Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies.

OBJECTIVE: Type 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The efficacy (HbA1c and glucose) and safety (serum aminotransferase) of once-daily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks. RESULTS: LY2409021 produced reductions in HbA1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA1c was -0.83% (10 mg), -0.65% (30 mg), and -0.66% (60 mg) (all P < 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA1c was -0.45% (2.5 mg), -0.78% (10 mg, P < 0.05), -0.92% (20 mg, P < 0.05), and -0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] ≤10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo. CONCLUSIONS: In patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed.

Empagliflozin added to metformin and sulfonylurea therapy in patients with sub-optimally controlled type 2 diabetes mellitus.

The combination of metformin and a sulfonylurea is commonly used in type 2 diabetes mellitus. Many patients on this combination therapy do not achieve or maintain glycemic targets and require the addition of a third antihyperglycemic agent. Among the options are the sodium glucose cotransporter 2 (SGLT2) inhibitors, a recently developed class of medications that effectively improve glycemic control and are associated with reduction in body weight and blood pressure. This article evaluates a 24-week, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin, added to metformin plus sulfonylurea regimens. Empagliflozin led to significant reductions in glycated hemoglobin and fasting plasma glucose, as well as body weight and systolic blood pressure. Adverse events typically recorded with SGLT2 inhibitors were observed; notably, genital infections occurred in more patients on empagliflozin than placebo. Overall, empagliflozin was well tolerated. These results indicate that SGLT2 inhibitors can be successfully added to metformin plus sulfonylurea regimens. SGLT2 inhibitors are not the only therapeutic option in this clinical situation; however, based on the secondary effects observed in this and other studies, they appear to be of particular value for patients who are obese or overweight.

Nifedipine plus candesartan combination increases blood pressure control regardless of race and improves the side effect profile: DISTINCT randomized trial results.

OBJECTIVES: DISTINCT (reDefining Intervention with Studies Testing Innovative Nifedipine GITS - Candesartan Therapy) aimed to determine the dose-response and tolerability of nifedipine GITS and/or candesartan cilexetil therapy in participants with hypertension. METHODS: In this 8-week, multinational, multicentre, randomized, double-blind, placebo-controlled study, adults with mean seated DBP of at least 95 to less than 110 mmHg received combination or monotherapy with nifedipine GITS (N) 20, 30 or 60 mg and candesartan cilexetil (C) 4, 8, 16 or 32 mg, or placebo. The primary endpoint, change in DBP from baseline to Week 8, was analysed using the response surface model (RSM); this analysis was repeated for mean seated SBP. RESULTS: Overall, 1381 participants (mean baseline SBP/DBP: 156.5/99.6 mmHg) were randomized. Both N and C contributed independently to SBP/DBP reductions [P < 0.0001 (RSM)]. A positive dose-response was observed, with all combinations providing statistically better blood pressure (BP) reductions from baseline versus respective monotherapies (P < 0.05) and N60C32 achieving the greatest reduction [-23.8/-16.5 mmHg; P < 0.01 versus placebo (-5.3/-6.7 mmHg) and component monotherapies]. Even very low-dose (N20 and C4) therapy provided significant BP-lowering, and combination therapy was similarly effective in different racial groups. N/C combination demonstrated a lower incidence of vasodilatory adverse events than N monotherapy (18.3 versus 23.6%), including headache (5.5 versus 11.0%; P = 0.003, chi-square test) and peripheral oedema over time (3.6 versus 5.8%; n.s.). CONCLUSION: N/C combination was effective in participants with hypertension and showed an improved side effect profile compared with N monotherapy.

Triple-combination treatment with olmesartan medoxomil/amlodipine/ hydrochlorothiazide in Hispanic/Latino patients with hypertension: the TRINITY study.

