Effectiveness of simvastatin therapy in raising HDL-C in patients with type 2 diabetes and low HDL-C

SUMMARY

Objective: To evaluate the efficacy of high and moderate doses of simvastatin (80 and 40?mg), for raising high density lipoprotein-cholesterol (HDL-C), improving HDL sub-fractions, and affecting other parameters, including high sensitivity C-reactive protein (hs-CRP), in patients with type 2 diabetes mellitus (DM) and low HDL-C.

Research design and methods: This double-blind, placebo-controlled, randomized, 3-period, complete block, 6-week crossover study examined the efficacy of simvastatin in adult men and women (N = 151) with stable type 2 DM (HbA_1C < 9%), low density lipoprotein-cholesterol (LDL-C) > 100?mg/dL (2.6?mmol/L), HDL-C < 40?mg/dL (< 1?mmol/L), and fasting triglyceride level > 150 (> 1.7?mmol/L) and < 700?mg/dL (< 7.9?mmol/L). This study included adult men (71%) and women (29%) of various races (89% white, 6% black, 1% Asian, 3% other) enrolled from 29 practice-based sites in the United States.

Main outcome measures: Percentage change in HDL-C from baseline at the end of each 6-week treatment interval.

Results: Both simvastatin 80 and 40?mg significantly increased total HDL-C from baseline (mean increases of 8% ± 1 [SE] and 5% ± 1, respectively; p < 0.001) compared with placebo, and significantly reduced plasma concentrations of LDL-C (?p < 0.001), triglycerides (?p < 0.001), apolipoprotein B (?p < 0.001), and hs-CRP (?p ≤ 0.012). Compared with simvastatin 40?mg, the 80?mg dose provided additional efficacy. Simvastatin 80?mg also significantly (?p < 0.001) increased HDL₂ from baseline (14% ± 3[SE]) and placebo phases (10 ± 3). An exploratory analysis showed 87% (simvastatin 80?mg) and 82% (simvastatin 40?mg) of patients reached the NCEP ATP III treatment goals for LDL-C compared with 14% on placebo.

Conclusions: Both simvastatin 80 and 40?mg raise HDL-C and improve other measures associated with elevated coronary risk in patients with type 2 DM and low HDL-C.     

Effects of exenatide versus sitagliptin on postprandial glucose,insulin and glucagon secretion,gastric emptying,and caloric intake: a randomized,cross-over study

ABSTRACT

Background: This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients.

Methods: This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33?±?5?kg/m²; HbA_1c: 8.5?±?1.2%; 2-h PPG: 245?±?65?mg/dL. Patients received exenatide (5?µg BID for 1 week, then 10?µg BID for 1 week) or sitagliptin (100?mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581).

Results: After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133?±?6?mg/dL versus 208?±?6?mg/dL, p?<?0.0001 (evaluable, N?=?61). Switching from exenatide to sitagliptin increased 2-h PPG by +73?±?11?mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by ?76?±?10?mg/dL. Postprandial glucose parameters (AUC, C_ave, C_max) were lower with exenatide than sitagliptin (p?<?0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (?15?±?4?mg/dL vs. ?19?±?4?mg/dL, p?=?0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50?±?0.26, p?=?0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88?±?0.03, p?=?0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90?±?0.04, p?=?0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56?±?0.05, p?<?0.0001). Exenatide reduced total caloric intake compared to sitagliptin (?134?±?97?kcal vs. +130?±?97?kcal, p?=?0.0227, N?=?25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature.

Conclusions: Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications.     

Exenatide effects on diabetes,obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years

ABSTRACT

Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A_1c (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of?≥?3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety.

Methods: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5?µg exenatide, or 10?µg exenatide for 30 weeks, followed by 5?µg exenatide BID for 4 weeks, then 10?µg exenatide BID for ≥3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas.

Results: 217 patients (64% male, age 58?±?10 years, weight 99?±?18?kg, BMI 34?±?5?kg/m², A1C 8.2?±?1.0% [mean?±?SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (?1.1?±?0.1% [mean?±?SEM]) were sustained to 3 years (?1.0?±?0.1%; p?<?0.0001), with 46% achieving A1C?≤?7%. Exenatide progressively reduced body weight from baseline (?5.3?±?0.4?kg at 3 years; p?<?0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n?=?116) had reduced ALT (?10.4?±?1.5?IU/L; p?<?0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (?6.1?±?0.6?kg vs. ?4.4?±?0.5?kg; p?=?0.03), however weight change was minimally correlated with baseline ALT (r?=??0.01) or ALT change (r?=?0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n?=?151). Triglycerides decreased 12% (p?=?0.0003), total cholesterol decreased 5% (p?=?0.0007), LDL-C decreased 6% (p?<?0.0001), and HDL-C increased 24% (p <?0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison.

Conclusion: Adjunctive exenatide treatment for ≥3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.     

