SGLT2 Inhibitors in Type 1 Diabetes

Alyson P. Lozicki, PharmD; Nicholas D. Franz, PharmD Candidate


March 09, 2018


Are SGLT2 inhibitors safe and effective in patients with type 1 diabetes?

  Response from
Alyson P. Lozicki, PharmD
Drug Information Research Fellow, Creighton University, Omaha, Nebraska
Nicholas D. Franz, PharmD Candidate
Creighton University School of Pharmacy and Health Professions, Omaha, Nebraska

Type 1 diabetes (T1D) is caused by the autoimmune destruction of insulin-producing islet cells in the pancreas, resulting in an absolute deficiency of insulin. Treatment requires the exogenous replacement of insulin. This etiology differs from type 2 diabetes (T2D), which is primarily characterized by insulin resistance, and treatment focuses on enhancing insulin sensitivity and lowering blood glucose.[1]

Current guidelines from the American Diabetes Association (ADA) support an intensive insulin regimen for T1D, citing the Diabetes Control and Complications Trial, which demonstrated improvements in vascular and all-cause mortality outcomes with such a regimen. The benefits are clear; however, the multiple injections and adverse effects of insulin compound the burden of disease. Weight gain and the risk for hypoglycemia are most concerning and can cause increased comorbidities and poor compliance.[2] Oral antidiabetic agents approved for T2D are presently being investigated as adjuncts to insulin to address these concerns.[1] Among these are sodium-glucose cotransporter 2 (SGLT2) inhibitors, which are potentially effective due to their mechanism independent of insulin and associated weight loss.[3] SGLT2 inhibitors reduce the reabsorption of glucose from the proximal renal tubules and lower the renal threshold for glucose, thus increasing urinary glucose excretion and decreasing blood glucose concentrations.[4]

Studies have demonstrated the effectiveness of SGLT2 inhibitors as adjunct therapy for promoting weight loss and improving glycemic control compared with insulin monotherapy in T1D.

Chen and colleagues[5] conducted a meta-analysis of four randomized controlled trials, including 529 patients, evaluating the efficacy and safety of SGLT2 inhibitors as adjunctive agents to insulin in T1D. The primary outcomes included effects on glycemic levels, body weight, total daily insulin dosage, and adverse events. The SGLT2 inhibitors studied were canagliflozin, dapagliflozin, empagliflozin, and sotagliflozin (a pipeline agent). The durations of these studies were relatively short, with one study lasting only 2 weeks, two for 4 weeks, and one for 18 weeks. The SGLT2 inhibitor group demonstrated a statistically significant reduction in fasting plasma glucose of 0.69 mmol/L, which is equivalent to a 12.4 mg/dL reduction, compared with placebo. The greatest decrease in fasting plasma glucose was seen with sotagliflozin, which resulted in a weighted mean difference compared with placebo of -3.2 mmol/L (-57.6 mg/dL). Improvement in glycated hemoglobin (A1c) also favored the SGLT2 inhibitor group, with a weighted mean difference of -0.37% compared with placebo. Additionally, SGLT2 inhibitor therapy significantly reduced body weight by 2.54 kg and total daily insulin requirements by approximately 6 IU. There were no significant differences between groups for total adverse events or for incidence of hypoglycemia or urinary tract infection. However, there were 19 reports of diabetic ketoacidosis or ketone-related adverse events in the SGLT2 inhibitors group, while none were reported in the placebo group. Although all cases were reportedly considered to be independent of SGLT2 inhibitor therapy, this remains a cause for concern.

The favorable outcomes seen with SGLT2 inhibitors are promising. However, these agents are not without risks of their own. The study by Chen and colleagues demonstrated no significant differences in safety between adjunctive SGLT2 inhibitor therapy and insulin monotherapy, but there are still several warnings and precautions unique to SGLT2 inhibitors that should be considered. These include but are not limited to fractures, genital mycotic infections, hypotension, lipid abnormalities, renal complications, and lower limb amputation. These agents have also been issued an FDA safety warning for the risk for ketoacidosis, in some cases occurring in patients presenting with normal or mildly elevated blood glucose, due to cases reported in both T1D and T2D.[4] This remains the largest concern of the ADA, and guidelines caution providers to educate patients on recognizing the symptoms of diabetic ketoacidosis.[1]

The favorable outcomes seen with SGLT2 inhibitors are promising. However, these agents are not without risks of their own.

As mentioned above, sotagliflozin is among two SGLT2 inhibitors currently in the pipeline and the only agent seeking approval as an adjunct to insulin in T1D in addition to treatment for T2D. The other, ipragliflozin, is being studied for use in T2D only. Sotagliflozin is also the only agent with dual SGLT1 and SGLT2 activity, which will theoretically provide greater glycemic control.

A recently published phase 3 clinical trial compared sotagliflozin versus matched placebo in addition to home insulin regimens (pump or injections) over a 24-week period.[6] The primary outcome was an A1c less than 7.0% at 24 weeks, with no episodes of severe hypoglycemia or ketoacidosis. A significantly greater proportion of patients in the study group achieved the primary outcome compared with the placebo group (28.6% vs 15.2%, respectively; P <.001). Thus, it is expected that for approximately every seven patients treated adjunctively with sotagliflozin, one additional patient will achieve an A1c less than 7.0% with no episodes of severe hypoglycemia or ketoacidosis. The study also showed significant differences in favor of sotagliflozin for the mean change in A1c from baseline, weight, blood pressure, and change in basal insulin dose from baseline. Regarding the safety outcomes, the rates of total adverse events were comparable between the sotagliflozin and placebo groups, but the sotagliflozin group experienced a greater number of gastrointestinal adverse events and general mycotic infections. Additionally, patients in the sotagliflozin group had a lower incidence of severe hypoglycemia but a higher rate of ketoacidosis compared with placebo.[6] These data support previous concerns regarding the safety of SGLT2 inhibitors.

Evidence supporting the efficacy of SGLT2 inhibitors currently on the market as adjunct therapy for T1D is favorable but limited. These agents have demonstrated a modest improvement in glycemic control and weight, with few differences in adverse event rates compared with insulin alone. However, studies to date have been of a relatively short duration and small sample size. Results of clinical trials support the superior efficacy of the SGLT1/2 inhibitor sotagliflozin adjunctive to insulin, compared with insulin alone, in T1D. Safety outcomes are also similar to those of other SGLT2 inhibitors in this population. The pending approval of sotagliflozin is a promising option for patients with T1D not controlled on insulin alone. However, more evidence is needed to assess the efficacy and safety of other SGLT2 inhibitors for this indication.

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