Sodium-Glucose Cotransporters as Potential Therapeutic Targets in Patients With Type 1 Diabetes Mellitus: An Update on Phase 3 Clinical Trial Data

Abstract

Objective: To review phase 3 trials of sodium-glucose cotransporter (SGLT) inhibitors in type 1 diabetes mellitus (T1DM) patients. Data Sources: A literature search of Ovid MEDLINE databases (1946 through May 17, 2019) limited to English-language human clinical trials was conducted using the following terms: sodium-glucose transporter 2 inhibitors, canagliflozin, dapagliflozin, empagliflozin, sotagliflozin, ertugliflozin, ipragliflozin, or remogliflozin combined with type 1 diabetes mellitus. Results were verified via Google Scholar and clinicaltrials.gov. Study Selection and Data Extraction: Articles were included if they were phase 3 trials in adults with T1DM. Data Synthesis: Phase 3 trials are available for dapagliflozin, empagliflozin, and sotagliflozin. All 3 drugs demonstrated statistically significant reductions in hemoglobin A1C, weight, and total daily insulin dose without an increased risk of hypoglycemia in up to 52 weeks of therapy. The incidence of diabetic ketoacidosis (DKA) was higher in patients on a SGLT inhibitor at all doses, with the exception of empagliflozin 2.5 mg (0.8% vs 1.2% with placebo). Relevance to Patient Care and Clinical Practice: SGLT inhibitors are potential adjuncts to insulin in T1DM patients, providing clinically meaningful benefits. Regulatory bodies have either approved or are reviewing these agents for use in T1DM. Clinicians should be familiar with the DKA risk associated with SGLT inhibitors and utilize DKA risk-mitigation strategies. Empagliflozin 2.5 mg warrants additional investigation given its efficacy without an increased incidence of DKA. Conclusions: Phase 3 trial data of SGLT inhibitors provide evidence for sustained efficacy in T1DM patients. Appropriate patient selection for therapy and routine monitoring are essential to minimize associated risks.

The Role of SGLT-2 Inhibitors as an Adjuvant to Insulin Therapy in Type-1 Diabetes Mellitus- Literature Review

“…In the inTandem3 trial, a 400mg/day sotagliflozin daily reduces HbA1c by 0.46%, weight loss around 3kg, and systolic blood pressure was 3.5mmHg in the sotagliflozin group compared to placebo [12][13]. The trial achieved HbA1c <7% without reported severe hypoglycemia or DKA at week 24 weeks in randomized patients to a 400mg of sotagliflozin compared to placebo, which is the primary endpoint [13][14]. Similarly, the addition of sotagliflozin to insulin therapy reduced total bolus and basal insulin doses [12].…”

Renal oxygenation: From data to insight

“…These are drugs that inhibit the type 2 sodium‐glucose co‐transporter (SGLT2), responsible for the reabsorption of glucose in the proximal tubule . They have been shown to reduce progression of CKD and mortality in patients with diabetes . However, there have been concerns that these drugs might promote renal medullary hypoxia by shifting some of the filtered load of sodium to other parts of the nephron (eg the distal end of the proximal tubule and the TALH).…”

“…102 They have been shown to reduce progression of CKD and mortality in patients with diabetes. [103][104][105] However, there have been concerns that these drugs might promote renal medullary hypoxia by shifting some of the filtered load of sodium to other parts of the nephron (eg the distal end of the proximal tubule and the TALH). For example, although the non-specific SGLT (1 and 2) inhibitor phlorizin improved cortical oxygenation in rats with type 1 diabetes, it also exacerbated medullary hypoxia.…”

“…106 Simulations using mathematical models predict this effect for the more specific SGLT2 inhibitors too, including in states of reduced nephron mass simulating CKD, 107 attributing it to reduced active transport of sodium in the cortex but increased active sodium transport in the medulla. 108 This line of research is extremely important, as SGLT2 inhibitors become more widely applied, 105 including in treatment of diabetic patients with chronic kidney disease. 104 It is also interesting that SGLT2 inhibitors appear to protect patients from development of AKI, 109 which seems counter to model predictions and experimental observations of reduced medullary tissue PO 2 .…”

Comment: Sodium-Glucose Cotransporters as Potential Therapeutic Targets in Patients With Type 1 Diabetes Mellitus: An Update on Phase 3 Clinical Trial Data

“…We read with great interest the article by Patel and Carbone, 1 “Sodium-Glucose cotransporters as potential therapeutic targets in patients with type 1 diabetes mellitus: an update on phase 3 clinical trial data.” Unfortunately, there is so far no approved oral antidiabetic treatment for type 1 diabetes mellitus (DM). Therefore, the study is very important.…”