OBJECTIVE(S): Evaluate efficacy/safety of olmesartan medoxomil (OM)/amlodipine (AML)/ hydrochlorothiazide (HCTZ) in Hispanic/Latino adults with hypertension. DESIGN: Randomized, double-blind, 12-week, parallel-group study followed by a 40-week open-label extension phase. SETTING: Clinical sites (317) in the United States and Puerto Rico. PATIENTS OR PARTICIPANTS: Individuals > or =18 years of age with mean seated blood pressure (BP) > or =140/100 or > or =160/90 mm Hg divided into Hispanic/Latino (369) and non-Hispanic/Latino (2122) subgroups. INTERVENTIONS: Participants were randomized to OM 40/AML 10 mg, OM 40/HCTZ 25 mg, AML 10/HCTZ 25 mg, or OM 40/AML 10/HCTZ 25 mg during the double-blind phase. During the open-label extension, all participants received OM 40/AML 5/HCTZ 12.5 mg; participants not reaching BP goal within 2 weeks were randomly titrated to OM 40/AML 10/HCTZ 12.5 mg or OM 40/AML 5/HCTZ 25 mg, then to OM 40/AML 10/ HCTZ 25 mg after another 2 weeks. MAIN OUTCOME MEASURE: Change in mean seated diastolic BP (SeDBP) from baseline (double-blind phase). RESULTS: Triple-drug therapy vs the dual therapies resulted in greater mean reduction in SeBP (Hispanic/Latino: 35.0/20.9 mm Hg vs 27.8-30.9/15.3-17.7 mm Hg; non-Hispanic/Latino: 39.0/21.7 mm Hg vs 28.9-31.5/14.6-17.8 mm Hg) and enabled more participants to reach BP goal (Hispanic/Latino: 56.8% vs 40.6%-51.2%; non-Hispanic/Latino: 65.7% vs 33.8%-46.6%) irrespective of ethnicity. The efficacy of triple-drug therapy in achieving BP goal was sustained long-term (40-week open-label extension period) in Hispanic/Latino (63.3%) and non-Hispanic/ Latino (64.2%) participants. Triple-drug therapy was well tolerated in Hispanic/Latino and non-Hispanic/Latino participants. CONCLUSIONS: In this study, OM/AML/HCTZ was an effective treatment option in Hispanic/ Latino patients with hypertension.

Linagliptin added to sulphonylurea in uncontrolled type 2 diabetes patients with moderate-to-severe renal impairment.

Glucose-lowering treatment options are limited for uncontrolled type 2 diabetes mellitus (T2DM) patients with advanced stages of renal impairment (RI). This retrospective analysis evaluated glycaemic efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin added to sulphonylurea. Three randomized phase 3 studies (n = 619) including T2DM subjects with moderate or severe RI [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m²] were analysed; only sulphonylurea-treated subjects who received additional linagliptin (n = 58) or placebo (n = 33) were evaluated. Linagliptin provided meaningful placebo-adjusted HbA1c reductions of -0.68% (95% confidence interval: -1.19, -0.17), -1.08% (-2.02, -0.14) and -0.62% (-1.25, 0.01) after 24, 18 and 12 weeks, respectively. There was a similar incidence of overall adverse events (linagliptin: 79.3%, placebo: 75.8%) and hypoglycaemia (linagliptin: 37.9%, placebo: 39.4%). Severe hypoglycaemia was more common with placebo (linagliptin: 1.7%, placebo: 6.1%). These data suggest that linagliptin is a safe and effective glucose-lowering treatment in T2DM patients with moderate-to-severe RI for whom sulphonylurea treatment is no longer sufficient.

Combined olmesartan, amlodipine, and hydrochlorothiazide therapy in randomized patients with hypertension: a subgroup analysis of the TRINITY study by age.

