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Dapagliflozin, an SGLT2 inhibitor, for diabetes

To assess the efficacy and tolerability of adjunct therapy with a sodium-glucose cotransporter-2 inhibitor, dapagliflozin, compared with insulin escalation for patients with uncontrolled type 2 diabetes on current insulin therapy.

A 12-month retrospective case–control study of patients with glycated hemoglobin (HbA1c) > 7% on insulin therapy. The study group received add-on therapy with dapagliflozin (10 mg once daily); the control group received titrated increases of their existing insulin dose by a mean of 21.6% from baseline. The primary endpoint was the change in HbA1c after 12 months. Secondary outcomes included changes in fasting plasma glucose, postprandial 2-h glucose levels, insulin requirements, and body weight.

After 12 months, the reduction in HbA1c was significantly greater in the dapagliflozin group than in the control group (from 8.9 ± 1.2% to 8.0 ± 1.0% vs 9.1 ± 1.2% to 8.7 ± 1.5%, respectively). Results for fasting plasma glucose and postprandial 2-h glucose were similar. Dapagliflozin therapy decreased systolic blood pressure (−4.7 mmHg) and body weight (−1.4 kg) significantly, whereas body weight increased by 0.6 kg in the control group. The dapagliflozin group showed significantly fewer hypoglycemic events than the control group (18.5% vs 32.6%, respectively). Daily insulin dose increased by 5.4 ± 6.1 U (21.6%) in the control group but decreased by 1.9 ± 5.3 U (−4.5%) in the dapagliflozin group (p < 0.001).

As an adjunct to insulin therapy, dapagliflozin therapy significantly improved glycemic control, with the clinical advantages of weight loss, insulin sparing, and less hypoglycemia.

Carbohydrates, the structural building blocks of genetic materials and vital source of energy, are integral part of the living cells as they play important roles in biological system, particularly in cellular and intracellular interactions. Since long back, a number of simple carbohydrates and their derivatives are used clinically for the successful treatment of various diseases. In addition to the structural diversity in carbohydrates (in terms of functional groups, linkages as well rings system), other important features such as hydrophilicity, low toxicity, biocompatibility, and bioavailability required to provide the optimum pharmacokinetics are truly inspiring. Thus, due to their prospective as drug molecules, pharmaceutical and diagnostic tool, they stimulate the medicinal chemists to explore them in order to get the diverse well-defined eccentric glycoconjugates for their complete chemical, biochemical, and pharmacological investigations. This chapter highlights the impact of diverse carbohydrates and their derivatives in drug discovery and development with their future perspectives.

Diabetes mellitus is a chronic disease caused by inherited and/or acquired deficiency in production of insulin by the pancreas or by the ineffectiveness of the insulin produced. In this chapter, we describe on the management of type 2 diabetes with an aid of carbohydrate-containing molecules. The carbohydrate-based glucosidase inhibitors and sodium glucose cotransporter 2 inhibitors are the major active classes of compounds for the management of diabetes.

Optimal prevention and treatment of chronic kidney disease in diabetes requires implementing therapies that specifically interfere with the pathogenesis of diabetic nephropathy. In this regard, significant attention has been given to alterations of the proximal tubule and resulting changes in glomerular filtration rate. At the onset of diabetes mellitus, hyperglycemia causes increases in proximal tubular reabsorption secondary to induction of tubular growth with associated increases in sodium/glucose cotransport. The increase in proximal reabsorption leads to a decrease in solute load to the macula densa, deactivation of the tubuloglomerular feedback, and increases in glomerular filtration rate. Because glomerular hyperfiltration currently is recognized as a risk factor for progression of kidney disease in diabetic patients, limiting proximal tubular reabsorption constitutes a potential target to reduce hyperfiltration. The recent introduction of sodium/glucose cotransporter 2 (SGLT2) inhibitors opens new therapeutic perspectives for this high-risk patient population. Experimental studies have shown that these new agents attenuate the progressive nature of diabetic nephropathy by blood glucose–dependent and –independent mechanisms. SGLT2 inhibition may prevent glomerular hyperfiltration independent of the effect of lowering blood glucose levels while limiting kidney growth, inflammation, and albuminuria through reductions in blood glucose levels. Clinical data for the potential role of the proximal tubule in the pathophysiology of diabetic nephropathy and the nephroprotective effects of SGLT2 inhibitors currently are limited compared to the more extensive experimental literature. We review the evidence supporting this working hypothesis by integrating the experimental findings with the available clinical data.

