Progression to insulin therapy among patients with type 2 diabetes treated with sitagliptin or sulphonylurea plus metformin dual therapy.

AIM: To assess time to insulin initiation among patients with type 2 diabetes mellitus (T2DM) treated with sitagliptin versus sulphonylurea as add-on to metformin. METHODS: This retrospective cohort study used GE Centricity electronic medical records and included patients aged ≥18 years with continuous medical records and an initial prescription of sitagliptin or sulphonylurea (index date) with metformin for ≥90 days during 2006-2013. Sitagliptin and sulphonylurea users were matched 1 : 1 using propensity score matching, and differences in insulin initiation were assessed using Kaplan-Meier curves and Cox regression. We used conditional logistic regression to examine the likelihood of insulin use 1-6 years after the index date for each year. RESULTS: Propensity score matching produced 3864 matched pairs. Kaplan-Meier analysis showed that sitagliptin users had a lower risk of insulin initiation compared with sulphonylurea users (p = 0.003), with 26.6% of sitagliptin users initiating insulin versus 34.1% of sulphonylurea users over 6 years. This finding remained significant after adjusting for baseline characteristics (hazard ratio 0.76, 95% confidence interval 0.65-0.90). Conditional logistic regression analyses confirmed that sitagliptin users were less likely to initiate insulin compared with sulphonylurea users [odds ratios for years 1-6: 0.77, 0.79, 0.81, 0.57, 0.29 and 0.75, respectively (p < 0.05 for years 4 and 5)]. CONCLUSIONS: In this real-world matched cohort study, patients with T2DM treated with sitagliptin had a significantly lower risk of insulin initiation compared with patients treated with sulphonylurea, both as add-on to metformin.

The efficacy and safety of ezetimibe/simvastatin combination compared with intensified lipid-lowering treatment strategies in diabetic subjects with and without metabolic syndrome.

AIMS: The objective was to assess the consistency of effect of switching to ezetimibe/simvastatin 10/20 mg versus doubling the baseline statin dose (to simvastatin 40 mg or atorvastatin 20 mg) or switching to rosuvastatin 10 mg across subgroups of subjects with (n = 617) and without (n = 191) metabolic syndrome (MetS). METHODS: This was a post hoc analysis of a randomized, double-blind, 6-week study of adults 18-79 years with cardiovascular disease and diabetes mellitus with low-density lipoprotein cholesterol (LDL-C) ≥70 and ≤160 mg/dl. The percent change in LDL-C and other lipids was estimated within each subgroup separately. Safety and tolerability were assessed. RESULTS: In subjects with MetS, percent changes in LDL-C and other lipids were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin, except high-density lipoprotein cholesterol and apolipoprotein (Apo) AI (mean percent changes in LDL-C were: -22.49% ezetimibe/simvastatin, -9.64% doubled baseline statin and -19.20% rosuvastatin). In subjects without MetS, percent changes in LDL-C, total cholesterol and Apo B were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin (mean percent changes in LDL-C were: -25.14% ezetimibe/simvastatin, -4.75% doubled baseline statin and -19.75% rosuvastatin). Safety profiles were generally similar. CONCLUSION: These results showed that switching to ezetimibe/simvastatin 10/20 mg was more effective at reducing LDL-C, total cholesterol and Apo B versus doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg regardless of MetS status. These results were generally similar to those of the full cohort.

Lipid-altering efficacy and safety profile of combination therapy with ezetimibe/statin vs. statin monotherapy in patients with and without diabetes: an analysis of pooled data from 27 clinical trials.

AIM: This post hoc analysis compared the lipid-altering efficacy and safety of ezetimibe 10 mg plus statin (EZE/statin) vs. statin monotherapy in hypercholesterolaemic patients with and without diabetes. METHODS: A pooled analysis of 27 previously published, randomized, double-blind, active- or placebo-controlled clinical trials comprising 21 794 adult patients with (n = 6541) and without (n = 15253) diabetes receiving EZE/statin or statin alone for 4-24 weeks evaluated percentage change from baseline in lipids and other parameters. Consistency of the treatment effect across the subgroups was tested using treatment × subgroup interaction. No multiplicity adjustments were made. RESULTS: Treatment effects within both subgroups were generally consistent with the overall population. EZE/statin was more effective than statin alone in improving low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), non-HDL-C, apolipoprotein (apo) B and high-sensitivity C-reactive protein (hs-CRP) in the overall population and both subgroups. Patients with diabetes achieved significantly larger reductions in LDL-C, TC and non-HDL-C compared with non-diabetic patients. Incidences of adverse events or creatine kinase elevations were similar between groups. A small but significantly higher incidence of alanine aminotransferase or aspartate aminotransferase elevations was seen in patients receiving EZE/statin (0.6%) vs. statin monotherapy (0.3%) in the overall population. CONCLUSIONS: Treatment with EZE/statin vs. statin monotherapy provided significantly larger reductions in LDL-C, TC, TG, non-HDL-C, apo B and hs-CRP and significantly greater increases in HDL-C, with a similar safety profile in patients with and without diabetes. Reductions in LDL-C, TC and non-HDL-C were larger in patients with diabetes than in patients without diabetes.

