Dapagliflozin as adjunct therapy to adjustable insulin in patients with type 1 diabetes was well tolerated and improved glycemic control with no increase in hypoglycemia versus placebo but with more DKA events.

The DEPICT-2 trial (NCT02460978) evaluated the efficacy and safety of dapagliflozin (DAPA) as add-on to adjustable insulin (INS) in patients (pts) with inadequately controlled T1D (A1c 7.5-10.5%) over 24 weeks. This phase 3 study randomized pts 1:1:1 to DAPA 5 mg (n=271), 10 mg (n=270) or placebo (PBO; n=272) plus INS. INS dose could be adjusted by the investigator according to self-monitored blood glucose readings, local guidance and individual circumstances. At Week 24, DAPA 5 and 10 mg significantly decreased A1c (0.37% and 0.42% reductions in the DAPA 5 mg and 10 mg groups respectively), total daily insulin dose (TDD), and body weight (Table). As measured by masked continuous glucose monitoring (CGM), mean interstitial glucose, mean amplitude of glucose excursion (MAGE) and mean percent of readings within target glycemic range (>70-≤180 mg/dL) vs. PBO were improved. There was an increase in pts who reduced their A1c by ≥0.5% without severe hypoglycemia (odds ratios [95% CI]: 2.71 [1.81, 4.06] and 3.07 [2.05, 4.60] for DAPA 5 and 10 mg respectively). Hypoglycemic events, including severe hypoglycemia were balanced between treatment groups. There were more adjudicated definite diabetic ketoacidosis (DKA) events on DAPA. In conclusion, DAPA vs. PBO as add-on to INS in pts with T1D was well tolerated, improved glycemic control and decreased variability without increasing hypoglycemia but with more DKA events. Week 24 outcomesDAPA 5 mg + INS (n=271)DAPA 10 mg + INS (n=270)Placebo + INS (n=272)HbA1c, % Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 8.45 (0.69) −0.34 (0.05) −0.37 (−0.49, −0.26) <0.0001. 8.39 (0.67) −0.39 (0.05) −0.42 (−0.53, −0.30) <0.0001. 8.40 (0.63) 0.03 (0.05) . .TDD, IU Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 59.09 (28.05) −8.73 (1.22) −10.78 (−13.73, −7.72) <0.0001. 59.28 (28.21) −9.(1.23) −11.(−14.04, −8.02) <0.0001. 56.45 (25.23) 2.29 (1.39) . .Body weight, kg Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 79.22 (17.21) −3.22 (0.27) −3.21 (−3.96, −2.45) <0.0001. 80.39 (18.51) −3.76 (0.27) −3.74 (−4.49, −2.99) <0.0001. 79.03 (19.05) −0.02 (0.28) . .24-h CGM glucose reading, mg/dL Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 192.67 (28.68) −6.46 (1.83) −15.66 (−20.26, −11.05) <0.0001. 191.53 (28.09) −10.54 (1.83) −19.74 (−24.34, −15.14) <0.0001. 190.89 (28.95) 9.20 (1.85) . .MAGE during 24-h CGM, mg/dL Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 169.35 (29.60) −10.17 (1.90) −9.85 (−14.66, −5.03) <0.0001. 171.02 (29.85) −9.68 (1.91) −9.36 (−14.16, −4.55) 0.0001. 168.38 (29.29) −0.33 (1.93) . .24-h interstitial glucose values within >70-≤180 mg/dL, % Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 43.50 (12.43) 5.92 (0.82) 9.02 (6.97, 11.06) <0.0001. 43.68 (11.83) 7.60 (0.82) 10.70 (8.66, 12.74) <0.0001. 43.53 (12.55) −3.10 (0.83) . .Safety data (patients with an event) ≥1 AE, n (%) ≥1 SAE, n (%) ≥1 related SAE, n (%) ≥1 event of hypoglycemia, n (%) ≥1 event of severe hypoglycemia, n (%) Definite DKA, n (%). 197 (72.7) 18 (6.6) 13 (4.8) 223 (82.3) 17 (6.3) 7 (2.6). 181 (67.0) 7 (2.6) 3 (1.1) 231 (85.6) 23 (8.5) 6 (2.2). 172 (63.2) 5 (1.8) 2 (0.7) 234 (86.0) 21 (7.7) 0 Disclosure C. Mathieu: Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novartis AG. Advisory Panel; Self; Novartis AG, Bristol-Myers Squibb Company. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca, Pfizer Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Hanmi Pharmaceutical. Research Support; Self; Roche Diagnostics Corporation. 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Apo E polymorphism influences serum lipoprotein levels in patients with IDDM and NIDDM. Apo E polymorphism may be a renal risk factor of clinical relevance in normolipidemic patients with IDDM.

