Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes.

AIM: The aim of this study was to assess the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on 24-h glucose control when added to the regimen of patients with type 2 diabetes who had inadequate glycaemic control on metformin therapy. METHODS: In a double-blind, randomized, placebo-controlled, two-period crossover study, patients with type 2 diabetes with inadequate glycaemic control on metformin monotherapy (i.e. on a stable dose of > or = 1500 mg/day for > or = 6 weeks prior to the screening visit and an haemoglobin A(1c) (HbA(1c)) > or = 6.5% and <10% and fasting plasma glucose (FPG) < or = 240 mg/dl) were recruited for participation. A total of 28 patients (baseline HbA(1c) range = 6.5-9.6%) receiving metformin were randomized into one of two treatment sequences: the addition of placebo for 4 weeks followed by the addition of sitagliptin 50 mg twice daily (b.i.d.) for 4 weeks, or vice versa. At the end of each treatment period, patients were domiciled for frequent blood sampling over 24 h. The primary endpoint was 24-h weighted mean glucose (WMG) and secondary endpoints included change in FPG, mean of 7 daily self-blood glucose measurements (MDG) and fructosamine. beta-cell function was assessed from glucose and C-peptide concentrations were measured during the 5-h period after a standard breakfast meal by using the C-peptide minimal model. RESULTS: Despite a carryover effect from period 1 to period 2, the combined period 1 and period 2 results for glycaemic endpoints were statistically significant for sitagliptin relative to placebo when added to ongoing metformin therapy. To account for the carryover effect, the period 1 results were also compared between the groups. Following period 1, there were significant least-squares (LS) mean reductions in 24-h WMG of 32.8 mg/dl, significant LS mean reduction from baseline in MDG of 28 mg/dl, FPG of 20.3 mg/dl and fructosamine of 33.7 mmol/l in patients treated with sitagliptin relative to placebo (p < 0.05). When added to ongoing metformin therapy, parameters of beta-cell function were significantly improved with sitagliptin compared with placebo. No weight gain or increases in gastrointestinal adverse events or hypoglycaemia events were observed with sitagliptin relative to placebo during this study. CONCLUSIONS: In this study, the addition of sitagliptin 50 mg b.i.d. to ongoing metformin therapy improved 24-h glycaemic control and beta-cell function, and was generally well tolerated in patients with type 2 diabetes.

Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies.

AIM: The efficacy, dose-response relationships and safety of an extended-release formulation of metformin (Glucophage) XR) were evaluated in two double-blind, randomized, placebo-controlled studies of 24 and 16 weeks' duration, in patients with inadequate glycaemic control despite diet and exercise. Protocol 1 provided an evaluation of metformin XR at a commonly used dosage. Protocol 2 evaluated different dosages of metformin XR. METHODS: In Protocol 1, 240 patients were randomized to receive metformin XR 1000 mg once daily. or placebo in a 2:1 ratio for 12 weeks (patients could receive metformin XR 1500 mg during weeks 12-24 if required). In Protocol 2, 742 patients were randomized to receive metformin XR 500 mg once daily, 1000 mg once daily, 1500 mg once daily, 2000 mg once daily, 1000 mg twice daily or placebo for 16 weeks. The primary endpoint in each study was the change from baseline in HbA(1C) at 12 weeks (Protocol 1) or 16 weeks (Protocol 2). RESULTS: Metformin XR reduced HbA(1C) in Protocol 1, with mean treatment differences for 1000 mg once daily vs. placebo of -0.7% at 12 weeks and -0.8% at 24 weeks (p < 0.001 for each). In Protocol 2, a clear dose-response relationship was evident at doses up to 1500 mg, with treatment differences vs. placebo of -0.6% (500 mg once daily), -0.7% (1000 mg once daily), -1.0% (1500 mg once daily) and -1.0% (2000 mg once daily). The efficacy of metformin XR 2000 mg once daily and 1000 mg twice daily were similar (mean treatment differences vs. placebo in HbA(1C) were -1.0% and -1.2%, respectively). More patients achieved HbA(1C) < 7.0% with metformin XR vs. placebo in Protocol 1 (29% vs. 14% at 12 weeks) and with once-daily metformin XR in Protocol 2 (up to 36% vs. 10% at 16 weeks). No significant changes in fasting insulin or body weight occurred. Total and low-density lipoprotein (LDL)-cholesterol improved (p < 0.05-p < 0.001) in metformin XR groups in Protocol 2. Metformin XR was well tolerated; gastrointestinal side effects were more common with metformin XR vs. placebo, but few patients withdrew for this reason (1.3% vs. 1.3% in Protocol 1 and 1.6% vs. 0.9% in Protocol 2). CONCLUSIONS: Once-daily metformin XR presents an effective and well-tolerated therapeutic option for delivering metformin in a convenient manner, which supports good compliance with therapy.

