Positioning SGLT2 Inhibitors/Incretin-Based Therapies in the Treatment Algorithm

Abstract

S154Diabetes Care Volume 39, Supplement 2, August 2016 SGLT2 THERAPYsensitizer (6,7). GLP-1 is part of the physiological system signaling satiety (8,9), reduces food intake and promotes weight loss in humans (10), and delays gastric emptying (11). Early studies showed that continuous subcutaneous GLP-1 infusion effectively lowered fasting and postprandial glucose levels and promoted weight loss in patients with T2DM (12). However, endogenous human GLP-1 has a short half-life (2-3 min) due to breakdown in the circulation by protease enzymes, notably, dipeptidyl peptidase (DPP)-4, which cleaves the molecule to leave the inactive GLP-1 (9-36). Hence, native GLP-1 has limited therapeutic efficacy. Pharmaceutical development took two routes: inhibition of the DPP-4-degrading enzyme and prolongation of the biological half-life by developing DPP-4-resistant GLP-1 receptor agonists (GLP-1 RAs). DPP-4 InhibitorsFour oral DPP-4 inhibitors (DPP-4i) are approved for use in both the U.S. and the European Union (sitagliptin, saxagliptin, alogliptin, and linagliptin) ( Table 1). Vildagliptin is approved in the European Union but not the U.S. Several other agents of this class are marketed worldwide (for example, omaragliptin and trelagliptin are available only in Japan). All five DPP-4i appear to have similar efficacy in terms of glucose lowering. An 18-week, phase 3b, multicenter, double-blind trial of saxagliptin versus sitagliptin has demonstrated noninferiority as add-on therapy to metformin (13). Trelagliptin, a once-weekly DPP-4i, was studied against alogliptin once daily and has demonstrated noninferiority in the Japanese population studied (14). Meta-analysis of DPP-4i has shown an average HbA 1c reduction (20.74%) (15) that is slightly less efficacious than sulfonylureas when used as monotherapy and similar to metformin and pioglitazone (16) but inferior to GLP-1 RAs. DPP-4i can be used in combination with other oral agents or with basal insulin (17), although the reduction of HbA 1c with insulin is modest (18,19). The DPP-4i are weight neutral and have a low risk of hypoglycemia. DPP-4i: Adverse EffectsIn general, the adverse effect profile of the DPP-4i is quite favorable. With the exception of linagliptin, the DPP-4i require dose reduction in patients with renal impairment. Some concern has been raised about the risk of pancreatitis and pancreatic cancer, based on preclinical studies and reports from postmarketing surveillance studies. However, the current data do not support a likely association (20). The U.S. Food and Drug Administration (FDA) has recently issued a warning about the possibility of joint pain developing during DPP-4i treatment after review of 33 cases reported over the past 8 years. However, the potential mechanism(s) are uncertain and a causal link is unproven, although symptoms appear to resolve after treatment withdrawal (21). Several large cardiovascular (CV) outcome trials have been completed, comparing these agents with placebo on the background of standard diabetes care (Table 2), and have ...

Treatment of Dyslipidemias to Prevent Cardiovascular Disease in Patients with Type 2 Diabetes

“…Sulfonylureas can also have negative lipid effects [71, 72, 73, 74]. The SGLT2 inhibitors can lower TG and raise HDL but may also raise LDL-C levels slightly; in the case of empagliflozin, this has been shown to be mainly due to hemoconcentration [75, 76]. Importantly, recent studies have demonstrated positive CV outcomes with several antidiabetic agents, including pioglitazone [77], empagliflozin [78], liraglutide [79], and semaglutide [80] without a clear relationship to effects on lipid levels.…”

60 years of metformin use: a glance at the past and a look to the future

“…Metformin has a clear advantage over sulfonylureas, which lead to a weight gain of 2-3 kg. However, compared with the glucose-lowering and weightreducing effects of glucagon-like peptide-1 (GLP-1) analogues and sodium−glucose cotransporter 2 (SGLT2) inhibitors, metformin appears not to provide any additional weight benefit [10].…”

Practical strategies for improving outcomes in T2DM: The potential role of pioglitazone and DPP4 inhibitors

“…Caution may be used in individuals with a history of HF based on the selected DPP4i, paying attention to signs and symptoms of heart failure during therapy. In these individuals, concomitant use of a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor may be considered also because of the reduced risk of HF and CV protection …”