardiovascular morbidity and all-cause mortality were similar but not statistically significant. No other significant associations of oral diabetes agents with fatal or nonfatal cardiovascular disease or all-cause mortality were observed. When compared with any other agent or placebo, rosiglitazone was the only diabetes agent associated with an increased risk of cardiovascular morbidity or mortality, but this result was not statistically significant (OR, 1.68; 95% CI, 0.92-3.06). CONCLUSIONS: Meta-analysis suggested that, compared with other oral diabetes agents and placebo, metformin was moderately protective and rosiglitazone possibly harmful, but lack of power prohibited firmer conclusions. Larger, long-term studies taken to hard end points and better reporting of cardiovascular events in short-term studies will be required to draw firm conclusions about major clinical benefits and risks related to oral diabetes agents.

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  • The clinically used drugs with known PGC-1α-modulating activity, such as fibrates, thiazolidinediones, metformin, and statins, display neurotoxicity and a limited ability to cross the blood-brain barrier.

    “The clinically used drugs with known PGC-1α-modulating activity, such as fibrates, thiazolidinediones, metformin, and statins, display neurotoxicity and a limited ability to cross the blood–brain barrier (BBB) [35,36,37,38].”

    From Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis (2021) · cites this paper as [37]

    The Discussion examines cardiovascular outcomes for oral diabetes medications, including metformin and thiazolidinediones. Neither those passages nor searches for PGC-1α modulation, neurotoxicity, and blood–brain barrier penetration address the properties attributed to the drugs in the claim. Page numbers were not available in our copy. (LLM, conf=0.76)

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Authors
Selvin, E., Bolen, S., Yeh, H.-C., Wiley, C., Wilson, L. M., Marinopoulos, S. S., Feldman, L., Vassy, J., Wilson, R., Bass, E. B., & Brancati, F. L.
Affiliations
  • Johns Hopkins University (US)
  • Washington University in St. Louis (US)
ORCID
Venue
Archives of Internal Medicine
Publisher
American Medical Association (AMA)
Published
2008-10-27
Volume
168
Issue
19
Pages
2070
ISSN
0003-9926 (ISSN-L)
DOI
10.1001/archinte.168.19.2070
PMC
PMC2765722
OpenAlex
W2094662494
Cited by
300
References
70
Citations by year
2026: 2 · 2025: 5 · 2024: 6 · 2023: 4 · 2022: 12 · 2021: 16 · 2020: 9 · 2019: 10 · 2018: 15 · 2017: 19 · 2016: 14 · 2015: 26 · 2014: 26 · 2013: 34 · 2012: 28
FWCI
17.90
Type
journal article
Language
en
Open access
Locations
  • Archives of Internal Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Public Health Service (290-02-0018)
  • National Institute of Diabetes and Digestive and Kidney Diseases (K24-DK62222, K01DK076595, K24DK062222, P30DK079637)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Keywords
type 2 diabetes, oral antidiabetic drugs, cardiovascular risk, metformin, rosiglitazone, sulfonylureas, biguanides, thiazolidinediones, meglitinides, myocardial infarction, stroke, cardiovascular mortality, all-cause mortality
MeSH terms
Cardiovascular Diseases, Humans, Hypoglycemic Agents, Diabetes Complications

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