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Incretins and pancreatitis—what happens next? A personal viewpoint

Most clinicians would agree with Dr Ryder that the major risks to people with Type 2 diabetes are cardiovascular diseases: premature heart attack, stroke, heart failure or death from these causes. For all previous drug classes reducing glycaemia in Type 2 diabetes, no overall cardiovascular benefit has been demonstrated and the cardiovascular efficacy of incretins is unknown. Contemporary meta-analyses for metformin, sulphonylureas, glitazones and trials of insulin do not show they improve overall cardiovascular outcome or total mortality. Intensive regimens to reduce glycaemia do not reduce major cardiovascular events and may be harmful, particularly when combined with insulin [1–7]. The only sufficiently powered incretin trial, saxagliptin compared with placebo (SAVOR), is negative for superiority of the primary cardiovascular outcome (Bristol-Myers Squibb press report, June 2013; NCT 01107886). In contrast, the list of drugs for diabetic glycaemia now banned because of unexpected harms has become lengthy, including phenformin, tolbutamide, benfluorex, troglitazone, rosiglitazone and pioglitazone in France, Germany and India [8]. In each case, controversy over benefits and harms have been obfuscated by the pharmaceutical industry and its extensive ties to professional, academic and regulatory bodies [9]. The incretins [comprising the oral dipeptidyl peptidase-4 (DPP-4) inhibitors: sitagliptin, saxagliptin, linagliptin, vildagliptin and the injectable glucagon-like peptide-1 (GLP-1) agonists; liraglutide and exenatide], also lack evidence of cardiovascular benefit and there is now concern by some about possible harm [10,11]. In my opinion, the systems of licensing and voluntary post-marketing surveillance have been unsatisfactory for almost 50 years, failing to ensure that drugs for diabetic glycaemia address either the main target, cardiovascular benefit, or that concerns about patient safety have a timely, independent and diligent response. There are three main issues arising from concerns over incretin therapies: evidence of benefit, evidence of harm and drug regulation. This is not the first time that these concerns have arisen over efficacy and adverse events with diabetes drugs and both historical context and recent evidence are relevant in helping clinicians decide what to do next, particularly in regard to the GLP-1 agonists.