Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

Importance: Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection. Objectives: To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes. Design, Setting, and Patients: Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014. Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized. Randomization was stratified by metformin use. Interventions: Once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks. Main Outcomes and Measures: The primary end point was change in hemoglobin A1c (HbA1c) from baseline to week 26. Secondary end points included change from baseline in body weight and adverse events. Results: Baseline characteristics were comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, -0.7% to -1.9%) and subcutaneous semaglutide (-1.9%) and placebo (-0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, -0.4% to -1.6%; P = .01 for 2.5 mg, Conclusions and Relevance: Among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks. These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety. Trial Registration: clinicaltrials.gov Identifier: NCT01923181

Basal Insulin Glargine (HOE 901) versus NPH Insulin in Patients With Type 1 Diabetes on Multiple Daily Insulin Regimes

WSTĘP. Insulina glargine (HOE 901, 21A-Gly-30Ba-L-Arg-30Bb-L-Arg typu ludzkiego) jest nowym rekombinowanym analogiem insuliny o przesuniętym punkcie izoelektrycznym. Przesunięcie to powoduje zwolnienie szybkości wchłaniania i wydłuża czas działania, co przypomina prawidłowe wydzielanie insuliny. Niedawno otrzymała ona akceptację Food and Drug Administration. Celem niniejszego badania była ocena dwóch różnych postaci insuliny glargine pod względem bezpieczeństwa i skuteczności leczenia chorych na cukrzycę typu 1. MATERIAŁ I METODY. W ciągu 4 tygodni 256 chorych na cukrzycę typu 1 otrzymywało insulinę NPH lub insulinę glargine zawierającą 30mg/ml cynku (insulina glargine [30]) lub 80 mg/ml cynku (insulina glargine [80]). Insulina glargine była podawana raz na dobę — wieczorem przed snem. Insulina NPH była podawana raz lub 2 razy dziennie (przed śniadaniem i przed snem) w zależności od wcześniej stosowanego schematu leczenia. Dawka początkowa insuliny glargine oraz NPH była uzależniona od wcześniejszej łącznej dawki dobowej insuliny NPH. WYNIKI. W momencie zakończenia badania w grupach otrzymujących insulinę glargine stwierdzono znamiennie niższe stężenie glukozy w osoczu na czczo (FPG, fasting plasma glucose) w porównaniu z grupą otrzymującą insulinę NPH oraz zmniejszenie średniego skorygowanego stężenia FPG o 2,2 mmol/l (p = 0,0001). Insulina glargine skuteczniej niż insulina NPH obniżała stężenie FPG w grupie chorych wcześniej otrzymujących insulinę NPH w 2 wstrzyknięciach dziennie, natomiast nie obserwowano różnic w grupie otrzymującej wcześniej pojedyncze wstrzyknięcia insuliny NPH. Stężenie FPG było bardziej stabilne u chorych leczonych insuliną glargine niż u leczonych insuliną NPH. W wydzielonej podgrupie pacjentów (n = 71) w nocy wykonywano co godzinę pomiary poziomu glukozy w osoczu. Insulina glargine powodowała obniżenia stężenie FPG po godzinie 5.00 rano; różnica osiągała znamienność statystyczną o godzinie 8.00 rano. Skorygowane stężenie FPG w czasie leczenia insuliną glargine [30] wynosiły 7,8 mmol/l; insuliną glargine [80] — 7,3 mmol/l i insuliną NPH — 10,7 mmol/l. Oba preparaty insuliny glargine były dobrze tolerowane, podobnie jak insulina NPH. WNIOSKI. Insulina glargine podawana raz na dobę przez 4 tygodnie jako metoda zapewnienia podstawowego stężenia insuliny u chorych na cukrzycę typu 1 leczonych wielokrotnymi wstrzyknięciami insuliny, bezpiecznie i skuteczniej niż insulina NPH obniża osoczowe stężenie glukozy na czczo.OBJECTIVE. Insulin glargine (HOE 901, 21A-Gly-30Ba- L-Arg-30Bb-L-Arg human insulin) is a novel recombinant analog of human insulin with a shift in the isoelectric point producing a retarded absorption rate and an increased duration of action that closely mimics normal basal insulin secretion. It recently received approval from the Food and Drug Administration. The aim of this study was to evaluate 2 formulations of insulin glargine for safety and efficacy in the treatment of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS. In a 4-week trial, 256 patients with type 1 diabetes received either NPH insulin or insulin glargine containing 30 µg/ml zinc (insulin glargine[30]) or 80 µg/ml zinc (insulin glargine[80]). Insulin glargine was given subcutaneously once daily at bedtime. NPH insulin was given either once daily (at bedtime) or twice daily (before breakfast and at bedtime), according to the patient’s prestudy regimen. The initial doses of insulin glargine and NPH were based on the previous NPH total daily dose. RESULTS. At study end point, insulin glargine–pooled groups had significantly lower fasting plasma glucose (FPG) levels than the NPH insulin group, with adjusted mean FPG levels reduced by 2.2 mmol/l (P = 0.0001). Insulin glargine was superior to NPH insulin in reducing FPG levels in patients who had previously received NPH insulin twice daily but not in patients who had previously received NPH once daily. FPG levels were more stable in patients using insulin glargine than in patients using NBH insulin. A subset of patients (n = 71) underwent hourly overnight plasma glucose measurements. Insulin glargine patients exhibited lower FPG levels after 5:00 A.M.; the difference was significant by 8:00 A.M. The adjusted mean FPG for insulin glargine[30] was 7.8 mmol/l; for insulin glargine[80], 7.3 mmol/l; and for NPH, 10.7 mmol/l. Both formulations of insulin glargine were well tolerated, similar to NPH insulin. CONCLUSIONS. Basal insulin glargine administered once daily for 4 weeks as part of a basal-bolus multiple daily insulin regimen was safe and more effective in lowering fasting plasma glucose levels than NPH in patients with type 1 diabetes

