Validation et contribution à l’étude de l’effet antihyperglycémique d’une plante médicinale, le Momordica charantia L.

Momordica charantia (L.) [Cucurbitaceae], more commonly known as the bitter cucumber or bitter melon, is a plant used for food and medicine. In the Ayurvedic tradition it is used to treat a range of disorders, including diabetes. This study has demonstrated the plant’s anti-hyperglycaemic effect in mice with alloxan monohydrate induced diabetes. Two extracts were prepared, from both the fresh and the dried fruit of the plant, and their effects on blood sugar levels were compared with the reference anti-diabetes molecule glibenclamide. Aqueous extract of the fresh fruit at a dose of 200 mg/kg demonstrated a significant reduction in glycemia (62%), comparable with that of glibenclamide at a dose of 10 mg/kg. The two extracts at different doses showed no signs of toxicity. Thus, aqueous extract of the edible plant M. charantia would appear to be a viable alternative for reducing glycemia as well as providing an auxiliary and complementary treatment which would limit the secondary effects of allopathic remedies using synthetic drugs.     

A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine

OBJECTIVE: The efficacy of the insulin analogs now available for multiple daily injection (MDI) and continuous subcutaneous insulin infusion (CSII) therapy in type 1 diabetes has not yet been established in pediatric patients. Our principal aim in this short-term study was to compare the efficacy of CSII to MDI with glargine in lowering HbA(1c) levels in children and adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Thirty-two youth with type 1 diabetes (age 8-21 years) were randomly assigned to receive either MDI treatment with once-daily glargine and premeal/snack insulin aspart or CSII with insulin aspart. Dose titration in both groups was based on home self-monitored blood glucose measurements and monthly HbA(1c). HbA(1c), total daily insulin dose (TDD), self-monitored blood glucose readings, and adverse events were compared after 16 weeks of therapy. RESULTS: While there was no significant change in the glargine group (HbA(1c) 8.2% at baseline vs. 8.1% at 16 weeks), youth randomized to CSII had a sharp reduction in HbA(1c) levels, from 8.1 to 7.2% after 16 weeks of therapy (P < 0.02 vs. baseline and <0.05 vs. glargine group). TDD was unchanged in the glargine group, but significantly dropped with CSII (1.4 units/kg at baseline vs. 0.9 units/kg at 16 weeks, P < 0.01). Both groups had similar basal doses and insulin-to-carbohydrate ratios. Fasting self-monitored blood glucose was similar in both groups, but lunch, dinner, and bedtime readings were significantly lower in the CSII group (P < 0.01). CONCLUSIONS: Lower HbA(1c) and premeal glucose levels were more achievable in this short-term study with CSII than with glargine-based MDI treatment. CSII is an efficacious treatment to improve metabolic control in youth with type 1 diabetes.     

Results of the glucose-lowering effect of WelChol study (GLOWS): a randomized, double-blind, placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes

OBJECTIVE: This study evaluated the glycosylated hemoglobin (HbA(1c)-lowering effect of colesevelam hydrochloride, a bile acid sequestrant, in subjects with type 2 diabetes that was inadequately controlled by existing antihyperglycemic therapy. METHODS: After a 4-week placebo run-in period, subjects with type 2 diabetes and an HbA(1c) value of 7.0% to 10.0% were randomized to receive colesevelam 3.75 g/d or matching placebo for 12 weeks. Subjects' previous oral anti hyperglycemic medication (sulfonylurea and/or metformin) was continued throughout the study. Fasting blood samples were obtained at weeks -5, -1, 0, 1, 4, 8, and 12. The primary efficacy end point was the change in HbA(1c) from baseline to week 12. Secondary end points included changes in fructosamine levels, fasting plasma glucose levels, postprandial glucose level, and meal glucose response (ie, difference between preprandial and postprandial levels), and percent changes in lipid parameters from baseline to week 12. RESULTS: The 65 randomized subjects (31 colesevelam, 34 placebo) had a mean age of 56.2 years and a mean body mass index of 32.4 kg/m(2); 55.4% were male and 53.8% were white. The difference in least squares (LS) mean (SE) change in HbA(1c) between the colesevelam group and the placebo group was -0.5% (0.18) (P = 0.007). In subjects with a baseline HbAIc > or = 8.0%, the difference in LS mean change in HbA(1c) was -1.0% (0.27) (P = 0.002). Relative to placebo, colesevelam treatment was associated with reductions in levels of fructosamine (-29.0 [10.9] pmol/L; P = 0.011) and postprandial glucose (-31.5 [13.6] mg/dL; P = 0.026). The mean percent change in low-density lipoprotein cholesterol was -9.6% in the colesevelam group, compared with 2.1% in the placebo group (treatment difference, -11.7% [4.2]; P = 0.007); the respective mean percent changes in total cholesterol were -4.0% and 3.4% (treatment difference, -7.3% [3.0]; P = 0.019). Colesevelam also was associated with significant decreases in the percent change in apolipoprotein B (P = 0.003) and low-density lipoprotein particle concentration (P = 0.037). The incidence of treatment-emergent adverse events (TEAEs) was similar in both groups, although treatment-related adverse events were more frequent in the colesevelam group than in the placebo group (29.0% vs 8.8%, respectively). The most frequent TEAEs in the colesevelam group were gastrointestinal disorders (22.6%), primarily constipation (19.4%), compared with an 8.8% incidence of gastrointestinal disorders (0% constipation) in the placebo group. There were no significant changes in body weight or the occurrence of hypoglycemia between treatment groups. CONCLUSIONS: In these subjects with type 2 diabetes, 12 weeks of colesevelam treatment were associated with significant reductions in HbA(1c) and in fructosamine and postprandial glucose levels compared with placebo. The 2 groups had a similar adverse-event profile, with the exception of an increased incidence of constipation in the colesevelam group. These results suggest that colesevelam may improve both lipid control and glycemic control in patients with type 2 diabetes receiving oral antihyperglycemic medications.     