Recombinant glucagon-like peptide-1 (7-36 amide) lowers fasting serum glucose in a broad spectrum of patients with type 2 diabetes.

AIMS: To evaluate the safety and efficacy of various doses of recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered subcutaneously (s. c.) via bolus injection or continuous infusion to lower fasting serum glucose (FSG) levels in subjects with type 2 diabetes treated by diet, hypoglycemic drugs, or insulin injection. METHODS: rGLP-1 was administered s. c. to 40 type 2 diabetics currently treated by diet, sulfonylurea (SU), metformin, or insulin in a double-blind, placebo-controlled, cross-over trial; preexisting treatments were continued during the study. In the bolus injection protocol, 32 subjects (8 from each of the 4 treatment groups) received 0.0, 0.5, 1.0, and 1.5 nmol rGLP-1/kg per injection (two injections, two hours apart, beginning one hour after the evening meal) in a randomized order on separate days. In the continuous s. c. infusion protocol, 40 subjects received rGLP-1 at 0.0, 1.5, 2.5, 3.5, and 4.5 pmol/kg/min for 10-12 hours overnight starting one hour after the evening meal. Fasting bloods were taken the morning after for glucose, insulin, and glucagon measurements. RESULTS: In the diet, SU, and metformin cohorts, bolus rGLP-1 injections produced modest reductions in mean FSG levels, averaging 17.4 mg/dl (7.3-27.5; 95 % CI) at the highest dose (p < 0.001 vs. placebo). Reductions in FSG levels were greater by continuous infusion at up to 30.3 mg/dl (18.8 - 41.8; 95 % CI; p < 0.001 vs. placebo). The greatest reduction in mean FSG occurred in the SU cohort (up to 43.9 mg/dl, 24.7 - 63.1; 95 % CI; p < 0.001). rGLP-1 infusions resulted in significant increases in fasting plasma insulin and decreases in fasting plasma glucagon levels. There were no serious adverse events; GI-related symptoms were dose-related and more commonly associated with injections. CONCLUSIONS: rGLP-1 (7-36) amide dose-dependently lowered FSG in a broad spectrum of type 2 diabetics when added to their existing treatment. Subcutaneous infusion was more effective than injection, and the combination with SU was more effective than with metformin.

Long-term efficacy and safety of cerivastatin 0.8 mg in patients with primary hypercholesterolemia.

BACKGROUND: Statins are the agents of choice in reducing elevated plasma low-density lipoprotein cholesterol (LDL-C). HYPOTHESIS: Cerivastatin 0.8 mg has greater long-term efficacy in reducing LDL-C than pravastatin 40 mg in primary hypercholesterolemia. METHODS: In this double-blind, parallel-group, 52-week study, patients (n = 1,170) were randomized (4:1:1) to cerivastatin 0.8 mg, cerivastatin 0.4 mg, or placebo daily. After 8 weeks, placebo was switched to pravastatin 40 mg. Patients with insufficient LDL-C lowering after 24 weeks were allowed open-labeled resin therapy. RESULTS: Cerivastatin 0.8 mg reduced LDL-C versus cerivastatin 0.4 mg (40.8 vs. 33.6%, p <0.0001) or pravastatin 40 mg (31.5%, p<0.0001), and brought 81.8% of all patients, and 54.1% of patients with atherosclerotic disease, to National Cholesterol Education Program (NCEP) goals. Cerivastatin 0.8 mg improved mean total C (-29.0%), triglycerides (-18.3%), and high-density lipoprotein cholesterol (HDL-C) (+9.7%) (all p < or = 0.013 vs. pravastatin 40 mg). Higher baseline triglycerides were associated with greater reductions in triglycerides and elevations in HDL-C with cerivastatin. Cerivastatin was well tolerated; the most commonly reported adverse events were arthralgia, headache, pharyngitis, and rhinitis. Symptomatic creatine kinase > 10x the upper limit of normal (ULN) occurred in 1, 1.5, and 0% of patients receiving cerivastatin 0.8 mg, cerivastatin 0.4 mg, and pravastatin 40 mg, respectively. Repeat hepatic transaminases >3 x ULN occurred in 0.3-0.5, 0.5, and 0% of patients, respectively. CONCLUSION: In long-term use, cerivastatin 0.8 mg effectively and safely brings the majority of patients to NCEP goal.

