Elsevier

Diabetes & Metabolism

Volume 33, Issue 4, September 2007, Pages 231-244
Diabetes & Metabolism

Review
Type 2 diabetes mellitus: epidemiology, pathophysiology, unmet needs and therapeutical perspectivesDiabète de type 2 : épidémiologie, physiopathologie, problèmes non résolus et perspectives thérapeutiques

https://doi.org/10.1016/j.diabet.2007.07.001Get rights and content

Abstract

In France, prevalence of drug-treated diabetes reached 3.60% in 2005, with 92% of type 2 diabetic patients. In 2007, there are probably nearly 3 000 000 diagnosed or undiagnosed diabetic patients. Ageing of the population and increase in obesity are the main causes of this “diabetes epidemic”. Type 2 diabetes is a multifactorial disease, defined as resulting from defects in insulin secretion (including abnormalities in pulsatility and kinetics, quantitative and qualitative abnormalities of insulin, β-cell loss progressing with time) associated with insulin resistance (affecting liver, and skeletal muscle) and increased glucagon secretion. The lack of compensation of insulin resistance by augmented insulin secretion results in rise in blood glucose. To achieve satisfactory glycaemic control in order to prevent diabetes related complications, drug therapy is generally required in addition to life style changes. Currently available oral therapies offer a large panel of complementary drugs, but they have several contraindications and side effects. In spite of major advances in the management of type 2 diabetes, and the strictness of new guidelines, some goals remain unachieved and the new family of insulin-secretors (DPP-IV inhibitors, GLP-1 analogues) should enrich therapeutic approaches.

Résumé

En France, la prévalence du diabète traité par médicaments atteignait 3,6 % en 2005, dont 92 % de diabète de type 2, et en 2007 existent probablement près de 3 000 000 de diabétiques connus ou ignorés. Le vieillissement de la population et l'obésité croissante sont les principales causes de ce développement « épidémique » du diabète. Le diabète de type 2 est une maladie multifactorielle, qui associe une dysfonction insulaire (qui comporte des anomalies de la pulsatilité et de la cinétique, des altérations quali- et quantitatives de l'insulinosécrétion, et une perte de la masse des cellules β s'aggravant avec le temps) d'origine génétique, un déficit de l'insulinosensibilité (touchant le foie et le muscle strié) lié à des facteurs d'environnement (sédentarité et excès pondéral) et une hypersécrétion de glucagon. Le défaut de compensation de l'insulinorésistance par un débit insulinosécrétoire insuffisant a pour conséquence l'élévation de la glycémie. L'obtention d'un contrôle glycémique satisfaisant dans le but de prévenir les complications liées au diabète, nécessite en général le recours à des agents pharmacologiques en plus du traitement hygiénodiététique. Les médicaments oraux actuellement disponibles offrent un large spectre sur le plan de leur mécanisme d'action, mais ils ont un certain nombre de contre-indications et d'effets indésirables. Malgré les progrès accomplis dans le traitement du diabète de type 2 et la rigueur des nouvelles recommandations, il reste des objectifs non atteints, et de nouveaux insulinosécréteurs, inhibiteurs du DPP-IV et analogues du GLP-1, pourraient contribuer à compléter avantageusement l'arsenal thérapeutique.

Section snippets

Epidemiology of type 2 diabetes in France

In 2007, type 2 diabetes represents a major public health issue all over the world, becoming a “diabetes epidemic” as stated by Zimmet [1]. A few years ago, the concern of the “diabetes epidemic” was restricted to the US while the other parts of the world were not considered as threatened. Unfortunately, the picture has moved and nowadays no country escapes the diabetes invasion. In the world, diabetes prevalence in adults aged 20 and over was 4.0% in 1995 and it is expected to increase to 5.4%

Abnormalities in insulin secretion

According to WHO, type 2 diabetes is defined as resulting from a defect in both insulin secretion and in insulin sensitivity. β-cell dysfunction includes abnormalities in pulsatility and in kinetics of insulin secretion, quantitative and qualitative abnormalities of insulin, β-cell loss and its progression.

Therapeutic overview: present and perspectives

Appropriate diet, weight reduction and physical activity are the cornerstones of the treatment of type 2 diabetes, but the achievement of optimal glycaemic control, which is essential for the prevention of diabetes related complications, generally requires the use of antidiabetic drugs. None of these are able to correct all the anomalies involved in the pathogenesis of type 2 diabetes. So, they generally fail after a few years of evolution of the disease [56]. Combination therapies and even

DPP-IV inhibitors

These inhibitors of dipeptidyl peptidase-IV (DPP-IV) have been recently launched in the US and will be soon on the European market after many large preclinical and clinical studies (mainly three pharmaceutical companies and drugs: sitagliptin vildagliptin and saxagliptin). DPP-IV inhibitors stabilize endogenous GLP-1 at physiological concentrations, and induce insulin secretion in a glucose-dependent manner; therefore, they do not demonstrate any hypoglycaemic effects since their effects, on

Long-acting GLP-1 analogues, and GLP-1-receptor agonists

Long-acting glucagon-like peptide 1 analogue (liraglutide), and GLP-1-receptor agonists (exenatide) are more powerful on glycaemic control compared to DPP-IV inhibitors. Effect of GLP-1 analogues starts later, after a few weeks, and produces a more marked benefit on weight. However, DPP-IV inhibitors compared with GLP-1 analogues are orally administered and cause little effects on gastric emptying, and subsequently few or no gastrointestinal side effects.

Conclusion

If one considers the international guidelines and the clinical results obtained with DPP-IV inhibitors, it is possible to suggest their integration in the following way. Admittedly, whether in the future, one can imagine DPP-IV inhibitors as an alternative first line of treatment for type 2 diabetes, metformin will probably remain, for years, the most evidence-based, recommended, less expensive and most used first line OAD. Long-term studies considering safety, durability on glycaemic effects

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