Lipid-altering efficacy of ezetimibe/simvastatin 10/20 mg compared with rosuvastatin 10 mg in high-risk hypercholesterolaemic patients inadequately controlled with prior statin monotherapy - The IN-CROSS study.

AIMS: To evaluate the efficacy of switching from a previous statin monotherapy to ezetimibe/simvastatin (EZE/SIMVA) 10/20 mg vs. rosuvastatin (ROSUVA) 10 mg. METHODS: In this randomised, double-blind study, 618 patients with documented hypercholesterolaemia [low-density lipoprotein cholesterol (LDL-C) > or = 2.59 and < or = 4.92 mmol/l] and with high cardiovascular risk who were taking a stable daily dose of one of several statin medications for > or = 6 weeks prior to the study randomisation visit entered a 6-week open-label stabilisation/screening period during which they continued to receive their prestudy statin dose. Following stratification by study site and statin dose/potency, patients were randomised to EZE/SIMVA 10/20 mg (n = 314) or ROSUVA 10 mg (n = 304) for 6 weeks. RESULTS: EZE/SIMVA produced greater reductions in LDL-C (-27.7% vs. -16.9%; p < or = 0.001), total cholesterol (-17.5% vs. -10.3%; p < or = 0.001), non-high-density lipoprotein cholesterol (HDL-C) (-23.4% vs. -14.0%; p < or = 0.001) and apolipoprotein B (-17.9% vs. -9.8%; p < or = 0.001) compared with ROSUVA, while both treatments were equally effective at increasing HDL-C (2.1% vs. 3.0%; p = 0.433). More patients achieved LDL-C levels < 2.59 mmol/l (73% vs. 56%), < 2.00 mmol/l (38% vs. 19%) and < 1.81 mmol/l (25% vs. 11%) with EZE/SIMVA than ROSUVA (p < or = 0.001). A borderline significantly greater reduction in triglycerides (p = 0.056) was observed for EZE/SIMVA (-11.0%) vs. ROSUVA (-5.3%). There were no between-group differences in the incidences of adverse events or liver transaminase and creatine kinase elevations. CONCLUSION: EZE/SIMVA 10/20 mg produced greater improvements in LDL-C, total cholesterol, non-HDL-C and apoB with a similar safety profile as for ROSUVA 10 mg.

Efficacy of ezetimibe/simvastatin 10/40 mg compared to doubling the dose of low-, medium- and high-potency statin monotherapy in patients with a recent coronary event.

OBJECTIVE: The aim of the study was to compare the efficacy/safety of doubling the dose of low-, medium- and high-potency statins on lipids/lipoproteins versus ezetimibe/simvastatin (EZE/SIMVA) 10/40 mg in patients with a recent coronary event. METHODS: In this open-label study, patients were stratified by baseline statin therapy (low, medium and high potency) and randomized equally to statin dose doubling or EZE/SIMVA 10/40 mg for 12 weeks. Primary analysis concerned change in low-density lipoprotein cholesterol for the whole population. Treatment-by-stratum interaction evaluated the consistency of treatment effect across statin potency strata. Post hoc analysis of between-group efficacy within strata was performed using ANCOVA. RESULTS: Within each stratum, EZE/SIMVA produced significantly greater reductions in low-density lipoprotein cholesterol, total cholesterol, apolipoprotein B and non-high-density lipoprotein cholesterol (HDL-C) compared to statin doubling. Numerical trends toward smaller between-group reductions were observed with higher-potency statins and reached statistical significance for apolipoprotein B and non-HDL-C. No significant between-group differences in HDL-C and C-reactive protein were observed within each stratum. EZE/SIMVA produced larger reductions in triglycerides versus low-potency statin, whereas it was similarly effective compared with intermediate-/high-potency statins. The safety/tolerability profiles of the treatments were similar across the strata. CONCLUSIONS: EZE/SIMVA 10/40 mg produced greater improvements in lipids with a similar safety profile compared to doubling the dose of low-, medium- and high-potency statins.