Relationship between obesity and cardiovascular risk factors: findings from a multi-state screening project in the United States

ABSTRACT

Objective: This study examined the impact of body mass index (BMI) category on cardiovascular risk factors such as systolic blood pressure (SBP), high-density lipoprotein (HDL) and total cholesterol (TC).

Methods: Voluntary coronary heart disease (CHD) risk screenings were conducted in 18 states. A mobile screening unit and team were used to collect data. Respondents were classified as per World Health Organization (WHO) guidelines based on BMI as non-overweight (BMI ≤ 25); overweight (BMI > 25 and ≤ 30); obese (BMI > 30 and ≤ 35); and severely obese (BMI > 35). Hierarchical multiple linear regression analyses were used to measure the impact of BMI on SBP, HDL, and TC after adjusting for age, race, gender, smoking, self-reported prevalence of hypertension and hyperlipidemia, presence of diabetes/CHD event.

Results: Of the 12?573 screened, 36% were overweight, 16.9% were obese and 7.9% were severely obese. Diabetes and prior CHD event were reported in 5.8% and 12.5% of the respondents, respectively. Mean 10‐year CHD risk scores were significantly higher in males (10.4 ± 9.3) than females (3.2 ± 4.8) (?p < 0.001). Compared to non-overweight respondents, SBP increased by 13.2?mmHg for severely obese (?p < 0.001); by 8.9?mmHg for obese (?p < 0.001), and by 5.2?mmHg (?p < 0.001) for overweight respondents, respectively. TC was 6.8?mg/dL higher in obese (?p < 0.01) and 6.9?mg/dL higher in overweight respondents (?p < 0.001) as compared to non-overweight respondents. As compared to non-obese respondents, HDL was 9.8?mg/dL lower in severely obese (?p < 0.001), 7.6?mg/dL lower in obese (?p < 0.001), and 4.6?mg/dL lower in overweight respondents (?p < 0.001).

Conclusions: Our results demonstrate a significant impact of increasing BMI category on the CHD risk factors of SBP and HDL in a US population. These data illustrate the importance of weight reduction in cardiovascular health.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized,double-blind,placebo-controlled study

ABSTRACT

Objectives: To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD).

Research design and methods: In a multicenter, double-blind, placebo-controlled clinical study, 493 patients 18–80 years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA_1c] 7.0–10.0%) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5?mg, alogliptin 25?mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted.

Main outcome measures: The primary efficacy endpoint was change in HbA_1c from baseline to Week 26. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG?≥?200?mg/dL [11.10?mmol/L]) and rescue for hyperglycemia.

Results: Least squares (LS) mean change in HbA_1c was significantly (p?<?0.001) greater for alogliptin 12.5?mg (?0.66%) or 25?mg (?0.80%) than for placebo (?0.19%). A significantly (p?≤?0.016) larger proportion of patients achieved HbA_1c?≤?7% with alogliptin 12.5?mg (44.2%) or 25?mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p?=?0.003) greater with alogliptin 12.5?mg (?19.7?mg/dL [?1.09?mmol/L]) or 25?mg (?19.9?mg/dL [?1.10?mmol/L]) than with placebo (?5.7?mg/dL [?0.32?mmol/L]). The percentage of patients with marked hyperglycemia was significantly (p?<?0.001) lower for alogliptin (≤25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo.

Conclusions: Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety.

Clinical trial registration: NCT00286494, clinicaltrials.gov.     

Efficacy and tolerability of initial combination therapy with nateglinide and metformin in treatment-naïve patients with type 2 diabetes

SUMMARY

Objective: To assess the efficacy and tolerability of the combination of nateglinide (120?mg, ac) and metformin (500?mg, tid) as initial treatment in drug-naïve patients with type 2 diabetes mellitus (T2DM).

Research design and methods: This study reports data from the treatment-naïve (TN) subgroup of patients in a previously published, randomized, multicenter, placebo-controlled, 24-week trial that compared nateglinide, metformin, and the combination therapy (CT) in 701 patients with T2DM with baseline HbA_1c between 6.8% and 11.0%. Of the 401 TN patients, 104, 104, 89, and 104 patients received nateglinide (120?mg, ac), metformin (500?mg, tid), CT, and placebo, respectively. The baseline characteristics of each group were similar, with mean age, BMI, duration of diabetes, HbA_1c, and fasting plasma glucose (FPG) levels of approximately 58 years, 30?kg/m², 4 years, 8.2%, and 10.2?mmol/L, respectively.

