Comparison of glycaemic control and cardiovascular risk profile in patients with type 2 diabetes during treatment with either repaglinide or metformin

Objective: To compare glycaemic control and cardiovascular risk profile in patients with type 2 diabetes following 12 months’ treatment with either repaglinide or metformin. Study design and methods: This was an open uncontrolled randomised study in n=112 patients with inadequately controlled type 2 diabetes not previously treated with oral hypoglycaemic agents. Patients beginning treatment with either repaglinide or metformin entered an 8-week titration period (to optimise dosage: repaglinide, 2–4 mg/day; metformin, 1500–2500 mg/day) followed by a 12-month treatment period. Glycaemic control and cardiovascular risk factors were determined at baseline and at the end of the treatment period. Results: Mean (S.D.) final drug doses were 3 (±1) mg/day in the repaglinide group and 2000 (±500) mg/day in the metformin group. Significant improvements in glycaemic control [glycated haemoglobin, fasting and 2-h postprandial plasma glucose (PPG)] were demonstrated in both treatment groups. The decrease in PPG was significantly greater in the repaglinide group (P<0.05). During the treatment period, fasting plasma insulin (FPI) decreased significantly in both groups, more so with metformin (P<0.05). Two-hour postprandial plasma insulin (PPI) levels decreased only in the metformin group (P<0.05). Significant improvements between baseline and final visit were demonstrated in one or both groups in the following cardiovascular risk factors: total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, plasminogen activator inhibitor, lipoprotein(a) and homocysteine. No changes were observed in high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I, apolipoprotein B, fibrinogen, body mass index (BMI) or blood pressure. Conclusions: The use of repaglinide or metformin in drug therapy-naïve patients with type 2 diabetes over a 12-month period is associated with improvements in both glycaemic control and cardiovascular risk profile. The latter cannot necessarily be attributed to the pharmacotherapy per se, but provides reassurance in the context of initiating oral hypoglycaemic drug therapy with these agents.     

Comparable long-term mortality risk associated with individual sulfonylureas in diabetes patients with heart failure

Aims

The aim was to investigate the outcomes of individual sulfonylureas in patients with heart failure (HF).

Methods

All patients hospitalized with HF for the first time in 1997-2006, alive 30 days after discharge, and who received anti-diabetic monotherapy with glimepiride (n = 1097), glibenclamide (glyburide) (n = 1031), glipizide (n = 557), gliclazide (n = 251), or tolbutamide (n = 541) were identified from nationwide registers. Risk of all-cause mortality was assessed by multivariable Cox regression models.

Results

Over the median observational time of 744 (Inter Quartile Range 268-1451) days, 2242 patients (64%) died. The analysis demonstrated similar hazard ratio (HR) for mortality for treatment with glimepiride (1.10 [95% confidence interval 0.92-1.33]), glibenclamide (1.12 [0.93-1.34]), glipizide (1.14 [0.93-1.38]), tolbutamide (1.04 [0.85-1.26]), and gliclazide (reference). Grouped according to pancreatic specificity, i.e., with tolbutamide, glipizide, and gliclazide as specific, and glibenclamide, and glimepiride as non-specific agents, no differential prognosis was found between the two groups (HR 1.04 [0.96-1.14], for non-specific, compared to pancreas specific agents). The prognosis was not dependent on prior acute myocardial infarction or ischemic heart disease (p for interactions >0.3).

Conclusions

In current clinical practice, it is unlikely that there are considerable differences in risk of mortality associated with individual sulfonylureas in patients with heart failure.     

Cardiovascular and mortality outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: A meta-analysis with the FREEDOM cardiovascular outcomes trial

Background and aimsFREEDOM, a cardiovascular outcome trial with a GLP-1 receptor agonist, testing a continuous subcutaneous infusion of exenatide (ITCA 650), recently reported its findings.MethodsWe meta-analysed its results with eight prior GLP-1 receptor agonists trials.ResultsGLP-1 receptor agonists reduced MACE by 13% (HR 0.87 [95% CI 0.81–0.94]; p = 0.00065) and all-cause mortality by 11% (HR 0.89 [0.83–0.95]; p = 0.00084). However, FREEDOM results appear dissimilar to prior GLP-1 receptor agonist trials.ConclusionFREEDOM results should not influence current considerations about the benefits or harms of approved formulations of GLP-1 receptor agonists. There is also an ongoing debate about the safety of ITCA 650.     

