Observational study of the efficacy of prolonged-release metformin in people with prediabetes.

Objectives: Prediabetes is characterized by elevation of indices of blood glucose that is insufficient to provoke a diagnosis of type 2 diabetes, but markedly increases the risk of developing type 2 diabetes in the future. Lifestyle interventions are the main therapeutic intervention for the management of prediabetes. Current guidelines also support treatment of prediabetes with metformin for selected subgroups of patients, and metformin has a therapeutic indication for this use in a number of countries.Methods: We performed an observational, non-interventional study of the effects on glycaemia of prolonged-release metformin (Glucophage XR, referred to henceforth as metformin XR) in 686 subjects with prediabetes. Metformin was prescribed according to physicians' usual care practices, and the study duration was 12 weeks.Results: Mean (SD) fasting plasma glucose (FPG) at baseline was 6.2 (0.4) mmol/L [111 (8) mg/dL) and was reduced by -0.55 (0.7) mmol/L [-10 (13) mg/dL] after 12 weeks of metformin XR. FPG was normalized to below the American Diabetes Association cut-off for the diagnosis of prediabetes (<5.7 mmol/L [100 mg/dL]) in 43% of subjects. Increasing age, increasing body mass index, not following a weight-loss diet and alcohol use predicted a lower probability of normalized FPG. Metformin was well tolerated, with most side effects occurring in the gastrointestinal system, as expected.Conclusions: Metformin XR normalized FPG in about two-fifths of subjects with prediabetes. These real-world data add further support a role for metformin in the management of prediabetes, in line with current guidelines in this area.

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.

AIMS: To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). METHODS AND RESULTS: A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'. CONCLUSIONS: Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group.

The effect of treatment with bisoprolol-first versus enalapril-first on cardiac structure and function in heart failure.

BACKGROUND: In CIBIS III, initiating chronic heart failure (CHF) treatment with bisoprolol (target dose 10 mg q.d.) followed by combination therapy with enalapril (target dose 10 mg b.i.d.), compared to the opposite order, showed similar effects on survival and hospitalization. By echocardiography, we evaluated the effects of these treatment strategies on cardiac structure and function. METHODS: In a single-centre substudy, we compared the impact on left ventricular (LV) dimensions and ejection fraction (EF) of treatment with bisoprolol-first (n=21) and enalapril-first (n=19) in 40 beta-blocker and angiotensin-converting-enzyme-inhibitor naive patients, with stable, mild or moderate CHF (NYHA II-III) and LVEF ≤35%. Echocardiography was performed at baseline, after the 6-month monotherapy phase and after 12 months, i.e. after 6 months combination therapy. RESULTS: Baseline characteristics were similar across treatment groups. After 6 months LVEF increased by 5.1±4.0 EF-% (P<0.0001) with Bisoprolol and 4.0±4.0 EF-% (P=0.0005), with enalapril (between-group P=0.47). LV end-diastolic volume (LVEDV) decreased by 8.1±4.7 ml (P<0.0001) with bisoprolol and by 4.6±8.2 ml (P=0.03) with enalapril (between-group P=0.16). Mean wall thickness (WT) decreased by 0.31±0.43 mm (P=0.004) with bisoprolol and by 0.18±0.48 mm (P=0.11) with enalapril (between-group P=0.29). From baseline to 12 months, LVEF increased by 7.5±4.0 EF-% (P<0.0001) in Bisoprolol first group and 6.0±4.6 EF-% (P<0.0001), in the enalapril first group (between-group P=0.31). LVEDV decreased by 12.9±6.3 ml (P<0.0001) with bisoprolol-first and by 7.9±7.7 ml (P=0.0006) with enalapril-first (between-group P=0.16) and WT decreased by 0.38±0.44 mm (P=0.0008) and 0.59±0.54 mm (P=0.0004), respectively (between-group P=0.10). CONCLUSION: During both monotherapy and combined therapy, bisoprolol-first and enalapril-first similarly reversed cardiac remodelling and improved LVEF.