Results: In patients receiving initial CT, HbA_1c decreased substantially (? = –1.6 ± 0.1%, p < 0.0001 vs. baseline or placebo) from a mean baseline of 8.2 ± 0.1%, an effect significantly greater than the 0.8% reduction observed with both monotherapies (?p < 0.001); whereas, in placebo-treated patients, HbA_1c increased modestly (? = +0.3 ± 0.1%, p < 0.05) from an identical baseline value. Seventy percent of CT-treated patients achieved a target HbA_1c of < 7.0%. Both fasting plasma glucose (FPG) and the 2-hour postprandial glucose excursion (PPGE) after a liquid meal challenge decreased by 2.3?mmol/L in patients receiving CT, while the changes from baseline values in FPG and PPGE were +0.2 ± 0.3?mmol/L and –0.5 ± 0.2?mmol/L, respectively, in placebo-treated patients. The incremental 30-minute post-load insulin levels increased by 88 ± 32?pmol/L (?p = 0.006) in patients receiving CT and did not change significantly in placebo-treated patients. Gastrointestinal side effects occurred in 27% of patients receiving CT (vs. 27.9% in the metformin monotherapy, and 14.4% in the placebo groups). Confirmed hypoglycemia (glucose ≤ 2.8?mmol/L) occurred in 3.4% of patients receiving CT.

Conclusions: Initial CT with the rapid-acting insulinotropic agent, nateglinide, and metformin, an agent with insulin-sensitizing effects in the liver and periphery, is a safe and effective means of achieving glycemic targets in TN patients with T2DM.     

Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes

ABSTRACT

Objective: To evaluate the efficacy and safety of once-daily saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes (T2D) and inadequate glycemic control.

Research design and methods: This study included a main treatment cohort (MTC) with 401 patients (HbA_1c?≥?7% and ≤10%) randomized and treated with oral saxagliptin 2.5, 5, or 10?mg once daily or placebo for 24 weeks and a separate open-label cohort (OLC) with 66 patients (HbA_1c?>?10% and ≤12%) who received saxagliptin 10?mg once daily for 24 weeks. Primary endpoint was HbA_1c change from baseline to week 24. Secondary endpoints included change from baseline to week 24?in fasting plasma glucose (FPG), proportion of patients achieving HbA_1c?<?7%, and changes in postprandial glucose area-under-the-curve (PPG-AUC). Efficacy analyses for continuous variables were performed using an ANCOVA model with last-observation-carried-forward methodology.

Results: In the MTC, saxagliptin demonstrated statistically significant decreases in adjusted mean HbA_1c changes from baseline (mean, 7.9%) to week 24 (?0.43%, ?0.46%, ?0.54%) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +0.19% for placebo (all p?<?0.0001). Adjusted mean FPG was significantly reduced from baseline (?15, ?9, ?17?mg/dL) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +6?mg/dL for placebo (p?=?0.0002, p?=?0.0074, p?<?0.0001, respectively). More saxagliptin-treated patients achieved HbA_1c?<?7% at week 24 (35% [p?=?NS], 38% [p?=?0.0443], 41% [p?=?0.0133]) for saxagliptin 2.5, 5, and 10?mg, respectively, than placebo (24%). PPG-AUC was reduced for saxagliptin 2.5, 5, and 10?mg (?6868, ?6896, ?8084?mg·min/dL, respectively) vs. placebo (?647?mg·min/dL) with statistical significance demonstrated for saxagliptin 5?mg (p?=?0.0002) and 10?mg (p?<?0.0001). HbA_1c, FPG, and PPG-AUC reductions were also observed in the OLC at 24 weeks. In the MTC, adverse event frequency was similar across all study arms. No cases of confirmed hypoglycemia (symptoms, with fingerstick glucose ≤50?mg/dL) were observed in either cohort. Saxagliptin was not associated with weight gain. Study limitations included the lack of a control group for the OLC and the use of prespecified rescue criteria, which limited the exposure time during which patients could remain on their originally randomized medication without the introduction of additional antihyperglycemic rescue treatment.

Conclusions: Once-daily saxagliptin monotherapy for 24 weeks was generally well tolerated and demonstrated clinically meaningful reductions in key parameters of glycemic control vs. placebo.

Trial Registration: Clinical Trials NCT00121641     

Effect of raloxifene on the incidence of elevated low density lipoprotein (LDL) and achievement of LDL target goals in postmenopausal women

SUMMARY

Objective: To determine the extent to which raloxifene can maintain low density lipoprotein cholesterol (LDL-C) levels below 160?mg/dL or reduce elevated LDL-C levels to below lipidlowering goals in postmenopausal women.

Patients and methods: The Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial randomized 7705 postmenopausal women to placebo or raloxifene (60?mg or 120 mg) daily for a core treatment phase of 3 years. Changes in LDL-C and other serum lipids in a subset of women was a predefined secondary objective. This post-hoc analysis included the 2413 women who did not take lipid-lowering medications at any time during the trial and for whom LDL-C measurements were available. The threshold for high LDL-C (≥ 160?mg/dL) and LDL-C lipid-lowering goals were defined according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines.