Type 2 diabetes mellitus (T2DM) is one of the most troubling chronic disease regarding the huge number of new cases diagnosed annually worldwide. Currently available oral antidiabetic drugs (OADs) attempt to correct the underlying pathophysiological dysfunctions leading to T2DM: insulin resistance for the insulin sensitizers (metformin and thiazolidinediones), and impaired insulin secretion for the insulin secretagogues (sulfonylureas, glinides and more recently incretin mimetics). Incretin-based therapies include GLP-1 receptor agonists that provide pharmacologic levels of GLP-1 receptor stimulation beyond those that would occur from the action of the native hormone alone, and dipeptidyl-peptidase-4 (DPP-4) inhibitors that preserve endogenous GLP-1 by decreasing its degradation by the DPP-4 enzyme. In 2012, the development of new OADs aims to target untapped pathophysiological aspects of the disease (kidney homeostasis, glucagon signalling, chronic low-grade inflammation) for tailoring glycaemic control in T2DM. SGLT-2 inhibitors are the most advanced new OADs that lower HbA1C by increasing glycosuria and lead to a moderate weight loss. Although there is genuine hope that the range of OADs can be extended, a long-term evaluation of side effects and true clinical benefits is necessary.

Le diabète de type 2 (DT2) représente l’une des maladies chroniques les plus préoccupantes, en regard du nombre exponentiel de nouveaux cas diagnostiqués chaque année dans le monde. Les thérapies hypoglycémiantes orales actuellement disponibles tentent de corriger les dysfonctionnements métaboliques qui caractérisent la maladie : « insulinorésistance », pour les traitements insulinosensibilisateurs (metformine et glitazones), et « insulinopénie relative » pour les traitements insulinosécrétagogues tels que les sulfamides hypoglycémiants, les glinides, et plus récemment les incrétinomimétiques. Ces derniers comprennent les agonistes du récepteur aux GLP-1 qui permettent d’obtenir des taux pharmacologiques supérieurs à ceux du GLP-1 endogène seul pour stimuler son récepteur spécifique, et les inhibiteurs de la dipeptidyl-peptidase 4 (DPP-4) qui s’opposent à la dégradation du GLP-1 endogène habituellement médiée par cette enzyme. En 2012, les traitements hypoglycémiants en cours d’évaluation dans le DT2 ciblent de nouveaux axes physiopathologiques jusqu’alors inexploités (homéostasie glucidique rénale, signalisation du glucagon, inflammation chronique) afin d’optimiser le contrôle glycémique, Les inhibiteurs de SGLT2 représentent, à ce stade, les molécules les plus avancées dans leur développement. Bien que l’éventail de ces nouvelles molécules soit large, une évaluation sur le long terme des effets indésirables et du réel bénéfice clinique est nécessaire.

Des taux circulants excessifs de glucagon s’observent dans toutes les formes expérimentales ou cliniques de diabète. L’hyperglucagonémie du diabète chez l’Homme résulte d’une sécrétion excessive de l’hormone et contribue, par une stimulation de la glycogénolyse et de la gluconéogenèse au niveau du foie, à l’établissement et au maintien de l’hyperglycémie, tant basale que post-prandiale.

Divers travaux récents suggèrent que l’hyperglucagonémie du diabète est la conséquence du déficit de sécrétion insulinique. Dans cet effet, un rôle essentiel semble être joué par des interrelations complexes de type paracrine entre les diverses cellules des îlots de Langerhans ; ils ont amené Unger et Orci à faire du diabète une « paracrinopathie ». Des arguments expérimentaux suggèrent qu’une perturbation du caractère pulsatile de la sécrétion d’insuline au sein des îlots joue un rôle déterminant dans l’établissement de l’hyperglucagonémie du diabète. Réduire la sécrétion excessive de glucagon, ou inhiber les effets de l’hormone au niveau de ses tissus cible, sont aujourd’hui des objectifs pour améliorer le traitement du diabète. Une telle approche doit toutefois prendre en compte la possibilité d’un accroissement du risque d’hypoglycémie, le glucagon étant reconnu, dans les mécanismes de contre-régulation, comme la première ligne de défense contre l’hypoglycémie.

Excessive circulating glucagon levels have been reported in all forms of diabetes, clinical or experimental. The hyperglucagonemia of diabetes in man results from an excessive secretion of the hormone. It contributes to the fasting and postprandial hyperglycemia of diabetes through increased hepatic glycogenolysis and gluconeogenesis. There is strong evidence that the hyperglucagonemia of diabetes results from the deficit in insulin secretion. Recent evidence supports a major role of the paracrine relationships between the various cells within the islets of Langerhans leading Unger and Orci to consider diabetes as a “paracrinopathy”. Experimental studies strongly suggest that the hyperglucagonemia of diabetes is the consequence of the disruption of the normal insulin pulsatile secretory pattern within the islets of Langerhans. Reducing the hypersecretion of glucagon or inhibiting its effects on its target cells are currently considered as news pathways to improve metabolic control in diabetes. However, glucagon being recognized as “the first line of defence” against hypoglycemia, caution is needed regarding the potential increased risk of hypoglycaemia when the secretion of glucagon is reduced or its effects on target cells inhibited or blocked.