The incretin-based agents and the SGLT2 inhibitors have brought great benefits to our management of diabetes. Although their effect in lowering blood glucose varies, their added value — in reducing blood pressure, lack of weight gain, and the absence of significant hypoglycemia – present major advantages that all clinicians should recognize when tailoring glycemic control regimens. The recently released results of the EMPA-REG Study of Empagliflozin in people with diabetes who have significant cardiac risk will cause a strong shift to the use of SGLT2 inhibitors.
At the same time, we must recognize that risks exist that need to be considered when evaluating the new agents. Nowhere is the struggle to assure safety more evident than in the process of the development of new diabetes drugs. Diabetes is a chronic condition that causes many long term problems, including microvascular damage to the retina, kidney, and nervous system, as well as cardiovascular complications – conditions that usually take many years and even decades to progress. In the past, the drug approval process for diabetes agents was based solely on a short-term demonstration that glucose levels were improved by use of an agent. "Safety" was loosely defined as lack of excessive undesirable events in a group treated with the investigational agent compared to placebo for a relatively short time, typically 24 to 52 weeks, followed by nonplacebo-controlled "long term" exposure, usually two years.
This approach to ensuring drug safety was shaken by a series of regulatory mishaps in the thiazolidinedione approval process, including deaths from troglitazone-induced liver failure as well as increased cardiovascular deaths in the muraglitazar program.1,2
The evidence for cardiovascular harm resulting from use of the thiazolidinediones (although the analyses were conflicting) led the FDA in 2008 to issue revised guidance for the evaluation of cardiovascular risk for diabetes drug development.3 The article by Rendell (reviewed herein) describes this new process. The FDA now requests that every submission for approval of a new diabetes drug contain a meta-analysis of all component Phase 2 and Phase 3 studies to determine a risk ratio for cardiovascular events. This assumes that the study population includes a sufficient percentage of individuals at risk for cardiovascular mortality, including elderly patients, patients with preexisting cardiovascular disease, and those with diabetic nephropathy. It also assumes that the controlled trials contributing to the meta-analysis be of sufficient duration to allow a meaningful chance for cardiovascular events to occur.
The FDA suggests that the 95% upper bound of the risk ratio for the new agent compared to placebo of less than 1.3 would be considered reassuring. They also stipulate that an upper bound greater than 1.8 would typically require a large cardiac outcomes trial prior to approval. A risk ratio upper bound falling in between 1.3 and 1.8 would allow approval but would require a postmarketing study.
This revised guidance has fundamentally changed the approach to approval of new agents for treatment of diabetes. Several such cardiovascular studies have been completed, finding neither evidence of harm nor of particular benefit. As reviewed in this issue by Tella and Rendell, long-term studies of the DPP-4 inhibitors saxagliptin (SAVOR),4 sitagliptin (TECOS),5 and alogliptin (EXAMINE),6 as well as of the GLP-1 agonist lixisenatide (ELIXA),7 all showed nonsignificant cardiovascular differences between those agents and standard medical care.
In contrast to these neutral studies, the EMPA-REG Study is the first of the cardiac-targeted approval studies to show a benefit of treatment of a diabetes agent. The paper by Zinman et al (reviewed in this issue) reported lower rates of death from cardiovascular and all causes, as well as lower rates of hospitalization for heart failure in patients treated with empagliflozin versus placebo.
Yet, as the Rendell article points out, the new approach to assessing cardiovascular risk/benefit (even very clear benefit as demonstrated in the EMPA-REG trial, showing a decrease in cardiovascular events and overall mortality) cannot reassure us of the absence of low-frequency unfavorable events. For example, there exists ongoing concern about GLP-1 receptor agonists and medullary carcinoma of the thyroid. In rats, liraglutide studies demonstrated a clear stimulation of C-cell hyperplasia and an increased incidence of associated C-cell neoplasms. While human studies initially showed an increase in calcitonin levels (although within the normal range) in patients treated with liraglutide over one year, extension of the studies to two years suggests that this effect diminishes with time.8 But despite these findings, the suspicion still remains that long-term exposure to GLP-1 RAs may lead to thyroid neoplasms in patients with diabetes.9
In late August 2015, the FDA issued a warning that there have been rare cases of DPP-4 inhibitor use associated with intense joint pain.10 They reported 33 cases, most associated with sitagliptin. On discontinuance of sitagliptin, the pain gradually disappeared. There is as yet no explanation of the possible relationship.
The process of drug and device development requires a constant and ongoing analysis of the benefit obtained from new agents versus the risk arising from those agents. A key (and perhaps the most important) benefit of the incretins and SGLT2 inhibitors compared to alternative agents is minimization of hypoglycemic events. While the ACCORD trial results,11 showing increased mortality in the intensive control group, were initially interpreted as suggesting that glucose levels should not be too tightly controlled, others believe that the ACCORD failure was a demonstration that intensive glycemic control is harmful only when it leads to hypoglycemia.12 Certainly, one of the contributing factors to the success of empagliflozin in EMPA-REG was the absence of hypoglycemia.
Yet, despite the potential advantages suggested by EMPA-REG for using SGLT2 inhibitors, we should be attentive to the potential risks of these agents, as pointed out by Scheen in his review. Genital and urinary tract infections, dehydration, and loss of bone mineral density are significant considerations. Further, the recent reports of diabetic ketoacidosis in SGLT2 inhibitor-treated patients (described by Peters et al) have also raised concerns.
The challenge we face today is that the risks of new therapy often take a very long time to discover, requiring long duration trials with a large number of subjects to arrive at a statistically valid conclusion. Unfortunately, there is no absolute safety. There is a misconception, among both clinicians and the public, that approval of a treatment is a guarantee of its benefit and absence of risk. Quite to the contrary: the true meaning of "safety" is an ongoing, evidence-based consensus that the balance of benefits of a treatment versus adverse consequences is advantageous.
The incretin agents and the SGLT2 inhibitors represent new options to pursue normalization of glucose levels without precipitating hypoglycemia. We would hope that other studies would follow the empagliflozin path to show significant long-term benefit outweighing unfavorable effects.
1. Gale EA. Lessons from the glitazones: a story of drug development. Lancet. 2001; 357(9271):1870-1875.
2. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005;294(20):2581-2586.
3. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) December 2008. Clinical Medical Guidance for Industry. Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Available from: Office of Communications, Division of Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration.
4. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013 Oct 3;369(14):1317-1326.
5. Green JB, Bethel MA, Armstrong PW, et al; TECOS Study Group. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015 Jul 16;373(3):232-242.
6. Zannad F, Cannon CP, Cushman WC, et al; EXAMINE Investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015 May 23;385(9982):2067-2076.
7. Bentley-Lewis R, Aguilar D, Riddle MC, et al; ELIXA Investigators. Rationale, design, and baseline characteristics in Evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo. Am Heart J. 2015 May;169(5):631-638
8. Hegedüs L, Moses AC, Zdravkovic M, Le Thi T, Daniels GH. GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab. 2011 Mar;96(3):853-60.
9. Gallo M. Thyroid safety in patients treated with liraglutide. J Endocrinol Invest. 2013 Feb;36(2):140-5
10. FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. 28 August, 2015, accessed 12 Sept 2015.
11. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59
12. Chow LS, Chen H, Miller ME, Marcovina SM, Seaquist ER. Biomarkers associated with severe hypoglycaemia and death in ACCORD. Diabet Med. 2015 Aug 11.