二甲双胍对2型糖尿病患者的心血管保护作用:证据及其潜在机制

二甲双胍是治疗2型糖尿病的一线药物.二甲双胍除了具有理想的降糖作用外,还具有一定的心血管保护效应,其中包括预防动脉粥样硬化的发生和发展、降低心血管事件风险、减轻心肌缺血-再灌注损伤、抑制心肌重构、延缓心力衰竭进展等.激活腺苷酸活化的蛋白激酶(AMPK)信号通路在二甲双胍的心血管保护作用中起着至关重要的作用.     

Extracellular vesicles number and cell subtype may be influenced by diabetes mellitus and metformin in patients at high cardiovascular risk

Background and aimsExtracellular vesicles (EV) represent a population of small vesicles deriving from all types of cells, generated by the extroflection of the plasma membrane, and released into the circulation. EV can have both pro- and anti-atherothrombotic effects depending on the clinical setting, origin cell, stimuli, and different treatments might affect their levels. The primary endpoint of our study was to compare the amount of circulating EV and specific EV subtypes derived from platelets, endothelial cells, and leucocytes in subject at high CV risk, with and without T2DM, and if any ongoing anti-diabetic drugs could affect the levels of EV.Methods and resultsThe levels of total EV (d = 0.576; p = 0.049), total Annexin + EV (d = 0.519; p = 0.011), CD41a+/AnnexinV+ platelet derived EV (d = 0.482; p = 0.0187) and CD31 endothelial derived EV (d = 0.590; p = 0.0041) were lower in diabetic patients vs. those without T2DM.Interestingly, after adjustment for variables no significantly different between groups, including HbA1c, differences in EV subtypes were no longer observed. Linear regression analysis showed that HbA1c was inversely related to total EV to (beta coefficients = ?10969; p = 0.0170), CD41a+/AnnexinV+ platelet-derived EV (beta coefficients = ?352.71125; p = 0.0529) and CD31+ endothelial-derived EV (beta coefficients = ?188.01952; p = 0.0095) in all patients. Among subjects with diabetes, CD41+ platelet-derived EV and CD41a+/AnnexinV+ platelet-derived EV (p = 0.0644 and p = 0.0635) were lower in patients on metformin treatment, even after adjustment for gender, hypertension, weight, waist circumference, total cholesterol, diuretics and statins use).ConclusionOur study showed that, among high CV risk patients, treated with the state-of-the-art preventive strategies, T2DM is associated with lower levels of total, platelet-and endothelial-derived EV, and that this difference may be accounted for, at least in part, by hyperglycemia and ongoing treatment with metformin, the most widely prescribed oral antidiabetic agent.     

Risk for cardiovascular events in an Italian population of patients with type 2 diabetes

Background and aim

This study aims to analyse the risk of cardiovascular events in a local cohort of patients with type 2 diabetes, and to evaluate the prognostic accuracy of four algorithms used to estimate cardiovascular risk: the Framingham study, United Kingdom Prospective Diabetes Study (UKPDS), Riskard study and Progetto Cuore.

Method and results

We analysed clinical charts of the Diabetes Clinics of Modena for the period 1991–95. Patients in the age range of 35–65 with type 2 diabetes and no previous cardiovascular disease were eligible. The incidence of new cardiovascular disease was compared with estimated rates deriving from the different functions. A stratification was obtained in subgroups at different cardiovascular risk, allowing comparison between the algorithms. A total of 1532 patients were eligible; women presented a worse cardiovascular risk profile. An absolute 10-year rate of cardiovascular events of 14.9% was observed. Comparing patients with events with event-free subjects, we found significant differences in systolic blood pressure, age at visit, smoking, high-density lipoprotein (HDL)-cholesterol, duration of diabetes, glycosylated haemoglobin (HbA1c) and co-morbidities. Comparing the estimated risk rate according to the different functions, Italian algorithms were more consistent with observed data; however, Progetto Cuore and Riskard show underestimation of events when applied to females.

Conclusions

Estimation of cardiovascular risk is dependent on the algorithm adopted and on the baseline risk of the reference cohort. Functions designed for a specific population, including risk variables peculiar for diabetes, should be adopted to increase the performance of such functions which is clearly unsatisfactory at present.     