Comparison of the Efficacy and Safety of Atorvastatin 40 mg/ω-3 Fatty Acids 4 g Fixed-dose Combination and Atorvastatin 40 mg Monotherapy in Hypertriglyceridemic Patients who Poorly Respond to Atorvastatin 40 mg Monotherapy: An 8-week,Multicenter, Randomized,Double-blind Phase III Study

PurposeResidual cardiovascular risk in patients with hypertriglyceridemia, despite optimal low-density lipoprotein cholesterol levels being achieved with intensive statin treatment, is a global health issue. The purpose of this study was to investigate the efficacy and tolerability of treatment with a combination of high-dose atorvastatin/Ω-3 fatty acid compared to atorvastatin + placebo in patients with hypertriglyceridemia who did not respond to statin treatment.MethodsIn this multicenter, randomized, double-blind, placebo-controlled study, patients who had residual hypertriglyceridemia after a 4-week run-in period of atorvastatin treatment were randomly assigned to receive UI-018 (fixed-dose combination atorvastatin/Ω-3 fatty acid 40 mg/4 g) or atorvastatin 40 mg + placebo (control). The primary efficacy end points were the percentage change from baseline in non–high density lipoprotein cholesterol (non–HDL-C) level at the end of treatment and the adverse events recorded during treatment. A secondary end point was the percentage change from baseline in triglyceride level.FindingsAfter 8 weeks of treatment, the percentage changes from baseline in non–HDL-C (–4.4% vs +0.6%; p = 0.02) and triglycerides (–18.5% vs +0.9%; p < 0.01) were significantly greater in the UI-018 group (n = 101) than in the control group (n = 99). These changes were present in subgroups of advanced age (≥65 years), status (body mass index ≥25 kg/m²), or without diabetes. The prevalences of adverse events did not differ between the 2 treatment groups.ImplicationsIn patients with residual hypertriglyceridemia despite receiving statin treatment, a combination of high-dose atorvastatin/Ω-3 fatty acid was associated with a greater reduction of triglyceride and non–HDL-C compared with atorvastatin + placebo, without significant adverse events.     

Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial

OBJECTIVE: Liraglutide is a long-acting glucagon-like peptide 1 analog designed for once daily injection. This study assessed the efficacy and safety of liraglutide after 12 weeks of treatment in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A double-blind, randomized, parallel-group, placebo-controlled trial with an open-label comparator arm was conducted among 193 outpatients with type 2 diabetes. The mean age was 56.6 years and the mean HbA(1c) was 7.6% across the treatment groups. Patients were randomly assigned to one of five fixed-dosage groups of liraglutide (0.045, 0.225, 0.45, 0.60, or 0.75 mg), placebo, or open-label sulfonylurea (glimepiride, 1-4 mg). The primary end point was HbA(1c) after 12 weeks; secondary end points were fasting serum glucose, fasting C-peptide, fasting glucagon, fasting insulin, beta-cell function, body weight, adverse events, and hypoglycemic episodes. RESULTS: A total of 190 patients were included in the intention-to-treat (ITT) analysis. HbA(1c) decreased in all but the lowest liraglutide dosage group. In the 0.75-mg liraglutide group, HbA(1c) decreased by 0.75 percentage points (P < 0.0001) and fasting glucose decreased by 1.8 mmol/l (P = 0.0003) compared with placebo. Improvement in glycemic control was evident after 1 week. Body weight decreased by 1.2 kg in the 0.45-mg liraglutide group (P = 0.0184) compared with placebo. The proinsulin-to-insulin ratio decreased in the 0.75-mg liraglutide group (-0.18; P = 0.0244) compared with placebo. Patients treated with glimepiride had decreased HbA(1c) and fasting glucose, but slightly increased body weight. No safety issues were raised for liraglutide; observed adverse events were mild and transient. CONCLUSIONS: A once-daily dose of liraglutide provides efficacious glycemic control and is not associated with weight gain. Adverse events with the drug are mild and transient, and the risk of hypoglycemia is negligible.     