OBJECTIVE -To evaluate the influence of renal impairment on the safety and efficacy of repaglinide in type 2 diabetic patients. RESEARCH DESIGN AND METHODS -This multinational, open-label study comprised a 6-week run-in period, continuing prestudy antidiabetic medication, followed by a titration period (1-4 weeks) and a 3-month maintenance period. Patients with normal renal function (n ϭ 151) and various degrees of renal impairment (n ϭ 130) were treated with repaglinide (maximal dose of 4 mg, three times daily). Safety and efficacy assessments were performed at baseline (end of run-in) and at the end of study treatment.RESULTS -The type and severity of adverse events during repaglinide treatment were similar to the run-in period. The number of patients with adverse events was not significantly related to renal function during run-in or repaglinide treatment. Percentage of patients with hypoglycemic episodes increased significantly (P ϭ 0.007) with increasing severity of renal impairment during run-in but not during repaglinide treatment (P ϭ 0.074). Metabolic control (HbA 1c and fasting blood glucose) with repaglinide was unchanged from that on previous antidiabetic medication. Final repaglinide dose tended to be lower for patients with severe and extreme renal impairment than for patients with less severe renal impairment or normal renal function (P ϭ 0.032).CONCLUSIONS -Repaglinide has a good safety and efficacy profile in type 2 diabetic patients complicated by renal impairment and is an appropriate treatment choice, even for individuals with more severe degrees of renal impairment.

BackgroundPrevious randomized controlled trials demonstrated a protective effect of renin angiotensin system blocking agents for the development of type-2 diabetes in patients with pre-diabetes. However, there are no real-world data available to illustrate the relevance for clinical practice.MethodsOpen, prospective, parallel group study comparing patients with an ACE inhibitor versus a diuretic based treatment. The principal aim was to document the first manifestation of type-2 diabetes in either group.ResultsA total of 2,011 patients were enrolled (mean age 69.1 ± 10.3 years; 51.6% female). 1,507 patients were available for the per-protocol analysis (1,029 ramipril, 478 diuretic group). New-onset diabetes was less frequent in the ramipril than in the diuretic group over 4 years. Differences were statistically different at a median duration of 3 years (24.4% vs 29.5%; p < 0.05). Both treatments were equally effective in reducing BP (14.7 ± 18.0/8.5 ± 8.2 mmHg and 12.7 ± 18.1/7.0 ± 8.3 mmHg) at the 4 year follow-up (p < 0.001 vs. baseline; p = n.s. between groups). In 38.6% and 39.7% of patients BP was below 130/80 mmHg (median time-to-target 3 months). There was a significant reduction of cardiovascular morbidity and mortality in favour of ramipril (p = 0.033). No significant differences were found for a change in HbA1c as well as for fasting blood glucose levels during follow-up. The rate of adverse events was higher in diuretic treated patients (SAE 15.4 vs. 12.4%; p < 0.05; AE 26.6 vs. 25.6%; p = n.s).ConclusionsRamipril treatment is preferable over diuretic based treatment regimens for the treatment of hypertension in pre-diabetic patients, because new-onset diabetes is delayed.