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BACKGROUND: The most used PD fluids contain glucose as a primary osmotic agent. Glucose peritoneal absorption during dwell decreases the osmotic gradient of peritoneal fluids and causes undesirable metabolic consequences. Inhibitors of sodium-glucose co-transporter (SGLT) type 2 are wildly used for the treatment of diabetes, heart and kidney failure. Previous attempts to use SGLT2 blockers in experimental peritoneal dialysis yielded contrasting results. We studied whether peritoneal SGLTs blockade may improve ultrafiltration (UF) via partial inhibition of glucose uptake from dialysis fluids. METHODS: Kidney failure was induced in mice and rats by bilateral ureteral ligation, and dwell was performed by injection of glucose-containing dialysis fluids. The effect of SGLT inhibitors on glucose absorption during fluid dwell and UF was measured in vivo. RESULTS: Diffusion of glucose from dialysis fluid into the blood appeared to be sodium-dependent, and blockade of SGLTs by phlorizin and sotagliflozin attenuated blood glucose increment thereby decreasing fluid absorption. Specific SGLT2 inhibitors failed to reduce glucose and fluid absorption from the peritoneal cavity in a rodent kidney failure model. CONCLUSIONS: Our study suggests that peritoneal non-type 2 SGLTs facilitate glucose diffusion from dialysis solutions, and we propose that limiting glucose reabsorption by specific SGLT inhibitors may emerge as a novel strategy in PD treatment to enhance UF and mitigate the deleterious effects of hyperglycaemia.

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In different large-scale clinic outcome trials, sodium (Na+)/glucose co-transporter 2 (SGLT2) inhibitors showed profound cardiac- and renal-protective effects, making them revolutionary treatments for heart failure and kidney disease. Different theories are proposed according to the emerging protective effects other than the original purpose of glucose-lowering in diabetic patients. As the ATP-dependent primary ion transporter providing the Na+ gradient to drive other Na+-dependent transporters, the possible role of the sodium-potassium adenosine triphosphatase (Na/K-ATPase) as the primary ion transporter and its signaling function is not explored.

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OBJECTIVE: Evaluate the effect of sotagliflozin, a dual inhibitor of sodium glucose cotransporter (SGLT) 1 and 2, on arterial stiffness in patients with type 1 diabetes (T1D) treated with sotagliflozin as adjunct to optimized insulin therapy. METHODS: In this post hoc analysis, indirect markers of arterial stiffness, including pulse pressure, mean arterial pressure (MAP), and double product, were calculated using observed systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse rate at 24 weeks using data from a pooled patient population from the inTandem1 and inTandem2 randomized controlled trials (n = 1575). RESULTS: Baseline characteristics were similar among groups. Relative to placebo at Week 24, sotagliflozin 200 mg and 400 mg reduced SBP by 2.03 mm Hg (95% CI -3.30 to -0.75; p = 0.0019) and 2.85 mm Hg (-4.12 to -1.57; p < 0.0001), respectively. DBP decreased by 1.1 and 0.9 mm Hg, MAP by 1.4 and 1.6 mm Hg, and double product by 202.5 and 221.1 bpm × mm Hg, respectively (p < 0.05 for all). No increases in heart rate were observed. CONCLUSION: In adults with T1D, adding sotagliflozin to insulin significantly reduced blood pressure and other markers of arterial stiffness and vascular resistance.

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AIM: To determine the clinical and biochemical variables associated with change in HbA1c in patients with type 2 diabetes who start sodium-glucose linked transporter (SGLT) inhibitor therapy. METHODS: We performed a prospective cohort study (ACTRN12616000833460) of 48 adults (30 male, 18 female) with type 2 diabetes who attended a tertiary hospital diabetes clinic. Fasting serum and urine samples, collected during clinic visits prior to and at 1, 12 and 24 weeks after commencing SGLT inhibitor treatment, were analysed for HbA1c, electrolytes, urea, creatinine and glucose. RESULTS: After 12 weeks, SGLT inhibitor therapy was associated with respective median (97% CI) decreases in weight, blood pressure, HbA1c and urine albumin/creatinine ratio of 3.0 (1.7-3.4) kg, 8 (2-16)/4 (3-9) mmHg, 6 (3-14) mmol/mol and 0.69 (0.18-1.8) mg/mmol. These effects persisted to 24 weeks. Urinary frequency and genitourinary infection were common adverse effects. Baseline HbA1c and eGFR independently predicted ΔHbA1c at 12 weeks whereas only baseline HbA1c independently predicted ΔHbA1c at 24 weeks. Urinary fractional glucose excretion and change in fasting glucose 1 week after starting SGLT inhibitor did not contribute to prediction of glycaemic response. CONCLUSIONS: SGLT inhibitor therapy in a hospital clinic setting was associated with clinical improvements comparable to those observed in clinical trials but with higher incidence of genitourinary side-effects. Baseline HbA1c and eGFR, but not urine fractional glucose excretion, predicted glycaemic response.