Results: The percent of women with LDL-C < 160?mg/dL was comparable between treatment groups at baseline (placebo, 57.5%; raloxifene 60?mg, 56.4%; raloxifene 120?mg, 56.8%). At 3 years, the percent of these women whose LDL-C had increased to above 160?mg/dL was significantly less in the raloxifene 60?mg and 120?mg groups compared with placebo by 65% (95% CI, 44%–78%) and 64% (95% CI, 43%–77%), respectively. Among women with elevated (defined for these analyses as ≥ 160?mg/dL) LDL-C at baseline, the proportion having elevated LDL-C at 3 years was significantly less in the raloxifene 60?mg and 120?mg groups compared with placebo by 32% (95% CI, 24%–40%) and 40% (95% CI, 32%–48%), respectively. Fifty percent and 13% of these women achieved LDL-C goals of <160?mg/dL and <130?mg/dL, respectively (P <0.001 vs. placebo for both) in the raloxifene 60?mg group, with similar results for the raloxifene 120?mg group.

Conclusions: In postmenopausal women with osteoporosis not taking concurrent lipid-lowering therapy, raloxifene significantly reduced the incidence of LDL-C ≥ 160?mg/dL and significantly increased the proportion achieving LDL-C goals for lipid-lowering compared with placebo. Whether these and other effects of raloxifene on cardiovascular risk markers will improve cardiovascular outcomes requires further study.     

Lipid-lowering property of Clausena anisum-olens in hypercholesterolemic rats

Context: Clausena anisum-olens (Blanco) Merr. (Rutaceae) is a medicinal shrub which has been reported to have various pharmacological uses. No study regarding the effects of C. anisum-olens on cholesterol-lowering has been reported.

Objective: The effects of the ethanol extract of C. anisum-olens leaves on the cholesterol level of hypercholesterolemic rats were evaluated.

Materials and methods: Acute oral toxicity of the extract (175, 550 and 2000?mg/kg) was determined using female Sprague-Dawley rats, as described in OECD 425 Main test guidelines. The lipid-lowering assay utilized 30 male Sprague-Dawley rats divided into five groups (A–E). Triton X-100 was administered to induce hypercholesterolemia. After hypercholesterolemia induction, oral treatment of Atorvastatin and crude ethanol extract was given daily to the treatment groups for 14 days. The total cholesterol, triglycerides, HDL and LDL were determined before induction, after induction, after first week of treatment and after second week of treatment.

Results: Acute oral toxicity showed the crude extract is nontoxic up to 2000?mg/kg. The lipid-lowering assay indicated reduction of serum cholesterol (87.21?±?5.10?mg/dL), triglycerides (58.09?±?4.10?mg/dL) and LDL (27.82?±?4.11?mg/dL) for 200?mg/kw extract. Reduction in serum cholesterol (74.72?±?3.64?mg/dL), triglycerides (52.79?±?2.98?mg/dL) and LDL (12.06?±?5.51?mg/dL) were observed for 400?mg/kg group. The result is comparable to Atorvastatin, which showed serum cholesterol (80.90?±?9.72?mg/dL), triglycerides (55.94?±?7.19?mg/dL) and LDL (22.09?±?7.60?mg/dL) reduction.

Discussion and conclusion: The crude extract of C. anisum-olens proved to be useful in lowering of cholesterol.     

Once-daily insulin detemir in a cohort of insulin-naïve patients with type 2 diabetes: a sub-analysis from the PREDICTIVE study

ABSTRACT

Objective: PREDICTIVE^* is a large, observational study of the empirical use of insulin detemir in patients with type 1 or type 2 diabetes (T1DM/T2DM). This post hoc analysis evaluates insulin-naïve patients with T2DM uncontrolled on oral antidiabetic drugs (OADs) who were initiated and remained on once-daily insulin detemir for 12 weeks.

Research design and methods: This observational, multinational, multi-center, open-label prospective study evaluated the efficacy and safety of insulin detemir in 1653 insulin-naïve patients with T2DM (mean age 60.8?±?10.9 years, BMI 29.8?±?4.8?kg/m², and HbA_1C 8.82?±?1.50%). Statistical comparisons were made between baseline and 12-week follow up data. Our study was subject to the usual limitations of observational studies.

Main outcome measures: Endpoints were: incidence of serious adverse drug reactions, including number of hypoglycemic events (total, major, and nocturnal), glycemic parameters, and weight change.

Results: Following insulin initiation, no significant change occurred in the number of nocturnal hypoglycemic events or total hypoglycemic events (p?=?0.4513), and no serious adverse drug reactions were observed during the 12 weeks of treatment. HbA_1C decreased by a mean 1.25% (SD?±?1.25%; p?<?0.0001), with 30% of patients (n?=?383) achieving HbA_1C <7% at 12 weeks. Mean changes in fasting blood glucose and fasting blood glucose variability were –3.62?mmol/L (SD?±?2.93; p?<?0.0001) and ?0.48?mmol/L (SD?±?1.03; p?<?0.0001), respectively. Body weight decreased by a mean 0.5?kg (SD?±?3.3; p?<?0.0001), with weight loss or no weight change occurring in a substantial percentage of patients in each BMI category (<25, 25–30, 30–35, and >35?kg/m²). Patients with higher baseline BMI lost the most weight, with the greatest weight loss (–1.20?kg) reported in those with BMI >35?kg/m².