Lipid-altering efficacy of ezetimibe/simvastatin 10/40 mg compared with doubling the statin dose in patients admitted to the hospital for a recent coronary event: the INFORCE study.

BACKGROUND: The aim of this study was to investigate the efficacy and safety profile of switching to ezetimibe/simvastatin (Eze/Simva) 10/40 mg compared with doubling the statin dose upon discharge in patients taking a statin and admitted to the hospital for the investigation of a coronary event. DESIGN: This phase IV, multi-centre, randomised, open-label, active-controlled, parallel group study enrolled 424 patients (aged >/= 18 years) hospitalised for an acute coronary event and taking a stable dose of a statin (>/= 6 weeks) that could be doubled per the product label. Upon discharge from the hospital, patients were stratified by their statin dose/potency (high, medium and low) and randomised 1 : 1 to doubling of the statin dose (n = 211) or Eze/Simva 10/40 mg (n = 213) for 12 weeks. The primary efficacy variable was the absolute low-density lipoprotein cholesterol (LDL-C) value (mmol/l) at study end-point. RESULTS: Mean baseline LDL-C for the two treatment groups were 2.48 and 2.31 mmol/l for the Eze/Simva and statin groups respectively. At study end-point, least squares mean LDL-C values were 1.74 mmol/l in the Eze/Simva group and 2.22 mmol/l in the statin group resulting in a significant between-group difference of -0.49 mmol/l (p /= 0.160). Significantly more patients achieved LDL-C levels < 2.5 (< 100 mg/dl; 86% vs. 72%), < 2.0 (< 77 mg/dl; 70% vs. 42%) and < 1.8 mmol/l (< 70 mg/dl; 60% vs. 31%) with Eze/Simva than statin (all p /= 3 x upper limit of normal (ULN) or creatine kinase >/= 10 x ULN between the groups. CONCLUSIONS: In patients taking a statin and admitted to the hospital for investigation of a coronary event, treatment with Eze/Simva 10/40 mg for 12 weeks produced greater improvements in lipids with a similar safety profile compared with doubling of the statin dose.

Comparison of irbesartan vs felodipine in the regression after 1 year of left ventricular hypertrophy in hypertensive patients (the SILVER trial). Study of Irbesartan in Left VEntricular hypertrophy Regression.

The SILVER (Study of Irbesartan in Left VEntricular hypertrophy Regression) trial is designed to test the hypothesis that the newly developed angiontensin-II receptor antagonist, irbesartan, will produce a greater reduction in left ventricular (LV) mass than felodipine ER, in a population of hypertensive patients defined by seated diastolic blood pressure (SeDBP) in the range 95-115 mmHg or seated systolic blood pressure (SeSBP) in the range 160-200 mm Hg. A population of 360 men and women of non-childbearing potential, >18 years of age, with hypertension, newly diagnosed or after a 3-week washout from previous anti-hypertensive or vasodilator therapies, will be randomised at approximately 80-90 European sites. Add-on therapy with hydrochlorothiazide and atenolol will be allowed for blood pressure control. Patients will be studied by two-dimensional and M-mode echocardiography at baseline (central validation of LV hypertrophy), on randomisation day, and after 6 and 12 months randomised therapy. Blinded analysis of echocardiograms will be performed at a central laboratory, which will provide measurements of the LV mass index (LVMI), determined by M-mode readings according to Devereux formula and using the Penn convention. The primary end-point of the study will be the change in LVMI from baseline to 12 months. The study power is 90% to detect differences between groups from baseline of approximately 8 g/m2.

Impact of a combination of a calcium antagonist and a beta-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and efflux of cholesterol in human macrophages and murine J774 cells.

