Incretins and the specific mechanism of action of liraglutide, the first applicable human glucagon-like peptide 1 analog in the treatment of type 2 diabetes

Correspondence: edoardo Mannucci Diabetologia Ponte Nuovo, via delle Oblate, 4-50141 Firenze, italy Tel +39 055 794 9742 Fax +39 055 794 9742 email [email protected] Abstract: Liraglutide is a once-daily glucagon-like peptide 1 (GLP-1) receptor agonist, approved for use as a treatment of type 2 diabetes. Like other drugs of the same class, liraglutide stimulates insulin secretion in a glucose-dependent fashion, has the potential of preventing β-cell mass decline, and inhibits food intake. In addition, experimental studies suggest that the GLP-1 receptor agonists could protect myocardium from ischemic injury, enhancing cardiac function. In clinical trials, liraglutide (in monotherapy or as add-on to 1 or 2 oral drugs) is as effective as, or more effective than, other agents (sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, insulin, and exenatide) in reducing hemoglobin A 1c ; induces weight loss; and has a blood pressure-lowering effect. The possible beneficial cardiovascular effects need to be confirmed by specifically designed long-term studies

Comment on Ferrannini et al. Diabetes Care 2016;39:1108–1114. Comment on Mudaliar et al. Diabetes Care 2016;39:1115–1122

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Glucagon and heart in type 2 diabetes: New perspectives

Increased levels of glucagon in type 2 diabetes are well known and, until now, have been considered deleterious. However, glucagon has an important role in the maintenance of both heart and kidney function. Moreover, in the past, glucagon has been therapeutically used for heart failure treatment. The new antidiabetic drugs, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors, are able to decrease and to increase glucagon levels, respectively, while contrasting data have been reported regarding the glucagon like peptide 1 receptors agonists. The cardiovascular outcome trials, requested by the FDA, raised some concerns about the possibility that the dipeptidyl peptidase-4 inhibitors can precipitate the heart failure, while, at least for empagliflozin, a positive effect has been shown in decreasing both cardiovascular death and heart failure. The recent LEADER Trial, showed a significant reduction of cardiovascular death with liraglutide, but a neutral effect on heart failure. A possible explanation of the results with the DPPIV inhibitors and empagliflozin might be related to their divergent effect on glucagon levels. Due to unclear effects of glucagon like peptide 1 receptor agonists on glucagon, the possible role of this hormone in the Leader trial remains unclear

Guida all'uso delle glifozine nel paziente diabetico

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Which antidiabetic drug indications are recommended for geriatric DM patients?

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Cardiovascular effects of basal insulins

Basal insulin is an important component of treatment for both type 1 and type 2 diabetes. One of the principal aims of treatment in patients with diabetes is the prevention of diabetic complications, including cardiovascular disease. There is some evidence, although controversial, that attainment of good glycemic control reduces long-term cardiovascular risk in both type 1 and type 2 diabetes. The aim of this review is to provide an overview of the potential cardiovascular safety of the different available preparations of basal insulin. Current basal insulin (neutral protamine Hagedorn [NPH], or isophane) and basal insulin analogs (glargine, detemir, and the more recent degludec) differ essentially by various measures of pharmacokinetic and pharmacodynamic effects in the bloodstream, presence and persistence of peak action, and within-subject variability in the glucose-lowering response. The currently available data show that basal insulin analogs have a lower risk of hypoglycemia than NPH human insulin, in both type 1 and type 2 diabetes, then excluding additional harmful effects on the cardiovascular system mediated by activation of the adrenergic system. Given that no biological rationale for a possible difference in cardiovascular effect of basal insulins has been proposed so far, available meta-analyses of publicly disclosed randomized controlled trials do not show any signal of increased risk of major cardiovascular events between the different basal insulin analogs. However, the number of available cardiovascular events in these trials is very small, preventing any clear-cut conclusion. The results of an ongoing clinical trial comparing glargine and degludec with regard to cardiovascular safety will provide definitive evidence

[Budget impact analysis of empagliflozin for the treatment of type 2 diabetes in Italy]

BACKGROUND: Empagliflozin is the most recent molecule in the SGLT-2i class, new antidiabetic drugs that reduce renal glucose absorption by determining the excretion in the urine. The high prevalence of T2D, the chronicity of the condition and the severe economic and social burden caused by the disease, impose the need for a careful health economic assessment on each therapeutic innovation in this area.AIM: The aim of this study was to assess the budget impact of adopting empagliflozin in the diabetic population currently treated with sulfonylureas and potentially eligible for treatment with SGLT-2i.METHODS: The budget impact analysis was conducted from the perspective of the Italian National Health Service over a period of three years, through an analytic model developed in MS Excel. The target population was estimated in about 170,000 patients currently treated with sulfonylureas, based on the growth forecasts of the Italian population, epidemiological estimates and drug-use information available in the literature on diabetes in Italy. In the base case was assumed a replacement rate of sulfonylureas equal to 10%, 20% and 30% respectively at the first, second and third year of analysis. A scenario analysis was considered assuming a constant uptake of 100% since the first year. The following direct healthcare costs were considered: 1) acquisition of antidiabetic drugs as the main therapy and as rescue therapy; 2) self-monitoring of blood glucose; 3) management of severe hypoglycemic events and 4) management of major cardiovascular events. Clinical effectiveness data was based on the published literature and unit costs were derived from current prices and tariffs. Oneway sensitivity analysis was developed to assess the impact of input's uncertainty on the overall result.RESULTS: The base case analysis presented a substantially neutral impact on the budget. The 3-year cumulative impact was -454.337 €, corresponding to a 0.1% saving. This means that the replacement of sulphonylureas with empagliflozin determines an increase in acquisition costs of drugs, which is entirely offset by the reduction in costs of self-monitoring of blood glucose, management of hypoglycemic events and cardiovascular events. The scenario analysis, based on the assumption of a full substitution of sulphonylureas with empagliflozin at the first year, yielded a more enhanced savings. The cumulative impact was -2.269.517 €, corresponding to a 0.6% saving.CONCLUSIONS: The present study shows that the replacement of sulfonylureas (a class of generic products) with empagliflozin, motivated by the advantageous efficacy and safety profile, can take place optimizing healthcare expenditure for the management of DT2.[In Italian