Conclusions: Empirical use of insulin detemir as an insulin initiation strategy can improve glycemic control with good tolerability, including a low risk of hypoglycemia and a weight benefit, in a majority of insulin-naïve patients uncontrolled on OADs.     

LDL‐C/HDL‐C ratio in subjects with cardiovascular disease and a low HDL‐C: results of the RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study

ABSTRACT

Background: The ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (LDL‐C/HDL‐C) is a reliable predictor of cardiovascular risk. Low HDL‐C levels in patients with coronary artery disease are associated with a high risk for cardiovascular events.

Objectives: This study compared the effects of rosuvastatin and atorvastatin on the LDL‐C/HDL‐C ratio in patients with cardiovascular disease and low HDL‐C.

Methods: Patients aged 40–80 years with established cardiovascular disease and HDL‐C < 1.0?mmol/L (< 40?mg/dL) entered a 6‐week dietary run-in period, before randomisation to open-label treatment with rosuvastatin 10?mg (n = 230) or atorvastatin 20?mg (n = 231) for 6 weeks. Doses were increased after 6 weeks to rosuvastatin 20?mg or atorvastatin 40?mg, and after 12 weeks to rosuvastatin 40?mg or atorvastatin 80?mg. Serum lipid parameters were measured at baseline and 6, 12 and 18 weeks.

Results: After 6 weeks of treatment, mean percentage change from baseline in LDL‐C/HDL‐C ratio was –47.0% in the rosuvastatin group and –41.9% in the atorvastatin group (?p < 0.05 for between-group comparison). After 12 and 18 weeks of treatment, change from baseline was –53.0% and –57.3%, respectively, for rosuvastatin, compared with –47.9% and –49.6%, respectively, for atorvastatin (?p < 0.01 and p < 0.001, respectively, for between-group comparison). Rosuvastatin also reduced LDL‐C, total cholesterol and non-HDL‐C significantly more than atorvastatin at all three time points, and significantly improved total cholesterol/HDL‐C and apolipoprotein B/A‐I ratios.

Conclusions: Rosuvastatin 10, 20 and 40?mg is significantly more effective than atorvastatin 20, 40 and 80?mg, respectively, in improving the LDL‐C/HDL‐C ratio in patients with cardiovascular disease and low HDL‐C. Further studies are required to clarify the benefits of rosuvastatin for reduction of cardiovascular risk.     

Effect of growth hormone treatment on trunk fat accumulation in adult GH‐deficient Japanese patients:a randomised,placebo-controlled trial

ABSTRACT

Objective: Patients with growth hormone deficiency (GHD), both Japanese and Caucasian, have an abnormal body composition with pronounced abdominal obesity. This study aimed to evaluate changes in trunk fat with GH treatment.

Design: Double-blind, placebo-controlled study.

Patients and measurements: Sixty-one Japanese adult GH deficient patients (mean age 37 years) were randomised to either GH, titrated to 0.012?mg/kg/day, (n = 30) or placebo (n = 31) for 24 weeks. Body composition, by dual-energy X-ray absorptiometry (DXA), was evaluated at a central laboratory for trunk fat, total body fat and lean body mass. Serum lipid levels were also determined centrally.

Results: At baseline, 26 (42.6%) patients had a body mass index (BMI) ≥ 25 kg/m², the threshold for obesity-related complications for Japanese subjects. Median trunk fat mass (FM) was ≥ 9.0 kg for each treatment and gender group, higher than the cut-off for increased age-adjusted risk for cardiovascular complications reported in the normal Japanese population. After 24 weeks of GH treatment, the change in percentage trunk FM was –3.4 ± 0.6%, versus 0.4 ± 0.6% with placebo (?p < 0.001). Change in total body FM was –2.8 ± 0.5% with GH and 0.0 ± 0.5% with placebo, indicating that the decrease in trunk fat was more pronounced than for total body fat. Total and low density lipoprotein (LDL)-cholesterol were both significantly (?p < 0.001) decreased compared with placebo. One patient discontinued due to a subdural haematoma and one had GH dose reduced due to hyperglycaemia.

Conclusions: Japanese patients with GHD have abnormal central fat accumulation, which is reduced by GH treatment over 24 weeks. This may reduce cardiovascular risk but the GH dose should be individualised to maintain IGF-I in the normal range.     

The prevalence of anemia in patients with chronic kidney disease

SUMMARY

Objective: Anemia is a complication of chronic kidney disease and may contribute to adverse clinical outcomes. Early identification and treatment of anemia may improve cardiovascular morbidity and mortality. No large-scale population data are available specifically for patients with chronic kidney disease regarding prevalence of anemia, subpopulations at risk, and relationships between anemia and kidney function. This study was undertaken to address these questions in patients with chronic kidney disease, and investigate the relationship between anemia and glomerular filtration rate.