BACKGROUND: Hypertension is often inadequately controlled in older people. OBJECTIVE: This prespecified subgroup analysis assessed the efficacy and safety of an olmesartan medoxomil (OM) 40 mg/amlodipine besylate (AML) 10 mg/hydrochlorothiazide (HCTZ) 25 mg triple-combination treatment compared with the 3 components as dual-combination treatments in participants with hypertension who were <65 and ≥ 65 years of age. Within the ≥ 65 years of age subgroup, efficacy and safety were also summarized for participants ≥ 75 years of age. STUDY DESIGN: 12-week, multicenter, double-blind, randomized, parallel-group study. SETTING: 317 ambulatory care sites in the US and Puerto Rico. PARTICIPANTS: Individuals ≥ 18 years of age with mean seated blood pressure (SeBP) ≥ 140/100 or ≥ 160/90 mmHg off antihypertensive medication on 2 consecutive clinic visits with no recent history of significant cerebrovascular disease, coronary artery disease, heart failure (New York Heart Association class III or IV), severe renal insufficiency, or uncontrolled diabetes (HbA1c >9 %). INTERVENTION: Participants were randomized, stratified by age, diabetes status, and race to one of four treatment assignments: OM 40/AML 10/HCTZ 25 mg, OM 40/AML 10 mg, OM 40/HCTZ 25 mg, or AML 10/HCTZ 25 mg. MAIN OUTCOME MEASURE: Least squares (LS) mean change from baseline in seated diastolic blood pressure (SeDBP) at week 12 (last observation carried forward) in each age subgroup (prespecified analysis). RESULTS: Of the 2492 randomized participants in the study (total cohort), 2021 (81.1 %) were <65 and 471 (18.9 %) were ≥ 65 years of age, including 79 (3.2 %) who were ≥ 75 years of age. OM 40/AML 10/HCTZ 25 mg triple-combination treatment resulted in a significantly greater reduction in LS mean SeDBP at week 12 than dual-combination component treatments in participants in both cohorts: <65 years (21.0 vs. 14.2-17.2 mmHg; p < 0.0001) and ≥ 65 years (23.7 vs. 17.3-20.0 mmHg; p ≤ 0.002). Similarly, triple-combination treatment resulted in a greater reduction in LS mean seated systolic blood pressure (SeSBP) at week 12 than dual-combination component treatments: <65 years (38.2 vs. 28.3-31.4 mmHg; p < 0.0001) and ≥ 65 years (39.2 vs. 29.3-31.1 mmHg; p < 0.0001). Triple-combination treatment was more effective than dual-combination treatments in enabling participants to reach SeBP goal (<140/90 mmHg [<130/80 mmHg in participants with diabetes, chronic kidney disease, or chronic cardiovascular disease]) in both age subgroups (<65 years: 65 vs. 34-50 %, respectively, p < 0.0001 and ≥ 65 years: 63 vs. 32-39 %; p ≤ 0.0004). All 4 treatments were safe and well tolerated with low discontinuation rates in both age subgroups. There were no clinically relevant differences in the incidence of treatment-emergent adverse events between participants <65 and ≥ 65 years of age receiving triple-combination treatment. CONCLUSION: Triple-combination treatment with OM 40/AML 10/HCTZ 25 mg was well tolerated and more effective in lowering BP than the component dual-combination treatments in elderly and non-elderly subgroups.

Efficacy and tolerability of linagliptin added to a sulfonylurea regimen in patients with inadequately controlled type 2 diabetes mellitus: an 18-week, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Some patients with type 2 diabetes mellitus (T2DM) receiving monotherapy with a sulfonylurea (SU) are unable to meet recommended glycemic targets over the long term and require additional pharmacologic agents to maintain glycemic control. This study was designed to assess the utility of adjunctive therapy with the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in patients with T2DM inadequately controlled with SU monotherapy. OBJECTIVE: To assess the efficacy and tolerability of linagliptin as add-on therapy in patients with inadequately controlled T2DM despite background therapy with an SU. METHODS: In this Phase III, multicenter, randomized, double-blind, placebo-controlled trial, patients with inadequately controlled T2DM on SU monotherapy were randomly assigned to receive treatment with linagliptin 5 mg once daily (n = 161) or placebo (n = 84) for 18 weeks. The primary end point was the mean change in hemoglobin (Hb) A(1c) from baseline to week 18, evaluated using ANCOVA. Tolerability was assessed using laboratory analysis, spontaneous reporting, and physical examination and interview. RESULTS: Mean baseline characteristics were similar in the linagliptin and placebo groups. Linagliptin treatment was associated with a placebo-corrected mean (95% CI) change in HbA(1c) from baseline (8.6%) to 18 weeks of -0.47% (-0.70 to -0.24; P < 0.0001). Patients in the linagliptin group were more likely compared with placebo to achieve the HbA(1c) target level of <7.0% after 18 weeks of treatment (15.2% vs 3.7%, respectively; odds ratio [OR] = 6.5; 95% CI, 1.7-24.8; P = 0.007). Similarly, patients in the linagliptin group were more likely to achieve an HbA(1c) reduction of ≥0.5% compared with those in the placebo group (57.6% vs 22.0%; OR = 5.1, 95% CI 2.7-9.6; P < 0.0001). The overall frequency of adverse events was similar between the linagliptin and placebo groups (42.2% vs 42.9%). The incidences of hypoglycemic events were not significantly different between the 2 groups (5.6% vs 4.8%), and none of the hypoglycemic episodes were assessed as severe by the investigator. The difference in the changes in mean body weight was not significant (+0.43 vs -0.01 kg; P = 0.12). CONCLUSIONS: The addition of linagliptin to SU therapy for 18 weeks in these patients with T2DM was associated with statistically significant and clinically meaningful reductions in HbA(1c) compared with placebo. The overall tolerability of linagliptin was similar to that of placebo, with a low risk for hypoglycemia and no significant weight gain. These findings support the use of linagliptin as adjunctive therapy in patients with T2DM inadequately controlled on SU monotherapy. ClinicalTrials.gov identifier: NCT00819091.