Reduced risk of hypoglycemia with once-daily glargine versus twice-daily NPH and number needed to harm with NPH to demonstrate the risk of one additional hypoglycemic event in type 2 diabetes: Evidence from a long-term controlled trial

AbstractAimsThis analysis evaluated HbA1c-adjusted hypoglycemia risk with glargine versus neutral protamine Hagedorn (NPH) over a 5-year study in patients with Type 2 diabetes mellitus (T2DM). Clinical significance was assessed using number needed to harm (NNH) to demonstrate the risk of one additional patient experiencing at least one hypoglycemic event.MethodsIndividual patient-level data for symptomatic documented hypoglycemia and HbA1c values from a 5-year randomized study comparing once-daily glargine (n=513) with twice-daily NPH (n=504) were analyzed. Symptomatic hypoglycemia was categorized according to concurrent self-monitoring blood glucose levels and need for assistance. Hypoglycemic events per patient-year as a function of HbA1c were fitted by negative binomial regression using treatment and HbA1c at endpoint as independent variables. An estimate of NNH was derived from logistic regression models.ResultsThe cumulative number of symptomatic hypoglycemia events was consistently lower with glargine compared with NPH over 5years. Compared with twice-daily NPH, once-daily glargine treatment resulted in significantly lower adjusted odds ratios (OR) for all daytime hypoglycemia (OR 0.74; p=0.030) and any severe event (OR 0.64; p=0.035), representing a 26% and 36% reduction in the odds of daytime and severe hypoglycemia, respectively. Our model predicts that, if 25 patients were treated with NPH instead of glargine, then one additional patient would experience at least one severe hypoglycemic event.ConclusionsThis analysis of long-term insulin treatment confirms findings from short-term studies and demonstrates that glargine provides sustained, clinically meaningful reductions in risk of hypoglycemia compared with NPH in patients with T2DM