Research design and methods: Large-scale, cross-sectional, US multicenter survey; 5222 patients (mean age, 68.2?years; 46.6% male); 237 physician practices. Eligible patients: ≥ 18?years of age; serum creatinine: 1.5?mg/dL–6.0?mg/dL (females), 2.0?mg/dL–6.0?mg/dL (males).

Main outcome measures: Primary study end point: prevalence and severity of anemia (hemoglobin ≤ 12?g/dL). Data further stratified by hemoglobin (≤ 12?g/dL, ≤ 10?g/dL).

Results: Primary etiologies of chronic kidney disease (5222 evaluable patients): diabetes (49.5%); hypertension (33.0%). Glomerular filtration rate: < 60?mL/min/1.73?m² for 97.7% of evaluable patients. Mean ± SD serum creatinine level: 2.2?mg/dL ± 0.9?mg/dL; 2.5?mg/dL ± 1.0?mg/dL for males, 2.0?mg/dL ± 0.8?mg/dL for females. Mean ± SD hemoglobin: 12.2?g/dL ± 1.6?g/dL (47.7% had hemoglobin ≤ 12?g/dL; 8.9% had hemoglobin ≤ 10?g/dL). Prevalence of anemia was strongly associated with declining glomerular filtration rate. Percentage of patients with hemoglobin ≤ 12?g/dL increased from 26.7% to 75.5% when glomerular filtration rate decreased from ≥ 60?mL/min/1.73?m² to < 15?mL/min/1.73?m². Prevalence of hemoglobin ≤ 10?g/dL increased substantially from 5.2% to 27.2% when glomerular filtration rate diminished from ≥ 60?mL/min/1.73?m² to < 15?mL/min/1.73?m². After controlling for other patient characteristics associated with increased prevalence of anemia, the prevalence odds ratio for hemoglobin ≤ 10?g/dL was 0.54 (0.49–0.60) and for hemoglobin ≤ 12?g/dL was 0.68 (0.65–0.72), with each 10-mL/min/1.73?m² increase in glomerular filtration rate. Predictors of anemia: diabetes, female sex, and race/ethnicity.

Conclusions: Anemia was present in 47.7% of 5222 predialysis patients with chronic kidney disease. Prevalence of anemia increased as kidney function decreased. Certain subgroups are at increased risk for anemia.     

Myrtenal alleviates hyperglycaemia,hyperlipidaemia and improves pancreatic insulin level in STZ-induced diabetic rats

Context: Myrtenal is monoterpene a constituent of essential oils found mainly in herbs such as mint, pepper, cumin, etc. It exerts admirable pharmacological activities against many diseases including diabetes. Hyperlipidaemia is a secondary complication of diabetes and also a major risk factor for cardiovascular diseases.

Objective: The present study investigated the possible antihyperlipidaemic efficacy of myrtenal on plasma glucose, pancreatic insulin, plasma and tissue lipid levels in streptozotocin (STZ) induced diabetic rats.

Materials and methods: Diabetes was induced in male Wistar rats by a single intraperitoneal injection of STZ (40?mg/kg b.w.). Myrtenal (80?mg/kg) was administered orally to diabetic rats for a period of 28 d. Plasma glucose, pancreatic insulin, TC, TGs, FFAs, PLs, LDL-C, HDL-C, VLDL, atherogenic index, (HMG-CoA) reductase, LPL, LCAT and liver histology were analyzed.

Results: Diabetic rats showed significantly (p?<?0.05) increased plasma glucose (273.18?mg/dL), total cholesterol (142?mg/dL), triglycerides (126?mg/dL), free fatty acids (118?mg/dL), phospholipids (153?mg/dL), low-density lipoprotein (88.07?mg/dL), very low-density lipoprotein (25.2?mg/dL), atherogenic index, whereas a decrease in the levels of pancreatic insulin (97.48?ng/mg) and high-density lipoprotein (29.12?mg/dL). In addition, the activity of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase (0.94 HMG-CoA ratio/(mevalonate) increased significantly in contrast to the activities of lipoprotein lipase (4.87 μmoles of glycerol liberated/h/L) and lecithin cholesterol acyltransferase (54.61 μmoles of cholesterol esterified/h/L) in diabetic rats. Treatment with myrtenal significantly (p?<?0.05) improved the levels of plasma glucose, pancreatic insulin and lipid profiles. Moreover, the histopathological analysis of liver was also in agreement with the biochemical findings.

Discussion and conclusions: The present study indicates that myrtenal possess antihyperglycaemic and antihyperlipidemic properties, and could potentially be a useful phytochemical in treating diabetes.     

Bisoprolol/amlodipine combination therapy improves blood pressure control in patients with essential hypertension following monotherapy failure

Objective: The efficacy of a bisoprolol/amlodipine fixed-dose combination (FDC) in patients with essential hypertension who had not responded to bisoprolol or amlodipine monotherapy was investigated.