Empagliflozin Monotherapy in Japanese Patients with Type 2 Diabetes Mellitus: a Randomized, 12-Week,Double-Blind,Placebo-Controlled,Phase II Trial

Introduction

This study was designed to determine the efficacy and tolerability of empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus (T2DM).

Methods

Patients with glycosylated hemoglobin (HbA1c) ≥7.0–≤10% were randomized via an interactive web response system, and treated double-blind with empagliflozin 5, 10, 25, 50 mg, or placebo once daily for 12 weeks. The primary endpoint was change from baseline in HbA1c at week 12. Other endpoints included percentage of patients with HbA1c <7.0% and changes from baseline in fasting plasma glucose (FPG), body weight, and systolic blood pressure (SBP) at week 12.

Results

A total of 547 patients were randomized and treated with empagliflozin 5 mg (n = 110), 10 mg (n = 109), 25 mg (n = 109), 50 mg (n = 110), or placebo (n = 109) for 12 weeks. Adjusted mean [95% confidence interval (CI)] differences vs. placebo in changes from baseline in HbA1c were ?0.72% (?0.87, ?0.57) with empagliflozin 5 mg, ?0.70% (?0.85, ?0.55) with 10 mg, ?0.95% (?1.10, ?0.80) with 25 mg, and ?0.91 (?1.06, ?0.76) with 50 mg (all p < 0.001). More patients with HbA1c ≥7.0% at baseline reached HbA1c <7.0% with empagliflozin (19–33%) than placebo (3%). Compared with placebo, empagliflozin reduced FPG, body weight (p < 0.001 for all doses for both endpoints) and SBP (p = 0.001, p = 0.014 and p = 0.003 for empagliflozin 10, 25, and 50 mg, respectively). Adverse events were reported by 42% of patients receiving placebo and 33–38% of patients receiving empagliflozin. There were few reports of confirmed hypoglycemic adverse events or events consistent with urinary tract infection or genital infection in any treatment group.

Conclusions

Empagliflozin monotherapy for 12 weeks in Japanese patients with T2DM reduced HbA1c, FPG, body weight and SBP, and was well tolerated.     

Efficacy of Ipomoea batatas (Caiapo) on diabetes control in type 2 diabetic subjects treated with diet

OBJECTIVE: To investigate the tolerability, efficacy, and mode of action of Caiapo, an extract of white sweet potatoes, on metabolic control in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 61 type 2 diabetic patients treated by diet were given 4 g Caiapo (n = 30; mean age 55.2 +/- 2.1 years; BMI 28.0 +/- 0.4 kg/m(2)) or placebo (n = 31; mean age 55.6 +/- 1.5 years; BMI 27.6 +/- 0.3 kg/m(2)) once daily for 12 weeks. Each subject underwent a 75-g oral glucose tolerance test (OGTT) at baseline and after 1, 2, and 3 months to assess 2-h glucose levels. Additionally, fasting blood glucose, HbA(1c), total cholesterol, and triglyceride levels were measured. RESULTS: After treatment with Caiapo, HbA(1c) decreased significantly (P < 0.001) from 7.21 +/- 0.15 to 6.68 +/- 0.14%, whereas it remained unchanged (P = 0.23) in subjects given placebo (7.04 +/- 0.17 vs. 7.10 +/- 0.19%). Fasting blood glucose levels decreased (P < 0.001) in the Caiapo group (143.7 +/- 1.9 vs. 128.5 +/- 1.7 mg/dl) and did not change in the placebo group (144.3 +/- 1.9 vs. 138.2 +/- 2.1 mg/dl; P = 0.052). A decrease in body weight was observed in both the placebo group (P = 0.0027) and in the Caiapo group (P < 0.0001), probably due to a better- controlled lifestyle. In the Caiapo group, body weight was related to the improvement in glucose control (r = 0.618; P < 0.0002). Two-hour glucose levels were significantly (P < 0.001) decreased in the Caiapo group (193.3 +/- 10.4 vs. 162.8 +/- 8.2 mg/dl) compared with the placebo group (191.7 +/- 9.2 vs. 181.0 +/- 7.1 mg/dl). Mean cholesterol at the end of the treatment was significantly lower in the Caiapo group (214.6 +/- 11.2 mg/dl) than in the placebo group (248.7 +/- 11.2 mg/dl; P < 0.05). No significant changes in triglyceride levels or blood pressure were observed, and Caiapo was well tolerated without significant adverse effects. CONCLUSIONS: This study confirms the beneficial effects of Caiapo on plasma glucose as well as cholesterol levels in patients with type 2 diabetes. For the first time, the long-term efficacy of Caiapo on glucose control was demonstrated by the observed decrease in HbA(1c). Thus, the neutraceutical Caiapo seems to be a useful agent in the treatment of type 2 diabetes.     

