Jan Bolinder

CONTEXT: Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion, and weight loss is a consistent associated finding. OBJECTIVES: Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components. DESIGN AND SETTING: This was a 24-wk, international, multicenter, randomized, parallel-group, double-blind, placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries. PATIENTS: Included were 182 patients with T2DM (mean values: women 63.3 and men 58.6 yr of age; hemoglobin A1c 7.17%, body mass index 31.9 kg/m2, and body weight 91.5 kg) inadequately controlled on metformin. INTERVENTION: Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk. MAIN OUTCOME MEASURES: Primary endpoint was total body weight (TBW) change from baseline at wk 24. Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass (FM) changes from baseline at wk 24, and patient proportion achieving body weight reduction of at least 5% at wk 24. In a subset of patients, magnetic resonance assessment of visceral adipose tissue (VAT) and sc adipose tissue (SAT) volume and hepatic lipid content were also evaluated. RESULTS: At wk 24, placebo-corrected changes with dapagliflozin were as follows: TBW, -2.08 kg [95% confidence interval (CI)=-2.84 to -1.31; P<0.0001]; waist circumference, -1.52 cm (95% CI=-2.74 to -0.31; P=0.0143); FM, -1.48 kg (95% CI=-2.22 to -0.74; P=0.0001); proportion of patients achieving weight reduction of at least 5%, +26.2% (95% CI=15.5 to 36.7; P<0.0001); VAT, -258.4 cm3 (95% CI=-448.1 to -68.6; nominal P=0.0084); SAT, -184.9 cm3 (95% CI=-359.7 to -10.1; nominal P=0.0385). In the dapagliflozin vs. placebo groups, respectively, serious adverse events were reported in 6.6 vs. 1.1%; events suggestive of vulvovaginitis, balanitis, and related genital infection in 3.3 vs. 0%; and lower urinary tract infections in 6.6 vs. 2.2%. CONCLUSIONS: Dapagliflozin reduces TBW, predominantly by reducing FM, VAT and SAT in T2DM inadequately controlled with metformin.

Importance: The majority of individuals with type 1 diabetes do not meet recommended glycemic targets. Objective: To evaluate the effects of continuous glucose monitoring in adults with type 1 diabetes treated with multiple daily insulin injections. Design, Setting, and Participants: Open-label crossover randomized clinical trial conducted in 15 diabetes outpatient clinics in Sweden between February 24, 2014, and June 1, 2016 that included 161 individuals with type 1 diabetes and hemoglobin A1c (HbA1c) of at least 7.5% (58 mmol/mol) treated with multiple daily insulin injections. Interventions: Participants were randomized to receive treatment using a continuous glucose monitoring system or conventional treatment for 26 weeks, separated by a washout period of 17 weeks. Main Outcomes and Measures: Difference in HbA1c between weeks 26 and 69 for the 2 treatments. Adverse events including severe hypoglycemia were also studied. Results: Among 161 randomized participants, mean age was 43.7 years, 45.3% were women, and mean HbA1c was 8.6% (70 mmol/mol). A total of 142 participants had follow-up data in both treatment periods. Mean HbA1c was 7.92% (63 mmol/mol) during continuous glucose monitoring use and 8.35% (68 mmol/mol) during conventional treatment (mean difference, -0.43% [95% CI, -0.57% to -0.29%] or -4.7 [-6.3 to -3.1 mmol/mol]; P < .001). Of 19 secondary end points comprising psychosocial and various glycemic measures, 6 met the hierarchical testing criteria of statistical significance, favoring continuous glucose monitoring compared with conventional treatment. Five patients in the conventional treatment group and 1 patient in the continuous glucose monitoring group had severe hypoglycemia. During washout when patients used conventional therapy, 7 patients had severe hypoglycemia. Conclusions and Relevance: Among patients with inadequately controlled type 1 diabetes treated with multiple daily insulin injections, the use of continuous glucose monitoring compared with conventional treatment for 26 weeks resulted in lower HbA1c. Further research is needed to assess clinical outcomes and longer-term adverse effects. Trial Registration: clinicaltrials.gov Identifier: NCT02092051.

Intensive self-management with frequent self-monitoring of blood glucose (SMBG) is important in type 1 diabetes to achieve good metabolic control (1–3). Nevertheless, many patients still experience episodes of unrecognized hypo- and hyperglycemia (4). Novel technologies for continuous glucose monitoring (CGM) that provide information about glucose excursions are now available. Previous studies reported the benefits of retrospective evaluation of CGM data (5–11), but few assessed effects on glycemic control (5,12–14), and only one showed improvements compared with SMBG (14). We evaluated the effect of a new real-time glucose monitor on glycemic control in patients with poorly controlled type 1 diabetes. The device, Guardian RT (Medtronic MiniMed, Northridge, CA), allows users to see glucose readings and set hypo- and hyperglycemic alarms and provides trend information on changing glucose values. The study included 81 children (median age 14.4 years [range 8.0–18.9]) and 81 adults (age 39.1 years [19.0–59.5]) with stable type 1 diabetes. All had adhered to intensified insulin treatment (continuous subcutaneous insulin infusion, n = 78; multiple daily injection, n = 84) but had HbA1c (A1C) levels ≥8.1%. Informed consent was obtained from patients regularly attending the eight participating centers. Subjects were randomly assigned 1:1:1 for 3 months to Guardian RT continuously (arm 1) or biweekly for 3-day periods every 2 weeks (arm 2) or to continue conventional SMBG (control). Treatment adjustments made by physicians and patients were based on SMBG profiles in control subjects and on real-time glucose profiles in arms 1 and 2. Patients were instructed to perform confirmatory SMBG measurements before therapeutical interventions or corrective action if hypo- or hyperglycemic alarms or symptoms occurred. …

OBJECTIVE: To assess the impact of continuous glucose monitoring on hypoglycemia in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: In this randomized, controlled, multicenter study, 120 children and adults on intensive therapy for type 1 diabetes and a screening level of glycated hemoglobin A(1c) (HbA(1c)) <7.5% were randomly assigned to a control group performing conventional home monitoring with a blood glucose meter and wearing a masked continuous glucose monitor every second week for five days or to a group with real-time continuous glucose monitoring. The primary outcome was the time spent in hypoglycemia (interstitial glucose concentration <63 mg/dL) over a period of 26 weeks. Analysis was by intention to treat for all randomized patients. RESULTS: The time per day spent in hypoglycemia was significantly shorter in the continuous monitoring group than in the control group (mean ± SD 0.48 ± 0.57 and 0.97 ± 1.55 h/day, respectively; ratio of means 0.49; 95% CI 0.26-0.76; P = 0.03). HbA(1c) at 26 weeks was lower in the continuous monitoring group than in the control group (difference -0.27%; 95% CI -0.47 to -0.07; P = 0.008). Time spent in 70 to 180 mg/dL normoglycemia was significantly longer in the continuous glucose monitoring group compared with the control group (mean hours per day, 17.6 vs. 16.0, P = 0.009). CONCLUSIONS: Continuous glucose monitoring was associated with reduced time spent in hypoglycemia and a concomitant decrease in HbA(1c) in children and adults with type 1 diabetes.