拜糖平和美迪康对2型糖尿病降糖作用的临床疗效比较

比较拜糖平和美迪康对２型糖尿病的临床疗效。方法将单纯饮食控制或加用磺脲类药物治疗不满意的２型糖尿病人８０例，随机分为拜糖平组４８例和美迪康组３２例，疗程为１６周。结果与结论美迪康对降空腹血糖的疗效率主同于拜糖平，耐糖平对降餐后２小时血糖的疗效高于美迪康；     

Risk of cardiovascular disease and mortality in overweight and obese patients with type 2 diabetes: an observational study in 13,087 patients

Aims/hypothesis  The aim of this study of type 2 diabetic patients in the Swedish National Diabetes Register was to study the associations of BMI, overweight (BMI 25–29.9 kg/m²) and obesity (BMI ≥ 30 kg/m²) with cardiovascular disease in type 2 diabetes, as these associations have not previously been clarified. Methods  Patients aged 30–74 years with no previous CHD or stroke (N = 13,087) were followed for a mean of 5.6 years until 2003 for fatal or non-fatal CHD, stroke, cardiovascular disease (CHD or stroke) and total mortality. In total, 1,922 cardiovascular-disease events occurred, based on 64,864 person-years. Results  The relative risks of CHD, stroke, cardiovascular disease and total mortality for a 5 unit increase in BMI at baseline were 15%, 11%, 13% and 27%, respectively, using Cox regression analysis, after adjusting for age, sex, diabetes duration, hypoglycaemic treatment and smoking (model 1), and were 9%, 4% (not significant), 7% and 20%, respectively, when adjusting also for HbA_1c, blood pressure, antihypertensive drugs, lipid-reducing drugs and microalbuminuria (model 2). Adjusted hazard ratios (model 1) for CHD, cardiovascular disease and total mortality with overweight were 1.27 (95% CI 1.09–1.48), 1.24 (1.09–1.41) and 1.16 (0.94–1.45), respectively, and 1.49 (1.27–1.76), 1.44 (1.26–1.64) and 1.71 (1.36–2.14) with obesity, as compared with normal weight. Significant hazard ratios were attenuated when adjusted according to model 2. For a 1 unit increase in BMI during follow-up, the relative risk of CHD (model 2) was 1.13 (1.04–1.23; p = 0.005). Conclusions/interpretation  Both overweight and obesity independently increased the risk of CHD and cardiovascular disease in patients with type 2 diabetes. The CHD risk was higher with increasing BMI than with stable or decreasing BMI during the study.     

Glycaemic control and adverse events in patients with type 2 diabetes treated with metformin + sulphonylurea: a meta-analysis

Aim:  The aim of this study was to quantify the effect of a sulphonylurea on glycaemic control and the risk adverse events when incorporated into the treatment regimen of patients with type 2 diabetes inadequately controlled on metformin.
Methods:  A systematic review was carried out to identify randomized controlled trials of sulphonylurea therapy in patients with type 2 diabetes whose glycaemic control was inadequate after maximal treatment with metformin. Data on reductions in haemoglobin A_1C (HbA_1C), fasting plasma glucose (FPG) and risk of hypoglycaemic events were extracted from each study and pooled in meta-analyses. Data on weight change were also extracted and tabulated.
Results:  Six studies including 1364 patients were identified. Based on random effects meta-analysis, the pooled estimate of change in HbA_1C from baseline was 0.9% (95% CI 0.7–1.1, p = 0.00011 vs. baseline) and for change in FPG from baseline was 1.8 mmol/l (95% CI 1.1–2.5, p = 0.0026 vs. baseline). The odds of experiencing a hypoglycaemic event was significantly higher in sulphonylurea-treated patients than in those on comparator treatments (OR = 5.3, 95% CI 1.7–16.3, p = 0.03). Mean weight change ranged from +2.5 to −0.1 kg, depending on the comparator treatment.
Conclusions:  This analysis has demonstrated that, in patients with type 2 diabetes whose control is inadequate on metformin monotherapy, the magnitude of incremental HbA_1C reduction achieved by the addition of a sulphonylurea is unlikely to exceed 1%, even after titration to maximum tolerated doses. Additionally, clinically relevant side-effects such as symptomatic hypoglycaemia and weight gain may be experienced.     

Retrospective comparison of voglibose or acarbose as an add-on therapy to sulfonylureas in Western Indian patients with uncontrolled overweight/obese type 2 diabetes

AimThe study was aimed to investigate the effect of voglibose or acarbose as an add-on treatment in overweight/obese type 2 diabetes (T2DM) patients who are uncontrolled with metformin and sulfonylureas (SUs) in Western part of India.Participants and methodsA retrospective study included 77 participants (BMI ≥ 25 kg/m²; HbA1c level > 8% and < 9.5%) with overweight/obese T2DM. These participants were treated with either voglibose or acarbose. Glycemic parameters (fasting blood glucose and glycated hemoglobin [HbA1c]), bodyweight, BMI and lipid parameters were evaluated at baseline, 3-month, 6-month and 9-month of treatment. Adverse events were also captured at respective time points.ResultsVoglibose showed significant reduction in HbA1c and bodyweight with short duration of treatment (6 months; P < 0.05 and 9 months; P < 0.01) whereas acarbose showed significant reduction with longer duration of treatment (9 months; P < 0.05) when compared with baseline. Moreover, both treatment groups were reported with reduction in BMI. Further, significant improvement in lipid parameters except LDL and HDL were observed in both treatment groups when compared with baseline. None of participant was discontinued due to side effects of the treatment. In addition, the frequency of hypoglycemia was decreased in both treatment groups.ConclusionVoglibose or acarbose as an add-on treatment with metformin and sulfonylureas in uncontrolled obese/overweight T2DM provides desired glycemic control, reduces bodyweight and improves lipid parameters with good tolerability profile.     