Improved patient-reported outcomes with iGlarLixi versus premix BIAsp 30 in people with type 2 diabetes in the SoliMix trial

AIM: To assess patient‐reported outcomes (PROs) in the SoliMix trial, which compared the efficacy and safety of iGlarLixi versus BIAsp 30 in people with type 2 diabetes (T2D). MATERIALS AND METHODS: SoliMix (EudraCT: 2017‐003370‐13), a 26‐week, open‐label study, randomized (1:1) 887 adults with T2D and HbA1c ≥7.5%‐≤10.0% (≥58‐≤86 mmol/mol) on basal insulin plus oral antihyperglycaemic drugs (OADs) to once‐daily iGlarLixi or twice‐daily premix insulin, BIAsp 30. PROs were assessed using the Treatment‐Related Impact Measure Diabetes (TRIM‐D) and Global Treatment Effectiveness Evaluation (GTEE) questionnaires. RESULTS: Over 26 weeks, iGlarLixi showed greater improvement from baseline versus BIAsp 30 in total TRIM‐D score (least squares mean difference [95% confidence interval]: 5.08 [3.69, 6.47]; effect size: 0.32) and in each TRIM‐D domain, with the greatest differences seen in diabetes management (8.47 [6.11, 10.84]) and treatment burden (6.95 [4.83, 9.07]). GTEE scores showed a greater proportion of participants and physicians rated a complete or marked improvement of diabetes control with iGlarLixi (80.5%, 82.8%) versus BIAsp 30 (63.3%, 65.1%) at week 26. Post hoc analyses showed that after adjusting for HbA1c, body weight and hypoglycaemia outcomes, iGlarLixi continued to show greater improvements in TRIM‐D total scores versus BIAsp 30. CONCLUSIONS: In addition to better glycaemic control, weight benefit and less hypoglycaemia, once‐daily iGlarLixi provided improved diabetes management, treatment burden and perceived effectiveness versus twice‐daily premix BIAsp 30, further supporting iGlarLixi as an advanced treatment option in people with suboptimally controlled T2D on basal insulin plus OADs

Hypoglycaemia events with iGlarLixi versus premix biphasic insulin aspart 30 (BIAsp 30) in people with type 2 diabetes advancing from basal insulin:An analysis of the SoliMix trial

Aims To explore details of the incidence and rates of daytime and nocturnal hypoglycaemia, levels of hypoglycaemia, and relationship to glycated haemoglobin (HbA1c), when comparing iGlarLixi versus premixed biphasic insulin aspart 30 (BIAsp 30) in the SoliMix randomized controlled trial. Materials and Methods This exploratory analysis of SoliMix used logistic regression and negative binomial regression analyses to assess between-treatment differences in the incidence and rates of hypoglycaemia by time of day. A negative binomial model was used to derive estimated annualized hypoglycaemia rates as a function of HbA1c. Results iGlarLixi was associated with lower incidence and rates of American Diabetes Association Level 2 (<54 mg/dL [<3.0 mmol/L]) hypoglycaemia during both night and day versus BIAsp 30. Incidence and rates of Level 1 (<70 to >= 54 mg/dL [<3.9 to >= 3.0 mmol/L]) hypoglycaemia were also mostly shown to be reduced with iGlarLixi versus BIAsp 30. Severe (Level 3) events were too few for analysis (n = 3). iGlarLixi was associated with lower modelled event rates of Level 2 and Level 1 hypoglycaemia over a wide range of HbA1c levels versus BIAsp 30. Conclusions These results show that the lower HbA1c levels and weight benefit seen with iGlarLixi versus premixed BIAsp 30 in people with type 2 diabetes advancing their basal insulin therapy in the SoliMix trial are also accompanied by a lower risk of hypoglycaemia at any time of day and across a broad range of HbA1c levels

Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET)

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