Calcium antagonists and beta-blockers may retard or inhibit atherogenesis. In the absence of data pertaining to the potential cardioprotective action of an association of such agents, we have investigated the impact of nifedipine and atenolol, alone or in combination, on the capacity of monocyte-macrophages (ex vivo) and copper ions (in vitro) to oxidize LDL and on intracellular metabolism and efflux of free and esterified forms of cholesterol in human macrophages and foam cells. At concentrations up to 100 micromol/L, atenolol had no effect on the oxidative resistance of LDL; on the contrary, nifedipine displayed a significant dose-dependent capacity to protect LDL during copper-mediated oxidation (100 micromol/L; P<.001). Using a DPPH radical generating system, nifedipine was shown to exert free radical-trapping activity (molar ratio of scavenging activity, nifedipine:alpha-tocopherol, 1:114). The addition of atenolol to nifedipine was without effect on the antioxidant activity of the calcium antagonist. In experiments in which oxidative modification was mediated by monocyte-macrophages, nifedipine but not atenolol conserved its antioxidant capacity. Furthermore, we demonstrated that association of atenolol with nifedipine did not modify the antioxidant properties of nifedipine itself. Using a human monocyte-derived macrophage culture system, nifedipine, atenolol, or a combination of the two drugs was ineffective in inhibiting foam cell formation induced by acetylated LDL or oxidized LDL. However, atenolol (100 micromol/L) increased cellular accumulation of cholesteryl ester (+17%; P<.05), whereas nifedipine (100 micromol/L) decreased total cholesterol (-37.4%; P<.05) accumulation induced by acetylated LDL in the mouse macrophage cell line J774. A combination of the two drugs neutralized these antagonistic effects. None of these results were reproduced during the oxidized LDL-induced transformation of murine J774 cells into foam cells. Furthermore, cholesterol efflux from preloaded human macrophages was equally unaffected by the addition of the drugs alone or in combination. It therefore seems unlikely that the beneficial effect of atenolol on coronary heart disease is mediated by changes in either LDL oxidizability or cholesterol metabolism in human macrophages and foam cells. Our findings with nifedipine suggest, however, that this calcium antagonist may potentially exert antiatherosclerotic properties via a reduction of the oxidative modification of LDL, thereby affecting a reduction in foam cell formation and in the pathophysiological cellular activities of oxidized lipids, rather than by inducing a direct reduction in cholesterol accumulation in human foam cells of macrophage origin.

[Arterial hypertension: current large therapeutic trials]. / Hypertension artérielle: les grands essais thérapeutique en cours.

In this review, the design and objectives of ongoing clinical trials in essential hypertension are discussed along with the main results obtained from previously published therapeutic trials. In a meta-analysis of 14 of the major primary prevention trials in hypertension, the difference in diastolic blood pressure between the intervention groups and the control groups was only 5-6 mmHg. This difference was associated with significant reductions in all stroke events (42 per cent), all coronary heart disease events (14 per cent) and in cardiovascular mortality (21 per cent). In elderly hypertensive patients, available studies have shown that antihypertensive treatment reduces the incidence of non-fatal cardiovascular events without significantly modifying cardiovascular mortality. Most of these results were obtained with beta-blockers or diuretics. Despite official recommendation as first line monotherapy, none of the three new antihypertensive classes has been shown to have beneficial effects on hard primary endpoints such as cardiovascular morbidity and mortality. Several ongoing large scale randomized controlled trials vs. beta-blockers or diuretics are addressing this important issue. Moreover, other effects of antihypertensive treatment such as the 'J-curve phenomenon', the rate of change in the carotid wall thickness or the exact beneficial effects in elderly patients are being investigated in some of these studies.

[Myocardial ischemia detected by Holter monitoring: analysis of therapeutical trials realised in stable angina]. / Ischémie myocardique détectée par enregistrement Holter: analyse des essais thérapeutiques realisés dans l'angor stable.

Silent myocardial ischaemia is the most frequent consequence of coronary artery disease and occurs in almost 70 per cent to 80 per cent of ischaemic episodes. In some studies, it has some predictive value of cardiovascular events either in stable or unstable angina or after myocardial infarction. In this last case, one year mortality is 30 per cent and 11 per cent respectively with and without silent ischaemia that has been recorded on the 8th day after myocardial infarction. This review has focused on controlled studies in patients with angina and Holter recorded ischaemia. Nitrates are very likely to be active substances on Holter recorded angina but no controlled studies have been performed to really demonstrate it. The efficacy of beta-blocking agents is well established with a 60 per cent reduction in the number of ischaemic events and a 80 per cent reduction in total ischaemic duration. Nifedipine efficacy appears lower than that of beta-blockers with an evaluated mean reduction of 39 per cent for the number of events and of 43 per cent for duration of episodes. Diltiazem induces a 48 per cent reduction of both ischaemic parameters. For drug associations, addition of a calcium antagonist to a beta-blocking agent provides only little benefit. The relationship between anti-ischaemic efficacy and long term prevention of cardiovascular events remains to be established for a given anti-ischaemic therapy.