A randomized controlled study of dose-finding,efficacy, and safety of mulberry leaves on glycemic profiles in obese persons with borderline diabetes

ObjectivesMulberry (Morus alba L.) leaves have been used in traditional medicine for treating hyperglycemia. However, there remains difficulties in the implementation of mulberry leaves in evidence-based practice. The aims of this study were to examine the optimal dose of 1-deoxynojirimycin (DNJ) in mulberry leaves and to determine the efficacy and safety of mulberry leaves in glycemic control in obese persons with borderline diabetes.DesignFirst, healthy adults were recruited into the dose-finding study and randomly allocated to ingest sucrose solution concurrently with mulberry leaf powder at weights equivalent to 0 (control), 6, 12, and 18 mg of DNJ. Postprandial glucose and undesirable effects were evaluated. Second, obese persons with borderline diabetes were randomly assigned into the mulberry-leaves treatment group (12 mg of mulberry DNJ three times daily) and the control group in the 12-week prospective study. Blood glucose and insulin as well as adverse effects were determined.ResultsTwelve mg of mulberry DNJ was the minimum effective dose attenuating postprandial hyperglycemia. Mulberry leaves decreased fasting plasma glucose (FPG) by 3.86 ± 5.99 mg/dL (p = 0.002) and glycated hemoglobin (HbA1c) by 0.11 ± 0.22 % (p = 0.011) when compared with the baseline levels. Improvement in glucose tolerance was not observed. Furthermore, mulberry leaves tended to ameliorate insulin resistance (p = 0.057). Adverse events of mulberry leaves commonly found in this study were gastrointestinal symptoms including bloating, flatulence, and loose stools.ConclusionMulberry leaves possessed favorable effects on glycemic profiles without serious side effects.     

Possible adaptogenic effects of Momordica charantia on high-intensity training-induced alteration in the hypothalamic-pituitary-adrenal axis

This study investigated the effects of a drink supplement containing Momordica charantia extract from bitter melon on physical fitness and levels of stress hormones during a four-week exercise training program in a hot environment. Ten male tennis players were orally administrated in a four-week (100 ml, 6 times a day), and the pre- and post-supplementation levels of different physical fitness variables and cortisol, and adrenocorticotropic hormone in plasma were measured at four time-points—before (baseline), during, and after the exercise, and on the next day of the supplementation. The findings showed that the supplementation has significant positive effects on enhancement of physical fitness parameters especially balance (d = 22.10, p = 0.013), flexibility (d = 4.83, p = 0.015), and cardiorespiratory fitness (d = 10.00, p = 0.030). Moreover, the adrenocorticotropic hormone levels were reduced during the exercise, and the cortisol levels showed the decreasing trend during and after the exercise, which was correlated with the change of cardiorespiratory fitness (r = 0.65, p<0.05). These results indicated the possible adaptogenic effects of Momordica charantia extract intake. Based on the findings, we suggest that Momordica charantia could be used as a source of adaptogenic supplement to alleviate the exercise- and environment-induced stress.     

Repaglinide/troglitazone combination therapy: improved glycemic control in type 2 diabetes

OBJECTIVE: This multicenter open-label clinical trial compared the efficacy and safety of repaglinide/troglitazone combination therapy, repaglinide monotherapy, and troglitazone monotherapy in type 2 diabetes that had been inadequately controlled by sulfonylureas, acarbose, or metformin alone. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes (n = 256) who had inadequate glycemic control (HbA1c > or =7.0%) during previous monotherapy were randomly assigned to receive repaglinide (0.5-4.0 mg at meals), troglitazone (200-600 mg once daily), or a combination of repaglinide (1-4 mg at meals) and troglitazone (200-600 mg once daily). After a 4-6 week washout period, the trial assessed 22 weeks of treatment: 3 weeks (weeks 0-2) of forced titration, 11 weeks of fixed-dose treatment (weeks 3-13), and 8 weeks (weeks 14-21) of titration to maximum dose. Changes in HbA1c and fasting plasma glucose (FPG) values were measured. RESULTS: The combination therapy showed a significant reduction in mean HbA1c values (-1.7%) that was greater than with either type of monotherapy Repaglinide monotherapy resulted in a reduction of HbA1c values that was significantly greater than troglitazone (-0.8 vs. -0.4%) (P < 0.05). Combination therapy was more effective in reducing FPG values (-80 mg/dl) than either repaglinide (-43 mg/dl) or troglitazone (-46 mg/dl) monotherapies. Adverse events were similar in all groups. CONCLUSIONS: Combination therapy with repaglinide and troglitazone leads to better glycemic control than monotherapy with either agent alone. Repaglinide monotherapy was more effective in lowering HbA1c levels than troglitazone monotherapy Repaglinide/troglitazone combination therapy was effective and did not show unexpected adverse events.     