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Many patients with type 1 diabetes (T1D) do not achieve the glycemic target goal with insulin treatment. In this study, we aimed to evaluate the efficacy and safety of add-on to insulin therapy in patients with T1D. We conducted direct and indirect network meta-analyses using Bayesian models and ranked hypoglycemic agents via mixed treatment comparison, using data from the CENTRAL, MEDLINE, EMBASE, and Science Citation Index Expanded databases. Randomized controlled trials (RCTs) involving patients with T1D treated with insulin and add-on metformin or sodium-glucose cotransporter inhibitors or glucagon-like peptide-1 receptor agonists from January 1970 to September 2019 were included in this study. Twenty-three RCTs with 5,151 subjects were divided into the following groups: insulin alone, insulin+metformin, insulin+canagliflozin, insulin+dapagliflozin, insulin+empagliflozin, insulin+sotagliflozin, insulin+liraglutide, and insulin+exenatide. HbA1c level in the insulin+sotagliflozin group was significantly lower than that in the insulin alone group (mean difference: -0.43, 95% credible interval: -0.62 to -0.23). Total daily insulin dose in the insulin+sotagliflozin group was significantly lower than that in the insulin alone group. Compared with that in the insulin alone group, body weight in the groups treated with insulin+add-on canagliflozin, sotagliflozin, and exenatide was significantly decreased by 4.5, 2.8, and 5.1 kg, respectively. Hypoglycemic episodes did not differ among the groups. In patients with T1D, insulin+sotagliflozin decreased the HbA1c level, daily insulin dose, and body weight without hypoglycemia compared with insulin monotherapy. Insulin+canagliflozin or insulin+exenatide was effective in reducing body weight compared with insulin alone. In conclusion, sotagliflozin treatment decreased not only the HbA1c levels and insulin dose but also the body weight without causing hypoglycemia in patients with T1D. Treatment with canagliflozin and exenatide effectively reduced body weight in patients with T1D. However, ketoacidosis associated with the use of SGLT inhibitors should be considered in these patients. Thus, our results suggest that sotagliflozin has a high probability of being ranked first as an adjunctive therapy to insulin in patients with T1D.

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PURPOSE: The purpose of this study was to conduct qualitative participant interviews to provide context to the meaningfulness of improvements in end points seen in 2 large-scale Phase III sotagliflozin trials in participants with type 1 diabetes. METHODS: Participants were eligible for an interview if they had exited one of the clinical trials within the previous 12 months. Participants were recruited by investigators at the clinical trial sites, and interviews were conducted by independent interviewers by telephone in accordance with a semistructured interview guide. Both interviewers and participants were blinded to treatment assignment. Qualitative analysis was conducted using ATLAS-ti version 7.5, and descriptive statistics were computed and summarized. FINDINGS: Across 3 countries, 41 participants were interviewed. Difficulty maintaining blood glucose within a desired range, described by participants as lack of blood glucose "stability," was the most concerning symptom that they reported, wanting to see it improved during the clinical trial because it negatively impacted their physical, mental, and emotional lives. Participants who reported symptom improvement also reported a positive psychosocial impact while taking the clinical trial medication. All participants who monitored ketones described themselves as being "pretty confident" to "very confident" that they could avoid diabetic ketoacidosis by monitoring both ketone levels and understanding the physical signs and symptoms of hyperglycemia. IMPLICATIONS: Improvements in glucose stability and control were important to participants with type 1 diabetes, as these improvements were correlated with improvements in the participants' lives. ClinicalTrials.gov identifiers: NCT02384941; NCT02421510.

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