Diabetes treatment: The coming paradigm shift

Abstract

Over the 3–4 years since publication of the findings of the Veteran's Administration Diabetes Trial (VADT),1 the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study,2 and the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial,3 there has been increasing recognition that a simple single glycemic goal for all people with diabetes may be an incorrect recommendation,4 likely because of adverse outcomes occurring in association with a greater frequency of hypoglycemia in these trials.5, 6 Are we approaching a paradigm shift, a change in basic assumptions, in effect an evolution to new concepts of balancing glycemic goals with other, equally important goals for the avoidance of harm from hypoglycemia? Might part of this change in concept lead to reassessment of the role of sulfonylureas (SU) as insulin secretagogues and their replacement with incretin-based treatments? The two groups of agents act in greatly different ways on the β-cell. The SU close KATP channels, overriding the effect of glucose in signaling the β-cell apparatus, principally by increasing intracytoplasmic concentrations of Ca2+, whereas incretins bind to a G-coupled protein receptor to activate adenylate cyclase, increasing sensitivity to the cytoplasmic calcium levels that drive greater degrees of insulin secretion at a given glucose level.7, 8 The dipeptidyl peptidase-4 inhibitors (DPP-4i) and SU have virtually identical glucose-lowering actions as add-on to metformin, as shown in studies of sitagliptin versus glipizide,9 saxagliptin versus glipizide,10 and vildagliptin versus glimepiride,11 but the two classes of drugs have a markedly different likelihood of causing hypoglycemia and with weight loss rather than weight gain. Meta-analyses confirm similar glycemic effects of the SU and DPP-4i, while demonstrating that SU are associated with weight gain, to a similar degree to that seen with the thiazolidinediones, and with hypoglycemia; neither of these phenomena is seen with the use of DPP-4i.12 Similar reports from large medical databases confirm the lower likelihood of hypoglycemia and, intriguingly, suggest a reduction in cardiovascular outcomes compared with levels seen in patients receiving SU.13 In more ill patients, such as those with chronic kidney disease, the DPP-4i have proven safe and, unlike SU, do not appear to be associated with hypoglycemia.14 The DPP-4i appear to be associated with fewer side effects than either metformin or the SU, with no significant increase or decrease in either infections, gastrointestinal disorders, musculoskeletal disorders, or skin or subcutaneous tissue disorders.15 Although there had been concern that the agents may cause pancreatitis, this has note been borne out in preclinical or clinical trial data.16 In contrast, for many years there has been concern that the extrapancreatic KATP channels, such as those in the myocardium and vasculature, may, under certain circumstances, increase myocardial ischemia with use of SU.17 Emerging data suggest that SU may be associated with worsening of renal insufficiency18 and with increased mortality,19 as worrisomely suggested by the metformin plus SU arm of the UK Prospective Diabetes Study.20 Most impressive has been the emerging group of studies suggesting that cardiovascular events occur significantly less often in patients receiving DPP-4i than comparators.21 Such findings have been reported in studies of individual agents, such as saxagliptin22 and linagliptin,23 with a recent meta-analysis confirming these trends with all the agents, as well as when compared with both metformin and SU, particularly in studies ≥1 year in duration.24 Ongoing cardiovascular outcome trials will be completed with sitagliptin, alogliptin, and saxagliptin in 2014 and with linagliptin in 2018.25,26 Even without evidence of cardiovascular benefit, cost–utility analysis suggests that the DPP-4i may, by virtue of their similar glycemic effect and lesser likelihood of causing weight gain and hypoglycemia, lead to an acceptable quality life year-adjusted cost.27 What if there is a reduction in cardiovascular outcome? Then, it may be that we will see a true paradigm shift, with a reduction in the use of SU and their replacement by DPP-4i and, when greater glucose lowering is required, with the more potent injected glucagon-like peptide-1 receptor activators.