Muraglitazar, a dual (alpha/gamma) PPAR activator: a randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) present a therapeutic target, and simultaneous activation of PPAR-alpha and PPAR-gamma may provide improvements in glycemic control and dyslipidemia in patients with type 2 diabetes. OBJECTIVE: The goal of this study was to evaluate the efficacy and safety of muraglitazar, a dual (alpha/gamma) PPAR activator, in adult patients with type 2 diabetes whose disease was inadequately controlled by diet and exercise. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter, 24-week monotherapy study in drug-naive, type 2 diabetes patients with inadequate glycemic control. Men and women aged 18 to 70 years with a body mass index < or =41 kg/m(2) and serum triglyceride levels < or =600 mg/dL were eligible for study participation. The study included double-blind and open-label treatment phases. Patients with glycosylated hemoglobin (HbA(1c)) levels > or =7.0% and < or =10.0% at screening were enrolled in the double-blind treatment phase. These patients received treatment with muraglitazar 2.5 mg, muraglitazar 5 mg, or placebo. Patients with HbA(1c) levels >10.0% and < or =12.0% who met all other study criteria were eligible for enrollment in a 24-week, open-label evaluation of muraglitazar 5 mg. The primary end point was the mean change from baseline in HbA(1c) levels after 24 weeks of treatment. RESULTS: A total of 340 patients (179 men, 161 women) participated in the double-blind treatment phase of the study. Patients had mean baseline HbA(1c) levels of 7.9% to 8.0%. Monotherapy with muraglitazar 2.5 and 5 mg significantly reduced HbA(1c) levels (-1.05% and -1.23%, respectively) compared with placebo (-0.32%; P < 0.001). At week 24, 58%, 72%, and 30% of the patients receiving muraglitazar 2.5 mg, muraglitazar 5 mg, and placebo, respectively, achieved the American Diabetes Association-recommended HbA(1c) goal of <7.0%. Fasting plasma glucose, free fatty acids, and fasting plasma insulin levels significantly decreased during muraglitazar treatment (P < 0.001), suggesting an increase in insulin sensitivity. Muraglitazar 2.5 and 5 mg provided improvements from baseline in triglyceride (-18% and -27%), high-density lipoprotein (HDL) cholesterol (10% and 16%), apolipoprotein B (-7% and -12%), and non-HDL cholesterol levels (-3% and -5%) (P < 0.05 vs placebo for each). In a parallel, open-label cohort of 109 drug-naive patients (56 men, 53 women; mean baseline HbA(1c) level, 10.6%), muraglitazar 5 mg decreased the overall mean HbA(1c) level from baseline by 2.62% (last observation carried forward) and by 3.49% in the 62 patients completing 24 weeks of study. Changes in lipid parameters during open-label treatment were similar to those observed during double-blind treatment. Muraglitazar was generally well tolerated. Edema-related adverse events of mild to moderate severity occurred in 8% to 11% of patients in all groups. Mean changes from baseline weight in the double-blind treatment groups were 1.1 kg for muraglitazar 2.5 mg, 2.1 kg for muraglitazar 5 mg, and -0.8 kg for placebo (P < 0.001); there was a mean 2.9-kg increase in the open-label muraglitazar 5-mg group. CONCLUSION: In this study, 24 weeks of treatment with muraglitazar 2.5 or 5 mg was an effective treatment option for these patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise.     

Dasiglucagon—A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia: Results of Phase 3 Randomized Double-Blind Clinical Trial

OBJECTIVETo evaluate the efficacy and safety of dasiglucagon, a ready-to-use, next-generation glucagon analog in aqueous formulation for subcutaneous dosing, for treatment of severe hypoglycemia in adults with type 1 diabetes.RESEARCH DESIGN AND METHODSThis randomized, double-blind trial included 170 adult participants with type 1 diabetes, each randomly assigned to receive a single subcutaneous dose of 0.6 mg dasiglucagon, placebo, or 1 mg reconstituted glucagon (2:1:1 randomization) during controlled insulin-induced hypoglycemia. The primary end point was time to plasma glucose recovery, defined as an increase of ≥20 mg/dL from baseline without rescue intravenous glucose. The primary comparison was dasiglucagon versus placebo; reconstituted lyophilized glucagon was included as reference.RESULTSMedian (95% CI) time to recovery was 10 (10, 10) minutes for dasiglucagon compared with 40 (30, 40) minutes for placebo (P < 0.001); the corresponding result for reconstituted glucagon was 12 (10, 12) minutes. In the dasiglucagon group, plasma glucose recovery was achieved within 15 min in all but one participant (99%), superior to placebo (2%; P < 0.001) and similar to glucagon (95%). Similar outcomes were observed for the other investigated time points at 10, 20, and 30 min after dosing. The most frequent adverse effects were nausea and vomiting, as expected with glucagon treatment.CONCLUSIONSDasiglucagon provided rapid and effective reversal of hypoglycemia in adults with type 1 diabetes, with safety and tolerability similar to those reported for reconstituted glucagon injection. The ready-to-use, aqueous formulation of dasiglucagon offers the potential to provide rapid and reliable treatment of severe hypoglycemia.     