Acetylsalicylic acid reduces niacin extended-release-induced flushing in patients with dyslipidemia.

BACKGROUND: Niacin extended-release (NER) is safe and effective for treatment of dyslipidemia. However, some patients discontinue NER treatment because of flushing, the most common adverse event associated with niacin therapy. OBJECTIVE: To evaluate the effect of daily oral acetylsalicylic acid (ASA) on NER-induced flushing in patients with dyslipidemia. METHODS: A randomized, double-blind, placebo-controlled, multicenter, 5-week study was conducted (ClinicalTrials.gov identifier: NCT00626392). Patients (n = 277) were randomly assigned to one of six treatment arms and received a 1-week run-in with ASA 325 mg or placebo followed by 4 weeks of ASA 325 mg or placebo 30 minutes before NER at a starting dose of 500 mg or 1000 mg; all patients were titrated to NER 2000 mg at week 3. The primary endpoint was the maximum severity of flushing events during week 1. RESULTS: In week 1, ASA run-in, ASA pretreatment, and a lower starting dosage of NER (500 mg/day) resulted in reductions in mean maximum severity of flushing; 48% fewer patients who received ASA experienced flushing episodes of moderate or greater intensity relative to placebo (absolute rates 15% vs 29%; p = 0.01). Over 4 weeks, ASA reduced the number of flushing episodes/patient/week by 42% relative to placebo. The discontinuation rate due to flushing was lower in the ASA group compared with placebo (1.8% vs 9.4%; p = 0.007). Overall safety was not different between groups. CONCLUSION: These data suggest that a clinically meaningful reduction in the severity and incidence of NER-induced flushing may be achieved with ASA use.

Efficacy and safety of a potent and selective peroxisome proliferator activated receptor alpha agonist in subjects with dyslipidemia and type 2 diabetes mellitus.

The weak peroxisome proliferator activated receptor-alpha (PPAR-alpha) agonists gemfibrozil and fenofibrate achieve only small increases in high-density lipoprotein (HDL) cholesterol. CP-778,875 is a more potent PPAR-alpha agonist developed to produce greater HDL cholesterol increases. This randomized, multicenter, double-blinded, placebo-controlled study evaluated the efficacy and safety of CP-778,875 in subjects with mixed dyslipidemia and type 2 diabetes. Eight-six subjects with low HDL cholesterol (< or =45 mg/dl for men and < or =55 mg/dl for women) and increased triglycerides (150 to 500 mg/dl) who had coexisting type 2 diabetes were randomized. Subjects received CP-778,875 doses of 0.5, 2, or 6 mg/day or placebo for 6 weeks. Any other lipid-altering therapy was stopped at screening. The primary end point was percent change in HDL cholesterol from baseline. The 2-mg/day dose of CP-778,875 significantly increased HDL cholesterol by 14%. The 2-mg dose also increased concentrations of apolipoprotein (apo) A-I, HDL(2) cholesterol, and HDL(3) cholesterol by 13%, 12%, and 19%, respectively. An unusual dose-response pattern was observed in that at 6 mg/day CP-778,875 only increased HDL cholesterol by 3% and decreased HDL(2) cholesterol by 24%. Fasting triglyceride levels were significantly decreased to a similar extent (26%) by all 3 doses of CP-778,875. CP-778,875 significantly increased homocysteine levels. There was no significant relation between change in homocysteine and change in apoA-I or HDL cholesterol. No subjects developed myopathy. In conclusion, CP-778,875 2 mg/day significantly increased HDL cholesterol, significantly lowered fasting triglycerides, and increased apoA-I and HDL subfractions. The clinical relevance of the increase in homocysteine levels is unknown.