Research design and methods: In an 18 week, multicenter, randomized, comparative phase III study (ClinicalTrials.gov identifier: NCT01977794), patients with blood pressure uncontrolled by bisoprolol or amlodipine monotherapy (5?mg OD) began treatment with bisoprolol/amlodipine FDC 5/5?mg OD. Patients with controlled blood pressure (BP) at week 6/12 continued at current FDC strength, and patients with uncontrolled BP received FDC dose uptitration (maximum dose: 10/10?mg). The primary efficacy endpoint was change in systolic blood pressure (SBP) at week 18 versus baseline (corresponding to SBP under monotherapy), and secondary endpoints included change from baseline in SBP after week 6/12 and percentage of BP-controlled patients at week 6, 12 and 18. Safety was assessed by number/types of adverse events (AEs).

Results: Two hundred patients were randomized to treatment (100 with uncontrolled BP under bisoprolol and 100 under amlodipine monotherapy). Overall, 196 patients were eligible for analysis. The patient groups displayed similar mean SBP reductions from baseline by study end (bisoprolol monotherapy failure: 25.9?±?12.82?mmHg reduction; amlodipine monotherapy failure: 24.7?±?11.67?mmHg reduction; p?<?0.001 for both). Overall mean SBP decreased by 25.3?±?12.25?mmHg (p?<?0.001). Mean heart rate reductions were also observed (bisoprolol monotherapy failure: 6.6?±?9.67 bpm reduction; amlodipine monotherapy failure: 11.5?±?8.65 bpm reduction; p?<?0.001 for both). Most patients (83.2%) displayed BP control with bisoprolol/amlodipine 5/5?mg at 6 weeks. Treatment was well tolerated at all dose levels; treatment-related AEs (mostly of mild/moderate intensity) were reported by 52.5% of patients, with no severe or serious treatment-related AEs reported. As the study focused on hypertension, total cardiovascular risk was not assessed.

Conclusions: Bisoprolol/amlodipine FDC therapy is associated with significant BP improvements in patients with essential hypertension following monotherapy failure.     

In-hospital treatment of hyperglycemia: effects of intensified subcutaneous insulin treatment

ABSTRACT

Background: Hyperglycemia is common in hospitalized patients; however, glycemic control obtained during hospitalization is often suboptimal. No methods for achievement of proper glycemic control in this population have been validated in the in-hospital setting.

Aims: To study the effect of a novel intensive subcutaneous insulin protocol on the quality of in-hospital glycemic control.

Methods: Included in this prospective controlled study were all diabetic patients admitted to the internal medicine departments in a tertiary medical center during a 1-year period. The study was divided into pre-intervention (n = 94), intervention (n = 102) and post-intervention (n = 79) periods. During the intervention period all hospitalized diabetic patients with blood glucose >?200?mg/dL were treated with an intensive multi-injection protocol consisting of two or four times daily regular/NPH insulin injections.

Results: Mean glucose level throughout hospitalization was 178.7 ± 47?mg/dL in the intervention period versus 198.8 ± 60?mg/dL in the pre-intervention period (?p < 0.05). During the intervention period, the difference between mean admission and discharge day glucose levels was 43?mg/dL in patients treated with four times daily insulin injections, in contrast to no change noted in the other treatment groups. During the post-intervention period the rate of implementation of the intensive protocol by the internal medicine teams declined to 47.5%, in contrast to a 78.4% implementation rate during the intervention period. This decline was associated with deterioration of glycemic control.

Conclusions: The use of intensified insulin regimen improved the glycemic control of hospitalized diabetic patients. Successful incorporation of such intensive protocols into daily medical routines requires close involvement and continuous physician guidance by the hospital diabetes team.     

Effectiveness of perindopril/amlodipine fixed dose combination in everyday clinical practice: results from the EMERALD study

Objective: The rates of blood pressure (BP) control worldwide are discouraging. This study had the purpose of assessing the effectiveness of perindopril/amlodipine fixed dose combination on BP-lowering efficacy, and recording adherence, safety and tolerability during a 4 month treatment period.

Research design and methods: In this multicenter, observational study 2269 hypertensive patients were prospectively enrolled. The data were recorded at 1 and 4 months of treatment.

Main outcome measures and results: Between the first and third visits mean BP values (systolic/diastolic) decreased from 158.4?±?13.6/89.9?±?8.7?mmHg to 130.0?±?7.9/77.7?±?6.3?mmHg (P?<?0.001). The magnitude of BP reduction depended on baseline blood pressure levels and total cardiovascular (CV) risk (P?<?0.001). Patients with grade 1, 2 and 3 showed a BP reduction of 21.9/10.0?mmHg, 34.4/14.2?mmHg and 51.4/21.2?mmHg, accordingly (P?<?0.001). Patients with very high, high, moderate and low added CV risk showed a BP reduction of 35.7/14.9?mmHg, 27.5/12.1?mmHg, 28.6/12.2?mmHg and 14.5/5.8?mmHg respectively (P?<?0.001). Adherence to treatment was high: 98.3% of the sample was taking the treatment “every day” or “quite often”, while only 15 patients (0.7% of the sample) prematurely discontinued treatment. Study interpretation may be limited by the fact that this is an observational study with no comparator and a short follow-up period.