A Multicenter,Randomized, Double-blind,Active-controlled,Factorial Design,Phase III Clinical Trial to Evaluate the Efficacy and Safety of Combination Therapy of Pitavastatin and Ezetimibe Versus Monotherapy of Pitavastatin in Patients With Primary Hypercholesterolemia

PurposePitavastatin is a unique lipophilic statin with moderate efficacy in lowering LDL-C levels by 30% to 50% with a tolerable safety profile. However, the efficacy of adding ezetimibe to pitavastatin in patients with dyslipidemia has not been well investigated. Therefore, the objective of this double-blind, multicenter, randomized, Phase III study was to compare the efficacy and safety of pitavastatin and ezetimibe combination therapy with those of pitavastatin monotherapy in Korean patients with primary hypercholesterolemia.MethodsKorean men and women aged >19 and <80 years with primary hypercholesterolemia requiring medical treatment were included in this study. During the 8-week screening period, all patients were instructed to make therapeutic lifestyle changes. The screening period consisted of a 4-week washout period and a placebo run-in period (4–8 weeks). During treatment period I, patients were randomly assigned to receive 1 of 4 treatments: pitavastatin 2 mg plus ezetimibe 10 mg, pitavastatin 2 mg, pitavastatin 4 mg plus ezetimibe 10 mg, or pitavastatin 4 mg. The 8-week double-blind treatment period then commenced. Adverse events (AEs), clinical laboratory data, and vital signs were assessed in all patients.FindingsThe percentages in LDL-C from baseline after 8 weeks of double-blind treatment decreased significantly in the pooled pitavastatin/ezetimibe (–52.8% [11.2%]) and pooled pitavastatin (–37.1% [14.1%]) groups. Treatment with pitavastatin/ezetimibe resulted in a significantly greater LDL-C–lowering effect than that with pitavastatin (difference, –15.8 mg/dL; 95% CI, –18.7 to –12.9; P < 0.001). The precentages of achieving LDL-C goal in pooled pitavastatin/ezetimibe and pooled pitavastatin groups were 94.2% and 69.1%, respectively (P < 0.001). There were no significant differences in the incidence of overall AEs and adverse drug reactions. Serious AEs were comparable between the groups.ImplicationsPitavastatin and ezetimibe combinations effectively and safely decreased LDL-C levels by >50% in patients with dyslipidemia. The safety and tolerability of pitavastatin and ezetimibe combination therapy were comparable with those of pitavastatin monotherapy. ClinicalTrials.gov identifier: NCT04584736.     

磷酸西格列汀联合二甲双胍治疗2型糖尿病的临床疗效

目的观察对接受药物初始治疗或近12周内未接受任何降糖药物治疗的2型糖尿病患者应用磷酸西格列汀和二甲双胍联合治疗的有效性及安全性。方法对接受药物初始治疗或近12周内未接受降糖药物治疗的90例2型糖尿病患者采用随机数字表法分为磷酸西格列汀联合二甲双胍组、二甲双胍单药治疗组、磷酸西格列汀单药治疗组,比较治疗16周后磷酸西格列汀联合二甲双胍组分别较单药治疗组对糖化血红蛋白(Hb A_1c)、空腹血糖(FBG)及餐后2 h血糖(PBG)的影响及服药期间不良反应的发生情况。结果治疗16周后,磷酸西格列汀和二甲双胍联合治疗组与磷酸西格列汀单药治疗组相比患者的FBG、PBG及Hb A_1c水平均差异有统计学意义(P0.05)。联合治疗组与二甲双胍单药治疗组相比,患者的FBG有所下降,但两组之间差异无统计学意义(P0.05),而联合治疗组所致的PBG及Hb A_1c水平的下降,差异有统计学意义(P0.05)。治疗期间各组患者低血糖的发生率相似,磷酸西格列汀和二甲双胍联合治疗组的腹泻、恶心、呕吐等胃肠道不良事件的发生率与各单药治疗组相比差异均无统计学意义(P0.05)。各治疗组均未有肝肾功能异常、胰腺炎等不良事件发生。结论磷酸西格列汀联合二甲双胍组在降糖疗效方面均优于二甲双胍及磷酸西格列汀单药治疗组,且低血糖、胃肠道等不良反应的发生率低。     

Effects of Elobixibat,an Inhibitor of Ileal Bile Acid Transporter,on Glucose and Lipid Metabolism: A Single-arm Pilot Study in Patients with T2DM