Efficacy and safety of cerivastatin 0.8 mg in patients with hypercholesterolaemia: the pivotal placebo-controlled clinical trial. Cerivastatin Study Group.

This pivotal, multicentre, double-blind, parallel-group study evaluated the efficacy and safety of cerivastatin 0.8 mg. Patients with primary hypercholesterolaemia were randomized, after 10 weeks' dietary stabilization on an American Heart Association (AHA) Step I diet, to treatment with cerivastatin 0.8 mg (n = 776), cerivastatin 0.4 mg (n = 195) or placebo (n = 199) once daily for 8 weeks. Cerivastatin 0.8 mg reduced mean low density lipoprotein-cholesterol (LDL-C) by 41.8% compared with cerivastatin 0.4 mg (-35.6%, P < 0.0001) or placebo. In 90% of patients receiving cerivastatin 0.8 mg LDL-C was reduced by 23.9 -58.4% (6th - 95th percentile). Overall attainment of the National Cholesterol Education Program (NCEP) goal was achieved by 84% of patients receiving cerivastatin 0.8 mg and by 59% of those with coronary heart disease (CHD). In the sub-population meeting the NCEP criteria for pharmacological therapy for LDL-C reduction, 74.6% of patients, including the 59% with CHD, reached the goal with cerivastatin 0.8 mg. Cerivastatin 0.8 mg also reduced mean total cholesterol by 29.9%, apolipoprotein B by 33.2% and median triglycerides by 22.9% (all P < 0.0001). Mean high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 were elevated 8.7% (P < 0.0001) and 4.5% (P < 0.0001), respectively, by cerivastatin 0.8 mg. Reductions of triglyceride and elevation in HDL-C were dependent upon triglyceride baseline levels; in patients having baseline triglyceride levels 250 - 400 mg/dl, cerivastatin 0.8 mg reduced median triglycerides by 29.5% and elevated HDL-C by 13.2%. Cerivastatin 0.8 mg was well tolerated. The most commonly reported adverse events included headache, pharyngitis and rhinitis (4 - 6%). Symptomatic creatine kinase elevations > 10 times upper limit of normal occurred in 0%, 1% and 0.9% of patients receiving placebo, cerivastatin 0.4 mg or cerivastatin 0.8 mg, respectively. Cerivastatin 0.8 mg is an effective and safe treatment for patients with primary hypercholesterolaemia who need aggressive LDL-C lowering in order to achieve NCEP-recommended levels.

Psyllium for the reduction of cholestyramine-associated gastrointestinal symptoms in the treatment of primary hypercholesterolemia.

OBJECTIVE: To determine if the bulk-forming laxative, psyllium hydrophilic mucilloid (PHM), reduces the gastrointestinal side effects and enhances the cholesterol-lowering efficacy of cholestyramine resin in patients with primary hypercholesterolemia. DESIGN: After a dietary lead-in period and 6 weeks of treatment with cholestyramine, the study followed a double-blinded, placebo-controlled, crossover format. SETTING: Lipid clinic affiliated with a large metropolitan community hospital. PARTICIPANTS: Twenty-seven randomly selected male and female patients with a diagnosis of primary hypercholesterolemia. Entry criteria required a fasting low-density lipoprotein cholesterol (LDL-C) concentration of 4.91 mmol/L (190 mg/dL) or greater and a triglyceride concentration of less than 2.26 mmol/L. Patients using steroids, beta-blockers, thiazide diuretics, and lipid-lowering agents, or having a history of allergy to psyllium or aspartame were excluded. INTERVENTION: The study consisted of four interventional phases of 6 weeks' duration that included (1) dietary stabilization (National Cholesterol Education Program Step I Diet); (2) cholestyramine therapy (4 g twice daily); (3) cholestyramine with study medication (PHM [5.1 g twice daily] or placebo); and (4) cholestyramine with crossover to alternate study medication. MAIN RESULTS: Following the 6-week dietary lead-in phase, four patients were eliminated from the study because their fasting LDL-C concentrations fell below 4.14 mmol/L (160 mg/dL), and one patient was eliminated because testosterone therapy was initiated by his internist. The remaining 22 patients entered the cholestyramine treatment phase. Four left the study within 2 weeks because of intolerable gastrointestinal tract symptoms. The 18 patients who completed this phase demonstrated significant reductions in their plasma total cholesterol (7.27 vs 6.67 mmol/L [281 vs 258 mg/dL]) and LDL-C (5.38 vs 4.63 mmol/L [208 vs 179 mg/dL]) concentrations compared with baseline levels. The addition of PHM to the cholestyramine regimen provided a tendency toward further reductions in total cholesterol and LDL-C levels (6.67 vs 6.46 mmol/L [258 vs 250 mg/dL] and 4.63 vs 4.29 mmol/L [179 vs 166 mg/dL], respectively), although statistical significance was not achieved. Psyllium hydrophilic mucilloid significantly reduced the frequency and severity of constipation, abdominal discomfort, and heartburn. No reports of new gastrointestinal tract symptoms or untoward effects were noted with the addition of PHM. CONCLUSION: These data suggest that the addition of PHM to cholestyramine therapy may improve a patient's compliance by reducing the associated gastrointestinal tract side effects.