Conclusions: A perindopril/amlodipine fixed dose combination significantly decreases BP levels. The degree of BP reduction is related to baseline BP levels and total CV risk.     

Impact of noncompliance with urate-lowering drug on serum urate and gout-related healthcare costs: administrative claims analysis

ABSTRACT

Objective: To determine the association between allopurinol compliance and serum urate (sUA) level; and examine the association between sUA and gout-related healthcare costs in a large managed care population.

Research design and methods: This retrospective administrative claims analysis examined subjects with gout (≥2 medical claims with ICD-9-CM diagnosis code 274.xx or ≥1 claim with a gout diagnosis and ≥1 pharmacy claim for allopurinol, probenecid, colchicine, or sulfinpyrazone) between January 1, 2002 and March 31, 2004. Each subject was observed during 1-year pre-index and 1-year post-index periods.

Main outcome measures: Outcomes were allopurinol medication possession ratio (MPR) and compliance (MPR?≥?0.80), sUA (mg/dL), and gout-related healthcare costs. ‘Post-allopurinol’ sUA was measured during three periods after the first observed allopurinol fill: 30–89 days; 90–149 days; ≥150 days. A baseline sUA on or before the start of the post-index period was also identified. Outcomes were stratified by post-allopurinol or baseline sUA and compliance. Generalized linear modeling (GLM) regression measured the impact of baseline sUA on gout-related healthcare costs, controlling for demographic and health status variables.

Results: The study sample comprised 18?243 subjects with mean age of 53.9 years. In all, 55% (n?=?10?073) of subjects used allopurinol. There were 1473 (8.1%) subjects with a post-allopurinol sUA and 2438 (13.4%) subjects with a baseline sUA result. Among all subjects with a post-allopurinol sUA, 45.6% were compliant; between 49.3% and 56.8% of compliant subjects had an sUA?<?6.0?mg/dL compared with 22.5–27.8% of non-compliant subjects, depending on the post-allopurinol time period (all p?<?0.001). GLM results showed gout-related costs associated with baseline sUA?≥?6.0 and?<?9.0?mg/dL were 58% higher (95% confidence interval (CI): 1.012 –2.456; p?=?0.044) than were costs for sUA?<?6.0?mg/dL. There was no significant difference in gout-related costs between baseline sUA?<?6.0?mg/dL and ≥9.0?mg/dL.

Conclusions: Analysis revealed an important associations between allopurinol compliance, sUA, and gout-related costs: compliance was positively associated with favorable sUA (<6.0?mg/dL) in unadjusted comparisons. GLM showed that baseline sUA?<?6.0 was inversely associated with gout-related costs relative to baseline sUA?≥?6.0 and <9.0?mg/dL. Nevertheless, a substantial portion of subjects, even compliant ones, did not achieve sUA?<?6.0?mg/dL. These results should be interpreted carefully in light of study limitations, including incomplete laboratory data, the potentially incorrect inference that medications were taken as prescribed, and lack of generalizability from Medicare managed care enrollees to the broader Medicare population.     

The effects of insulin glargine treatment and an educational programme on glycaemic control in type 2 diabetes patients in clinical practice

ABSTRACT

Objective: This retrospective analysis was performed to establish the effect of initiating insulin glargine (LANTUS; sanofi-aventis, Paris, France), a once-daily basal insulin analogue, in combination with an educational programme on glycaemic control and body weight in sub-optimally controlled patients with Type 2 diabetes in clinical practice.

Research design and methods: We undertook a retrospective review of the medical records of 46 patients (mean age 61.5 ± 8.6 years) with Type 2 diabetes. These patients had previously been treated with oral antidiabetic agents (OADs; n = 18) or insulin only (n = 28) and had then received insulin glargine in combination with OADs or prandial insulin, for 30 months. Records of metabolic control and body weight data were analysed at 9 and 30 months. Patients had taken part in a diabetes educational programme before initiation of insulin glargine and received continued physician consultations throughout.

Results: Following initiation of insulin glargine, patients showed a significant decrease in HbA_1c from 8.14 ± 1.7% to 7.18 ± 0.9% at 30 months (?p < 0.001). When the results were analysed by pre-treatment, patients pre-treated with OADs showed a reduction in HbA_1c of 2.3% at 30 months (?p < 0.001), while patients pre-treated with insulin only showed a decrease in HbA_1c of 0.4% (?p < 0.005). There was no significant change in body weight. No unexpected adverse events or episodes of severe hypoglycaemia (blood glucose < 40?mg/dL [< 2.2?mmol/L]) occurred.

Conclusions: Insulin glargine in combination with educational support and close clinical supervision significantly improved metabolic control without significant weight change in patients with Type 2 diabetes in clinical practice over 30 months. Additional studies are required to establish if similar results can be obtained in a larger cohort of patients.