PurposeThe ileal bile acid transporter inhibitor elobixibat was recently approved in Japan for use in the treatment of patients with chronic constipation. Elobixibat has been associated with increased plasma glucagon-like peptide 1 level through Takeda G protein receptor 5, which is a membrane receptor of bile acids. The present study assessed the metabolic effects of elobixibat in patients with type 2 diabetes mellitus (T2DM)-related constipation.MethodsIn this single-arm pilot study, 21 patients with T2DM and constipation were administered elobixibat 10 mg/d for 12 weeks (period 1). The primary end point was the change in hemoglobin (Hb) A_1c at week 12. Secondary end points included physical parameters; constipation symptoms; and blood parameters, such as low-density lipoprotein cholesterol (LDL-C), arachidonic acid (AA), and fatty acid fractions. Thereafter, the study participants chose whether to continue therapy for an additional 12 weeks (period 2), at which point HbA_1c and lipid levels were reevaluated. Safety information, including adverse events, discontinuation and interruption of the drug, was collected at each visit during the trial.FindingsPeriod 1: the levels of HbA_1c, LDL-C, and AA were significantly reduced after administration of elobixibat for 12 weeks (–0.2%, –21.4 mg/dL, and –16.1 µg/dL, respectively; P = 0.016, P < 0.001, and P = 0.010). Period 2: at week 24, the change from baseline in HbA_1c was significantly greater among those who continued elobixibat treatment than in those who discontinued after 12 weeks (–0.23% vs +0.21%; P = 0.038). No serious or severe adverse events were observed.ImplicationsElobixibat may benefit patients with T2DM by improving glucose metabolism and lowering serum LDL-C and AA levels, in addition to ameliorating constipation. This single-arm pilot study was of a small sample size. The findings provide a basis for designing a larger-scale study to confirm the effects of elobixibat on glucose and lipid metabolism. (UMIN Clinical Trials Registry identifier: UMIN000045508; https://www.umin.ac.jp/ctr/index.htm)     

Efficacy of blood glucose self-monitoring on glycemic control in patients with non-insulin-treated type 2 diabetes: A meta-analysis

ObjectiveTo evaluate the efficacy of blood glucose self-monitoring on glycemic control in patients with non-insulin-treated type 2 diabetes by performing a meta-analysis.MethodsRandomized controlled trials (RCTs) of the efficacy of blood glucose self-monitoring were collected from the PubMed, EMBASE, Cochrane Library, CNKI, and VIP databases. Data were analyzed by RevMan 5.1 software.ResultsSeven RCTs were included in this meta-analysis. The results indicated that blood glucose self-monitoring significantly reduced the glycated hemoglobin (HbA1c) level by 0.41%. Subgroup analysis showed that while implementation of a diabetes management regimen based on the blood glucose self-monitoring results effectively reduced the HbA1c level by 0.42%, no significant improvement in HbA1c level control was observed with the implementation of blood glucose self-monitoring alone.ConclusionBlood glucose self-monitoring combined with diabetes management effectively improves glycemic control in patients with non-insulin-treated type 2 diabetes.     

Efficacy and Safety of Linagliptin in Subjects With Long-standing Type 2 Diabetes Mellitus (>10 Years): Evidence From Pooled Data of Randomized,Double-blind,Placebo-controlled,Phase III Trials

PurposeLong duration of type 2 diabetes mellitus (T2DM) is associated with progressive β-cell loss and may pose a challenge to maintenance of good glycemic control. This study aimed to assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in an understudied population of patients with long-standing T2DM.MethodsData from 202 individuals with T2DM for >10 years were pooled from 2 randomized, placebo-controlled, Phase III trials. Participants received either linagliptin 5 mg once daily (n = 122) or placebo (n = 80) for 24 weeks as an add-on to their current glucose-lowering therapy.FindingsLong-standing T2DM was associated with older age (mean [SD], 69.1 [10.0] years) and a high prevalence of diabetes-related complications (78% with diabetic kidney disease and 83% with macrovascular disease). The mean baseline glycosylated hemoglobin (HbA_1c) level was 8.22% (1.08%), and mean baseline fasting plasma glucose level was 161.8 (49.2) mg/dL. Linagliptin significantly improved glycemic control after 24 weeks, with a placebo-adjusted mean change in HbA_1c from baseline of −0.66% (95% CI, −0.95 to −0.38; P < 0.0001). This change was accompanied by a significant reduction in fasting plasma glucose, with a placebo-adjusted mean change from baseline of −15.5 mg/dL (95% CI, −29.6 to −1.3; P = 0.0323) at week 24. Overall, linagliptin was well tolerated, with drug-related adverse events in 21.3% and 16.3% of the linagliptin and placebo groups, respectively. Investigator-reported hypoglycemia occurred more often with linagliptin (25.4%) compared with placebo (12.5%). However, no severe hypoglycemic events were reported with linagliptin. Moreover, in patients not receiving concomitant sulfonylureas, the incidence of hypoglycemia with linagliptin (12.5%) was similar to that with placebo (12.2%). Patients’ mean weight remained unchanged in both groups.ImplicationsThis pooled analysis found that linagliptin was well tolerated and significantly improved hyperglycemia in a clinically challenging population of patients with long-standing T2DM (>10 years). Although T2DM is commonly associated with diminished β-cell function, the extent of glucose lowering was similar to that in linagliptin trials, which largely included patients in earlier stages of the disease. Thus, this observation supports the hypothesis that regulation of glucagon release from pancreatic α cells may be of particular relevance for improving hyperglycemia in patients with long-term T2DM (NCT01194830 and NCT01084005).     

