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  • Review Article
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Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy

Nature Reviews Drug Discovery volume 5, pages 295–309 (2006)Cite this article

Key Points

  • The metabolic syndrome is a clustering of factors associated with an increased risk for atherosclerotic cardiovascular disease. The core 'metabolic risk factors' are atherogenic dyslipidaemia, elevated blood pressure, elevated plasma glucose, a prothrombotic state and a pro-inflammatory state, each of which has several components.

  • There are two potential therapeutic approaches to the metabolic syndrome. One strategy is to identify each risk factor separately and to treat this risk factor unrelated to its clustering with other risk factors. The alternative strategy is to target all or multiple risk factors with single therapies.

  • The former strategy will continue to be part of effective therapies, but, increasingly, the latter approach is attractive and available. This article explores the latter approach, with an emphasis on the potential utility of drug therapy for the metabolic syndrome.

  • Each of the risk factors of the metabolic syndrome is considered as a possible primary drug target, and potential secondary or tertiary targets are also discussed. Emphasis is placed on the development of multifunctional drugs that could alleviate problems with polypharmacy.

Abstract

The metabolic syndrome — a collection of factors associated with increased risk for cardiovascular disease and diabetes — is becoming increasingly common, largely as a result of the increase in the prevalence of obesity. Although it is generally agreed that first-line clinical intervention for the metabolic syndrome is lifestyle change, this is insufficient to normalize the risk factors in many patients, and so residual risk could be high enough to justify drug therapy. However, at present there are no approved drugs that can reliably reduce all of the metabolic risk factors over the long term, and so there is growing interest in therapeutic strategies that might target multiple risk factors more effectively, thereby minimizing problems with polypharmacy. This review summarizes current understanding of the nature of the metabolic syndrome, and discusses each of the risk factors of the metabolic syndrome as possible primary drug targets; potential secondary or tertiary targets are also considered.

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Figure 1: Characteristics of the metabolic syndrome.
Figure 2: Progression of the metabolic syndrome.
Figure 3: Obesity and the metabolic syndrome.
Figure 4: Pathways of lipoprotein metabolism associated with atherogenic dyslipidaemia: potential targets for drug therapy.
Figure 5: Actions of antidiabetic drugs on metabolic risk factors.
Figure 6: The metabolic syndrome and effects on the arterial wall.

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  1. Center for Human Nutrition and Departments of Clinical Nutrition and Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Y3.206, Dallas, 75390-9052, Texas, USA

    Scott M. Grundy

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Competing interests

During the past 5 years, S.M.G. has been an investigator on research grants awarded to the University of Texas Southwestern Medical Center, Dallas, Texas, USA, from Merck, Abbott and Kos Pharmaceuticals. He has also served as a consultant for Merck, Merck Schering Plough, Kos, Abbott, Fournier, Bristol-Myers Squibb, Sankyo, AstraZeneca and Sanofi-Aventis.

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DATABASES

OMIM

Type 2 diabetes

Glossary

Atherogenic dyslipidaemia

Atherogenic dyslipidaemia consists of elevations of lipoproteins containing apolipoprotein B (apo B), which include very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), elevations of VLDL triglycerides (and VLDL remnants), increased small LDL particles, and low levels of high-density lipoprotein (HDL).

Adiponectin

A product of adipose tissue shown to reduce systemic insulin resistance.

Renin–angiotensin–aldosterone system

(RAAS). The renin–angiotensin–aldosterone system is a key regulator of blood pressure. It involves the enzymes renin and angiotensin-converting enzyme, which are part of a pathway that converts angiotensinogen to angiotensin II. This acts on the angiotensin II type 1 receptor, leading to various effects that influence blood pressure, including aldosterone release.

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Grundy, S. Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov 5, 295–309 (2006). https://doi.org/10.1038/nrd2005

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