Antihypertensive efficacy and tolerability of irbesartan/hydrochlorothiazide in hypertensive patients stratified by body mass index and type 2 diabetes mellitus status: a post hoc subgroup analysis of the Irbesartan/HCTZ Blood Pressure Reductions in Diverse Patient Populations trial.

OBJECTIVE: This was a post hoc subgroup analysis of efficacy and tolerability data from the Irbesartan/HCTZ Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) trial stratified by baseline body mass index (BMI). The BMI subgroup data were also analyzed according to the presence or absence of type 2 diabetes mellitus (T2DM) at baseline. METHODS: The 18-week, prospective, multicenter, open-label, single-arm INCLUSIVE trial evaluated the efficacy and tolerability of a fixed-dose combination of irbesartan/hydrochlorothiazide (HCTZ) in adult hypertensive patients with systolic blood pressure (SBP) that was uncontrolled after >or=4 weeks of monotherapy. Patients received placebo for 4 to 5 weeks, HCTZ 12.5 mg for 2 weeks, irbesartan/HCTZ 150/12.5 mg for 8 weeks, and irbesartan/HCTZ 300/25 mg for 8 weeks. Patients were stratified into BMI subgroups based on values at screening. Normal weight was defined as a BMI or=30 kg/m(2). The primary efficacy end point was the mean change in SBP from baseline (end of the placebo phase) to week 18 in the overall intent-to-treat (ITT) population. Secondary efficacy end points were the mean changes in SBP and diastolic blood pressure (DBP) from baseline to week 18 in each BMI subgroup, the proportions of patients in each BMI subgroup achieving their SBP target (<140 mm Hg [<130 mm Hg for patients with T2DM]) and DBP target (<90 mm Hg [<80 mm Hg for patients with T2DM]), and the mean SBP and DBP responses at the end of each treatment period. RESULTS: The ITT population included 736 patients, of whom 99 (13.5%) were normal weight, 243 (33.0%) were overweight, and 394 (53.5%) were obese. Mean baseline SBP and DBP values were similar across BMI subgroups. Obese patients were generally younger than normal-weight and overweight patients, and numerically more obese patients had T2DM and metabolic syndrome. The mean reductions in SBP and DBP at week 18 were statistically significant in all subgroups (all, P < 0.001); SBP and DBP goals were achieved by a respective 83.8% and 93.9% of normal-weight patients, 75.3% and 87.7% of overweight patients, and 76.9% and 77.2% of obese patients. Rates of SBP/DBP control to <140/90 mm Hg in normal weight, overweight, and obese patients without T2DM were 88.2%, 79.8%, and 80.9%, respectively; the corresponding rates of control to <130/80 mm Hg in patients with T2DM were 50.0%, 41.5%, and 38.5%. CONCLUSION: In this post hoc subgroup analysis of the INCLUSIVE trial, irbesartan/HCTZ combination therapy had comparable antihypertensive efficacy and tolerability regardless of BMI or diabetes status.

The JNC 7 approach compared to conventional treatment in diabetic patients with hypertension: a double-blind trial of initial monotherapy vs. combination therapy.

