SGLT-2 inhibitors continue to be studied in type 1 diabetes despite the FDA warning about euglycemic diabetic ketoacidosis (DKA) and knowing that patients with type 1 diabetes are at increased risk of DKA compared to their type 2 counterparts. 1 Perhaps, it’s because of the blood pressure lowering, weight loss, and positive cardiovascular outcomes observed in type 2 diabetes. It sure would be exciting if these drugs could be viable options for patients with type 1 diabetes.
So, what does the literature say? The DEPICT-12 trial was a double-blind, randomized, parallel-controlled, study that included patients with uncontrolled type 1 diabetes. Patients were randomly assigned to dapagliflozin 5 mg or 10 mg once daily or placebo. The primary outcome was change in A1C after 24 weeks. In total, 833 patients were included: mean baseline A1C=8.53%, mean BMI=28kg/m2. At week 24, both doses of dapagliflozin significantly reduced A1C compared with placebo (mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was −0.42% [95% CI −0.56 to −0.28; p<0.0001] and for dapagliflozin 10 mg vs placebo was −0.45% [−0.58 to −0.31; p<0.0001]). Rates of hypoglycemia and DKA were similar between groups. The authors concluded that dapagliflozin is a promising adjunct treatment to insulin to improve glycemic control in patients with inadequately controlled type 1 diabetes. It’s important to note that the study design limited insulin reduction to 20% based on previous studies to limit DKA events.3 It seemed to work in this case!
The newest SGLT2 inhibitor to be explored is sotagliflozin which is actually a dual SGLT1 and SGLT2 inhibitor. SGLT1 has additional effects on the proximal intestine and by inhibiting SGLT1, there is reduced glucose absorption which improves postprandial hyperglycemia. In a phase III, double-blind, randomized, controlled trial (InTandem3)4, 1402 patients with type 1 diabetes were randomized to sotagliflozin 400mg/day or placebo for 24 weeks. Baseline characteristics include mean BMI of 28kg/m2 and 71% of patients with BMI≥25 kg/m2. Mean insulin doses were 56-58 units/day and mean A1C was 8.2%. Significantly more patients in the sotagliflozin group compared to placebo achieved A1C lower than 7% (207 patients [29.6%] vs. 111 [15.8%]). The A1C reduction from baseline to week 24 was significantly greater in the sotagliflozin group (difference, −0.46%; P<0.001). There was also greater weight loss with sotagliflozin (difference=−2.98 kg; P<0.001). In the sotagliflozin group, the placebo-corrected reductions from baseline in the mean daily total, bolus, and basal doses of insulin were −5.3 units per day (−9.7%), −2.8 units per day (−12.3%), and −2.6 units per day (−9.9%), respectively (P <0.001 for all comparisons). Overall, rates of hypoglycemia were similar between groups. Diarrhea (4.1% vs 2.3%) and genital mycotic infections (6.4% vs 2.1%) were more common with sotagliflozin compared with placebo, respectively. The rate of acidosis-related adverse events was 8.6% in the sotagliflozin group and 2.4% in the placebo group with actual DKA occurring in 3.0% in the placebo group and 0.6% in the placebo and more cases in those on insulin pumps.
The clinical efficacy is quite remarkable, but the increase risk of DKA is concerning, especially because the trial included a higher level of education and monitoring for DKA than what occurs in most usual clinical practice. Sotagliflozin is also most similar structurally to canagliflozin, and although bone loss and amputations have not been seen with sotagliflozin, we lack long term outcomes.5
A meta-analysis by Chen and colleagues6, reviewed over 11 trials and 581 patients, assessed the safety and efficacy of SGLT2 inhibitors vs. placebo in those with T1DM who were on insulin. The mean baseline characteristics included age of 41, duration of diabetes 21.28 years, A1C 8.026%, and BMI 27.25 kg/m2 . Hemoglobin A1C was reduced by 0.37% and total body weight was reduced by 2.54kg, Total adverse effects were similar between groups, but not surprisingly, there was an increase in DKA in those on SGLT2 inhibitors.
Overall, SGLT-2 inhibitors show promise in type 1 diabetes for weight control and A1C lowering. Based on EMPA-REG and CANVAS, they may even have potential to improve cardiovascular outcome as seen in patients with type 2 diabetes. Perhaps, if we follow the rule in the DEPICT-1 dapagliflozin trial and limit insulin reduction to no more than 20%, we can prevent DKA from occurring?
What do you think? Is the benefit worth the risk? This is such a difficult population to achieve A1C goal, which is often plagued by hypoglycemia and unpredictable hyperglycemia and hypoglycemia. (See Adam Brown’s 42 factors that can impact BG7) . It would be nice to have another tool to treat these patients. Yet, DKA can be life threatening and is it worth the gamble even if the overall rates are low? It reminds me a bit of Russian roulette. Is it just bound to happen if we use these agents enough?
Then again, maybe one day, insulin pump technology will advance that every patient will have an artificial pancreas. But until that day comes, it sure would be nice to have another medication to use in this difficult to treat population.
- FDA Drug Safety Communication. Available at: https://www.fda.gov/drugs/drugsafety/ucm475463.htm. Accessed 3/18/18.
- Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017;8587(17):1-13. doi:10.1016/S2213-8587(17)30308-X.
- Henry RR, Rosenstock J, Edelman S, et al. Exploring the potential of the SGLT2 inhibitor dapaglif lozin in type 1 diabetes: A randomized, double-blind, placebo-controlled pilot study. Diabetes Care. 2015;38(3):412-419. doi:10.2337/dc13-2955.
- Garg SK, Henry RR, Banks P, et al. Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. N Engl J Med. 2017:NEJMoa1708337. doi:10.1056/NEJMoa1708337.
- Rendell MS. Efficacy and safety of sotagliflozin in treating diabetes type 1. Expert Opin Pharmacother. 2017;0(0):14656566.2017.1414801. doi:10.1080/14656566.2017.1414801.
- Chen J, Fan F, Wang JY, et al. The efficacy and safety of SGLT2 inhibitors for adjunctive treatment of type 1 diabetes: A systematic review and meta-analysis. Sci Rep. 2017;7(March):1-9. doi:10.1038/srep44128.
- Factors Affect BG Control. Diatribe. Available at: https://diatribe.org/42factors. Accessed 3/18/18.
Written by: Diana Isaacs, PharmD, BCPS, BC-ADM, CDE, Clinical Pharmacy Specialist, Cleveland Clinic Diabetes Center