Thiazolidinediones: the Forgotten Diabetes Medications

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Abstract

Purpose of Review

Thiazolidinediones (TZDs) are the only pharmacologic agents that specifically treat insulin resistance. The beneficial effects of TZDs on the cardiovascular risk factors associated with insulin resistance have been well documented. TZD use has been limited because of concern about safety issues and side effects.

Recent Findings

Recent studies indicate that cardiovascular toxicity with rosiglitazone and increase in bladder cancer with pioglitazone are no longer significant issues. There are new data which show that pioglitazone treatment reduces myocardial infarctions and ischemic strokes. New data concerning TZD-mediated edema, congestive heart failure, and bone fractures improves the clinician’s ability to select patients that will have minimal significant side effects.

Summary

Thiazolidinediones are now generic and less costly than pharmaceutical company–promoted therapies. Better understanding of the side effects coupled with clear benefits on the components of the insulin resistance syndrome should promote TZD use in treating patients with type 2 diabetes.

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Most cited references 50

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Banting lecture 1988. Role of insulin resistance in human disease.

G M Reaven (1988)

Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in approximately 25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the beta-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration. Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulin-stimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one.(ABSTRACT TRUNCATED AT 400 WORDS)

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Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence.

E. Ford (2005)

In recent years, several major organizations have endorsed the concept of the metabolic syndrome and developed working definitions for it. How well these definitions predict the risk for adverse events in people with the metabolic syndrome is only now being learned. The purpose of this study was to summarize the estimates of relative risk for all-cause mortality, cardiovascular disease, and diabetes reported from prospective studies in samples from the general population using definitions of the metabolic syndrome developed by the National Cholesterol Education Program (NCEP) and World Health Organization (WHO). The author reviewed prospective studies from July 1998 through August 2004. For studies that used the exact NCEP definition of the metabolic syndrome, random-effects estimates of combined relative risk were 1.27 (95% CI 0.90-1.78) for all-cause mortality, 1.65 (1.38-1.99) for cardiovascular disease, and 2.99 (1.96-4.57) for diabetes. For studies that used the most exact WHO definition of the metabolic syndrome, the fixed-effects estimates of relative risk were 1.37 (1.09-1.74) for all-cause mortality and 1.93 (1.39-2.67) for cardiovascular disease; the fixed-effects estimate was 2.60 (1.55-4.38) for coronary heart disease. These estimates suggest that the population-attributable fraction for the metabolic syndrome, as it is currently conceived, is approximately 6-7% for all-cause mortality, 12-17% for cardiovascular disease, and 30-52% for diabetes. Further research is needed to establish the use of the metabolic syndrome in predicting risk for death, cardiovascular disease, and diabetes in various population subgroups.

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Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.

H C Gerstein, S Yusuf, J. Bosch … (2006)

Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The aim of this study was to assess prospectively the drug's ability to prevent type 2 diabetes in individuals at high risk of developing the condition. 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00095654. At the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo group. 306 (11.6%) individuals given rosiglitazone and 686 (26.0%) given placebo developed the composite primary outcome (hazard ratio 0.40, 95% CI 0.35-0.46; p<0.0001); 1330 (50.5%) individuals in the rosiglitazone group and 798 (30.3%) in the placebo group became normoglycaemic (1.71, 1.57-1.87; p<0.0001). Cardiovascular event rates were much the same in both groups, although 14 (0.5%) participants in the rosiglitazone group and two (0.1%) in the placebo group developed heart failure (p=0.01). Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or both.

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Author and article information

Contributors

Harold E. Lebovitz: hlebovitz1@hotmail.com

Journal

Journal ID (nlm-ta): Curr Diab Rep

Journal ID (iso-abbrev): Curr. Diab. Rep

Title: Current Diabetes Reports

Publisher: Springer US (New York )

ISSN (Print): 1534-4827

ISSN (Electronic): 1539-0829

Publication date (Electronic): 27 November 2019

Publication date PMC-release: 27 November 2019

Publication date (Print): 2019

Volume: 19

Issue: 12

Electronic Location Identifier: 151

Affiliations

ISNI 0000 0001 0693 2202, GRID grid.262863.b, SUNY Downstate Medical Center, ; 450 Clarkson Avenue, Box 1205, Brooklyn, NY 11203 USA

Article

Publisher ID: 1270

DOI: 10.1007/s11892-019-1270-y

PMC ID: 6881429

PubMed ID: 31776781

SO-VID: 9791b2a2-2e83-49f1-a205-8ec1b1c0ecbd

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: type 2 diabetes,pparγ agonists,insulin resistance,cv outcomes,heart failure,bone fractures

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: type 2 diabetes, pparγ agonists, insulin resistance, cv outcomes, heart failure, bone fractures

Thiazolidinediones: the Forgotten Diabetes Medications

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Abstract

Purpose of Review

Recent Findings

Summary

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GLUT4 biology

Most cited references 50

Banting lecture 1988. Role of insulin resistance in human disease.

Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence.

Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.

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