The JNC 7 states that persons with blood pressure (BP) more than 20/10 mm Hg above goal should be started on combination drug therapy. This criterion includes patients with BP >160/100 mm Hg and diabetics with hypertension. The goal BP for persons with diabetes mellitus is <130/80 mm Hg. A randomized, double-blind trial force titrated initial combination therapy utilizing an angiotensin receptor blocker (ARB) combination (losartan/hydrochlorothiazide [LOS/HCTZ]) compared with an angiotensin-converting enzyme (ACE) inhibitor (ramipril), for 8 weeks, and tested the hypothesis that combination therapy is more likely to achieve goal BP vs. monotherapy. At 4 weeks, 30.5% of LOS/HCTZ and 14.4% of ramipril recipients achieved goal diastolic BP (p<0.001). More participants achieved goal systolic BP in the ARB/HCTZ group at 4 weeks (29.8% vs. 14.4%; p<0.001). At 4 weeks, mean diastolic BP had decreased 10.2+/-7.4 mm Hg in the LOS/HCTZ group compared with 6.4+/-6.8 mm Hg in the ramipril group (p<0.001), and systolic BP had fallen 15.4+/-13.1 mm Hg in the ARB/HCTZ compared with 9.2+/-10.2 mm Hg in the ACE-inhibitor group (p<0.001). Significant differences favoring the combination were also noted at 8 weeks. Drug-related adverse experiences were 10.3% for the combination compared with 12.7% for the monotherapy group. Initial combination therapy with an ARB/HCTZ was more effective than ACE-inhibitor monotherapy in achieving BP goals in participants with diabetes with no significant differences in the incidence of adverse experiences. These observations confirm other studies of combination therapies, such as b blocker/diuretic, ACE inhibitor/diuretic, or ACE inhibitor/calcium channel blocker. The use of two medications will achieve goal BP in more patients than monotherapy. This observation is important in treatment of high-risk patients with diabetes.

Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm.

OBJECTIVE: Ragaglitazar is a novel insulin sensitizer with dual peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-alpha stimulating activities that improve plasma glucose and lipid profiles. The aim of the present dose-ranging study was to assess the efficacy and safety of ragaglitazar in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This study included 177 hypertriglyceridemic type 2 diabetic subjects who participated in a 12-week, double-blind, parallel, randomized, placebo-controlled dose-ranging study (open pioglitazone arm). Subjects received ragaglitazar (0.1, 1, 4, or 10 mg), placebo, or pioglitazone (45 mg). Efficacy parameters included fasting plasma levels of triglycerides and glucose (FPG) along with other lipid levels, A1C, and insulin. RESULTS: Ragaglitazar in doses of 1, 4, and 10 mg resulted in a significant decrease from baseline as compared with placebo in FPG (-48, -74, -77 mg/dl) and triglycerides (-40, -62, -51%), free fatty acids (-36, -54, -62%), apolipoprotein B (-13, -29, -25%), LDL cholesterol (-14 and -19% for 4- and 10-mg groups), and total cholesterol (-16 and -15% for 4 and 10 mg) and a significant increase in HDL cholesterol (20 and 31% for 1- and 4-mg groups, respectively). Changes in triglycerides and FPG for pioglitazone treatment were similar to 1 mg ragaglitazar. Mean A1C values of the 1-, 4-, and 10-mg ragaglitazar and pioglitazone groups were significantly reduced compared with placebo (-0.5, -1.3, -1.1, and -0.3%, respectively). Common adverse events were edema, weight increase, leukopenia, and anemia. CONCLUSIONS: Ragaglitazar provided glycemic control that was comparable with that of pioglitazone and, compared with placebo, provided significant improvement in the lipid profile.

