||SGLT stands for sodium glucose transporter, a critical component responsible for the reabsorption of glucose in the kidney. SGLT-2 is in the first part of the proximal tubule, and is responsible for 90% of the reabsorbed glucose in the kidney; SGLT1 is responsible for the other 10%. A television ad explains the mechanism simply: the kidneys filter out sugar and return it to the body; the SGLT-2 inhibitor agent diverts some of this returning sugar to the urinary tract. The result is less circulating plasma glucose.
There are currently three FDA approved SGLT-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) commercially available in the US, with others in various stages of the approval process. In addition, there is current development of agents that target SGLT-1, as well as preliminary studies investigating the role of dual blockade of SGLT-2 and SGLT-1.
All SGLT-2 agents are approved for use in type 2 diabetes only, and can be used as second or third-line agents, including in combination with insulin. In addition, given their insulin-independent mechanism of action, they may have a role in type 1 diabetes as well.
In the clinical trials, SGLT-2 inhibitors were found to lower A1c by about 0.5 to 0.7%, similar to the DPP-4 inhibitors. They have also shown modest weight loss and BP- lowering effects. Genital infections are the most common adverse effect, and the risk of hypoglycemia is relatively low. However, both hypoglycemia and osmotic diuresis-related events increase when SGLT-2s are taken in combination with insulin.
Because SGLT-2s work in the kidney, they are contraindicated in patients with renal insufficiency. Glomerular filtration rate (GFR) < 60 is a relative contraindication for both canagliflozin and dapagliflozin; GFR < 45 is a relative contraindication for empagliflozin. All available agents are contraindicated for GFR < 30 and end-stage renal disease or hemodialysis.
The March 2015 issue of Diabetes Care, the leading clinical journal in diabetes, was devoted specifically to the role of SGLT-2 inhibitors in diabetes management. Of the 12 articles published on the use of this drug class in diabetes, nine were randomized, controlled trials (RTCs). The issue reported on investigations into the glycemic efficacy as well as the important nonglycemic effects (ie, weight loss and blood pressure control) for the SGLT-2 inhibitors in patients with type 2 diabetes, as well as one small pilot study in type 1 diabetes.
The four papers reviewed in this newsletter address relevant clinical scenarios and inform our clinical practice by providing important information about the safety and efficacy of this newest class of glycemic control agents. As a caveat, however, we must remember that long-term efficacy data on clinical outcomes (cardiovascular disease, microvascular complications, etc) are lacking.
The incretin-based therapies — DPP-4 inhibitors and GLP-1 receptor agonists - are being used on an ever-expanding basis for the management of type 2 diabetes. The oral DPP-4 inhibitors in particular have gained wide acceptance, especially in the primary care arena; increased use of the injectable GLP-1 receptor agonists, while providing greater glucose-lowering, has been slower, most likely because of both clinician and patient resistance to "going on the needle." While a large body of evidence has shown that these agents are generally safe to use in a wide variety of patients, two safety-related controversies have arisen.
The most current controversy revolves around the cardiovascular safety of both DPP-4 inhibitors and GLP-1 receptor agonists. Earlier meta-analyses of many smaller studies suggested potential benefits of DPP-4 inhibitors in reducing major cardiovascular events.1,2 However, more recent research has identified the potential for an increased risk for congestive heart failure in patients treated with these agents. During the past several years, a number of randomized clinical trials exploring the cardiovascular safety of both incretin-based therapies were initiated. The first two of these, studying DPP-4 inhibitors, have been published and are summarized in this newsletter. While these trials were not powered to confirm or refute the heart failure concern, they do provide important data on the long-term cardiovascular safety of DPP-4 inhibitors in patients receiving "standard-of-care" treatment to prevent cardiovascular complications. Others trials, involving both DPP-4 inhibitors and GLP-1 receptor agonists, are being completed and will be published later this year and within the next few years.
More recently, an extensive 2014 meta-analysis of the available data from 84 RTCs found the overall risk of congestive heart failure was higher in patients treated with DPP-4 inhibitors in comparison with those treated with placebo/active comparators (MH-OR: 1.19[1.03; 1.37]; P = 0.015), suggesting that DPP-4 inhibitors as a class could be associated with an increased risk of heart failure (although without any clear evidence of differences among specific agents).3 Further, in April 2015, the FDA, describing that findings of its own sensitivity analyses of deaths occurring while patients were on saxagliptin treatment "suggested significant or near-significant increases in all-cause mortality," convened a meeting of its Endocrinologic and Metabolic Drugs Advisory Committee to assess the possibility of heart failure as an incretin class effect.4
A longer-standing controversy, regarding an increased possibility of pancreatitis and/or pancreatic cancer with the use of incretin agents, remains unsettled.5,6 Although they caution that the matter is not yet settled, the current position of the FDA and the European Medicines Agency (EMA) is that the incretin-mimetic agents appear to be clinically devoid of a significant adverse signal in this regard.6 However, due to concerns raised from certain animal data, there is a need for completion of the ongoing studies before a final determination can be made.7 Analysis of the large number of patients studied with saxagliptin in the SAVOR trial, reviewed in this newsletter, provides additional insight.
With the anticipated completion of most of the ongoing RCTs with DPP-4 inhibitors, and GLP-1 agonists in the foreseeable future, it is hoped that more definitive conclusions on both these safety issues can be drawn once those data become available.
1. Patil HR, Al Badarin FJ, Al Shami HA, et al. Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. Am J Cardiol. 2012 Sep 15;110(6):826-833.
2. Monami M, Ahrén B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013 Feb;15(2):112-120.
3. Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials Nutr Metab Cardiovasc Dis. 2014 Jul;24(7):689-697.
4. FDA. Endocrinologic and Metabolic Drugs Advisory Committee Meeting Briefing Material. April 14, 2015.
5. Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013 Apr 8;173(7):534-539.
6. Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs--FDA and EMA assessment. N Engl J Med. 2014 Feb 27;370(9):794-797.
7. Bonner-Weir S, In't Veld PA, Weir GC. Reanalysis of study of pancreatic effects of incretin therapy: methodological deficiencies. Diabetes Obes Metab. 2014 Jul;16(7):661-666.