A Paradigm Shift in Dyslipidemia Management in Primary Care: A 12-Month Cohort Study

PurposeLDL-lowering therapy is beneficial to reduce the risk of cardiovascular disease (CVD). Higher statin doses lower LDL-C levels and prevent CVD; however, they increase adverse events, such as muscle-related adverse events and new-onset diabetes mellitus (DM). Ezetimibe combined with statin therapy improves LDL-C–lowering levels and tolerability in patients with established CVD. We aimed to analyze the efficacy and safety of a fixed-dose rosuvastatin and ezetimibe (R+E) combination therapy in intermediate-risk patients with hypercholesterolemia and no DM after 12 months of visiting a primary physician.MethodsThis multicenter, open-label, single-arm, prospective observational study involved 5717 patients from 258 primary health care centers in Korea enrolled between 2016 and 2018. Patients had no DM or previous CVD but had cardiovascular risk factors and were taking a statin or a fixed-dose combination of E (10 mg) + R (5, 10, or 20 mg). We analyzed 700 patients using propensity score matching.FindingsA fixed-dose R+E combination therapy significantly reduced LDL-C in 5/10 mg R+E (29.35%), 10/10 mg R+E (36.19%), and 20/10 mg R+E (41.83%) compared with statin monotherapy (19.09%) at 12-month follow-up (P = 0.017). Compared with statin monotherapy, HDL-C levels increased in 5/10 mg R+E (mean change at 12 months; P = 0.004), and triglyceride levels decreased in 10/10 mg R+E (mean change at 12 months; P = 0.033). The fixed-dose R+E combination therapy was associated with fewer adverse events and a neutral effect on glucose deterioration compared with statin monotherapy at 12 months of follow-up.ImplicationsIn a possible paradigm shift, a fixed-dose R+E combination therapy may be beneficial for primary cardiovascular prevention with potent LDL-lowering efficacy and tolerability; however, further large prospective studies are needed.     

甘精胰岛素联合阿卡波糖治疗初诊2型糖尿病的疗效观察

目的探讨首次诊断2型糖尿病患者应用甘精胰岛素联合阿卡波糖治疗的疗效。方法 54例初诊的2型糖尿病患者应用甘精胰岛素联合阿卡波糖治疗12周,比较治疗前后空腹血糖、餐后2 h血糖、糖化血红蛋白(HbA1c)及低血糖发生率。结果治疗12周后,所有患者空腹血糖、餐后2 h血糖及HbA1c均控制在比较理想的水平,低血糖发生率低,未见严重不良反应。结论对于初诊2型糖尿病患者,应用精胰岛素联合阿卡波糖治疗是一种安全有效的治疗方案。     

Effects of zinc supplementation on superoxide dismutase activity and gene expression,and metabolic parameters in overweight type 2 diabetes patients: A randomized,double-blind,controlled trial

ObjectiveDespite the current guidelines for the management of type 2 diabetes mellitus (T2DM), patients still struggle with the hyperglycemia consequences. Imbalance in zinc homeostasis, in particular, renders diabetic patients more susceptible to the damages of oxidative stress. This study aimed to evaluate the effects of zinc supplementation on the superoxide dismutase gene expression and enzyme activity in overweight individuals with T2DM. Additionally, biochemical parameters, such as fasting blood glucose (FBG), insulin, glycated hemoglobin (HbA1c), homeostasis model of assessment-insulin resistance (HOMA-IR), serum levels of zinc and lipid profile, were assessed.MethodsIn this randomized, double-blind, placebo-controlled trial, 70 overweight (BMI > 25) T2DM patients were selected based on the inclusion criteria. They were divided into two groups for supplementation of daily 50 mg zinc gluconate or placebo for 8 weeks. Blood samples were collected from all the individuals in the zinc group and controls for analysis.ResultsThe results showed that, in comparison with the control group, zinc supplementation increased both gene expression and enzyme activity of SOD (p < 0.01) as well as the levels of insulin (p = 0.02) among the patients in the zinc group. Moreover, there was a meaningful reduction in the levels of FBG, HbA1c and HOMA-IR value (p < 0.001), triglycerides and total cholesterol (p < 0.05) after the zinc treatment.ConclusionsTaken together, the current study suggests that daily supplementation with 50 mg zinc gluconate could be a useful approach for the management of overweight T2DM.Clinical Trial Registration: IRCT2015083102.