Insulin excess counteracts the effects of HDL on intracellular sterol accumulation in cultured human skin fibroblasts.

Both Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic individuals are at increased risk of developing ischaemic heart disease. Insulin excess, present in both diabetic groups, may play an important pathophysiologic role in accelerating the atherogenic process. In this study, cultured human skin fibroblasts were incubated with varying concentrations of insulin to test the role of insulin on cell cholesterol homeostasis and on HDL3-mediated removal of excess cholesterol from cells. Insulin excess (1-100 nmol/l) resulted in a significant dose-dependent reduction in HDL3-mediated cholesterol efflux from the intracellular unesterified cholesterol pool of cultured human skin fibroblasts. Similar insulin concentrations resulted in impaired HDL-mediated cholesterol efflux from the cell membrane but had no effect on non-HDL-mediated efflux. The effect of insulin on cholesterol esterification and biosynthesis was assessed by 14C-oleate labelling. The addition of HDL3 (50 micrograms) resulted in a significant decrease in 14C-labelled cholesterol ester, reflecting a decrease in intracellular unesterified cholesterol, which was partially reversed by the addition of insulin. Insulin had no effect on the incorporation of 14C-oleate into unesterified cholesterol. During simultaneous incubation of fibroblasts with LDL and HDL, insulin resulted in an increase in cholesterol esterification and inhibited ability of HDL to promote the decrease in esterification. Thus, we have shown that insulin excess counteracts the beneficial effects of HDL that involve removal of cellular cholesterol and may in part promote atherogenesis by this mechanism.

Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B.

PURPOSE: To test whether low-density lipoprotein (LDL) from subjects with an atherogenic lipoprotein phenotype characterized by small, dense LDL (pattern B) demonstrates greater susceptibility to oxidative modification than LDL from subjects exhibiting primarily larger, more buoyant LDL particles (pattern A). PATIENTS AND METHODS: Measures of susceptibility to oxidative modification were compared in six density subfractions of LDL isolated from pattern A and pattern B subjects. Seven male and three female pattern A subjects and five male and two female pattern B subjects, classified on the basis of peak LDL particle size, were studied. Plasma lipid and lipoprotein levels, apolipoprotein B, mean LDL particle diameter, lag phase, and rate of oxidation after initiation of oxidation by copper sulfate were measured. RESULTS: The lag time, a measure of resistance to oxidative modification, was inversely related (p < 0.001) to LDL density in both groups of subjects, without an independent effect of phenotype. The fraction that had the major LDL peak had a shorter lag time (p < 0.05) in pattern B than in pattern A. Pattern B subjects also demonstrated an increased rate of oxidation (p < 0.005) in fraction 1, which includes remnants of triglyceride-rich lipoproteins. CONCLUSIONS: The increased atherogenic risk associated with the pattern B phenotype may result in part from increased concentrations of lipoprotein subpopulations that are relatively susceptible to oxidative modification.

The effect of probucol on HDL-mediated sterol translocation and efflux from cells.

It has been suggested that the antioxidant drug probucol can prevent arterial cholesterol accumulation in part by promoting HDL-mediated cholesterol removal from cells. In this study, the effect of probucol in vitro on the interaction of HDL3 with cultured skin fibroblasts, bovine aortic endothelial cells and human monocyte-derived macrophages was tested. Treatment of cholesterol-loaded cells with up to 20 microM probucol had no effect on [3H]cholesterol efflux from plasma membranes. No effect of probucol on HDL3-mediated efflux of labeled sterol was seen after intracellular sterol was labeled either with the biosynthetic precursor [3H]mevalonolactone or after incubation with lipoprotein-associated [3H]cholesterol linoleate. Further, no effect of probucol on cell cholesterol mass efflux was observed. Thus these results demonstrate that probucol does not affect movement of sterol from different cellular radiolabeled sterol pools. Within the limitations of cell culture studies, it is suggested that the proposed antiatherogenic effect of probucol in vivo is not likely to be the result of modulation of major cellular pathways for removal of cholesterol.