Effects of simvastatin on the lipid profile and attainment of low-density lipoprotein cholesterol goals when added to thiazolidinedione therapy in patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Coronary heart disease is the major cause of mortality in individuals with diabetes mellitus (DM). Given the increasingly aggressive low-density lipoprotein cholesterol (LDL-C) goals for patients with DM set by the National Cholesterol Education Program Adult Treatment Panel III and the American Diabetes Association, many patients remain above target. Treatment with thiazolidinediones (TZDs) improves glycemic control but does not lower (and may raise) LDL-C concentrations. OBJECTIVE: This study assessed the lipid-modifying efficacy and tolerability of adding the hydroxymethylglutaryl coenzyme A-reductase inhibitor simvastatin to existing TZD therapy in patients with type 2 DM. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Patients with type 2 DM who were taking a stable dose of pioglitazone or rosiglitazone and had a glycosylated hemoglobin (HbA1c) value < or =9.0% and an LDL-C concentration > 100 mg/dL were randomized to receive simvastatin 40 mg (the recommended initial dose for patients with DM) or placebo for 24 weeks. The primary end point was the effect of treatment on LDL-C concentrations. Other lipid, lipoprotein, and safety measures were also assessed. RESULTS: Two hundred fifty-three patients (127 [50.2%] men, 126 [49.8%] women; mean age, 56 years) were randomized to treatment (123 simvastatin, 130 placebo). At the end of the study, mean LDL-C concentrations were reduced 34.)% from baseline (from 134.3 to 89.5 mg/dL) in the simvastatin group and were unchanged in the placebo group (P<0.001). Simvastatin produced significant reductions in concentrations of total cholesterol, triglycerides (TG), non-high-density lipoprotein cholesterol, and apolipoprotein (apo) B compared with placebo (all, P<0.001 ) and significant increases in concentrations of high-density lipoprotein cholesterol (HDL-C) ( P=0.002 ) and apo A-I ( P=0.006 ). In patients who had not attained target concentrations of LDL-C (<100 mg/dL), TG (<150 mg/dL), or HDL-C (>45 mg/dL) at baseline, significantly more simvastatin recipients had achieved these goals at the end of the study compared with placebo recipients (LDL-C: 67.3% vs 5.2%, respectively, P<0.001; HDL-C: 95.3% vs 83.6%, P<0.05; TG: 40.8% vs 11.0%, P<0.001 ). Simvastatin was well tolerated, and no clinically meaningful differences in the incidence of serious adverse events, treatment-related adverse events, or discontinuations due to adverse events were observed between groups. There were no significant between-group differences in glycemic control (HbA1c) or concentrations of fasting insulin, creatine phosphokinase, or hepatic transaminases. CONCLUSION: Simvastatin was an effective and generally well tolerated treatment for hyperlipidemia when used in combination with TZD therapy in this population of patients with type 2 DM.

Self Reported Sexual Dysfunction in Men and Women Treated With Bisoprolol, Hydrochlorothiazide, Enalapril, Amlodipine, Placebo, or Bisoprolol/Hydrochlorothiazide.

Quality of life may be impaired by antihypertensive therapy. Perceived sexual dysfunction by antihypertensive drugs diminishes quality of life and results in noncompliance with antihypertensive therapy. To assess the impact of various classes of antihypertensive therapy vs. combination therapy, self reported adverse reactions were catalogued by gender using COSTART (Coding Symbols for Thesaurus of Adverse Reaction Terms) of impotence or libido decrease in six randomized, blinded, prospective trials in which subjects received placebo, 5 mg qd-20 mg bid enalapril, 2.5-10 mg qd amlodipine, 6.25-25 mg qd hydrocholorothiazide (HCTZ), bisoprolol 5 mg qd, or a combination of 2.5-10 mg qd bisoprolol/6.25 mg HCTZ. The average duration of drug exposure was 6-14 weeks (range of 1 day to 23 weeks). Comparison among groups was performed using Fisher's exact test. There was no statistical difference between treatment with respect to impotence (p equals 0.688), decrease in libido (p equals 0.970), or overall sexual dysfunction (p equals 0.705) for 1251 men. Of the 661 women studied, decrease in libido was reported in only two subjects. It is concluded that short term exposure to antihypertensive drugs is associated with self reported impotence at no greater prevalence than it is with placebo in men. The combination of bisoprolol/6.25 mg HCTZ is not more likely to be associated with sexual dysfunction than placebo, HCTZ, bisoprolol, enalapril, or amlodipine. Also sexual dysfunction is reported less frequently in women than men. (c)1999 by Le Jacq Communications, Inc.