Coffee consumption and risk of total and cardiovascular mortality among patients with type 2 diabetes

AIMS/HYPOTHESIS: Higher habitual coffee drinking has been associated with a lower risk of developing type 2 diabetes. The relation between coffee consumption and risk of cardiovascular disease (CVD) has been examined in many studies, but the issue remains controversial. This study was designed to assess the association between coffee consumption and CVD mortality among patients with type 2 diabetes. METHODS: We prospectively followed 3,837 randomly ascertained Finnish patients with type 2 diabetes aged 25 to 74 years. Coffee consumption and other study parameters were determined at baseline. The International Classification of Diseases was used to identify CHD, CVD and stroke cases using computerised record linkage to the national Death Registry. The associations between coffee consumption at baseline and risk of total, CVD, CHD, and stroke mortality were analysed by using Cox proportional hazards models. RESULTS: During the average follow-up of 20.8 years, 1,471 deaths were recorded, of which 909 were coded as CVD, 598 as CHD and 210 as stroke. The respective multivariate-adjusted hazard ratios in participants who drank 0-2, 3-4, 5-6, and > or =7 cups of coffee daily were 1.00, 0.77, 0.68 and 0.70 for total mortality (P<0.001 for trend), 1.00, 0.79, 0.70 and 0.71 for CVD mortality (P=0.006 for trend), 1.00, 0.78, 0.70 and 0.63 for CHD mortality (p=0.01 for trend), and 1.00, 0.77, 0.64 and 0.90 for stroke mortality (p=0.12 for trend). CONCLUSIONS/INTERPRETATION: In this large prospective study we found that in type 2 diabetic patients coffee drinking is associated with reduced total, CVD and CHD mortality.     

吡格列酮与二甲双胍治疗2型糖尿病的疗效对比观察

目的观察吡格列酮与二甲双胍分别治疗2型糖尿病的临床效果。方法将96例首次就诊诊断为2型糖尿病的患者半随机分为对照组和治疗组,各48例。对照组采用二甲双胍治疗,治疗组采用吡格列酮治疗。治疗1个月后,对两组的临床疗效、血糖水平改善情况及不良反应进行对比观察。结果对照组总有效率为87.5%（42/48）,治疗组总有效率为89.6%（43/48）,两组治疗效果差异无统计学意义（P〉0.05）;治疗组空腹血糖和餐后2 h血糖水平改善幅度略大于对照组（P〉0.05）;对照组不良反应的发生率大于治疗组,差异有统计学意义（P〈0.01）。结论二甲双胍、吡格列酮均能有效控制2型糖尿病患者的血糖值。     

Effects of diabetes type 2 and metformin treatment in Swedish patients with colorectal cancer

The association between type 2 diabetes mellitus (DM) and colorectal cancer (CRC) has been thoroughly investigated and reports have demonstrated that the risk of CRC is increased in DM patients. The association between DM and the survival of patients with CRC is controversial. Evidence suggests that metformin with its anti-inflammatory effects is a protective factor against the development of CRC among DM patients and that metformin therapy is associated with a better prognosis in patients with DM. In our cohort, we did not find any associations between the presence of DM or metformin and cancer specific survival or any relation to plasma levels of a panel of 40 inflammatory factors and irisin. On the other hand, we identified that the insulin-like growth factor binding protein 7 single nucleotide polymorphism rs2041437 was associated with DM in CRC patients. The dominance of the T bearing genotypes in patients with DM was statistically significant (P = 0.038), with an odds ratio of 1.66 (95% confidence interval: 1.03-2.69).     

Glyburide increases risk in patients with diabetes mellitus after emergent percutaneous intervention for myocardial infarction — A nationwide study

Background

Sulfonylureas have been linked to an increased cardiovascular risk by inhibition of myocardial preconditioning. Whether individual sulfonylureas affect outcomes in diabetic patients after emergent percutaneous coronary intervention for myocardial infarction is unknown.

Methods

All Danish patients receiving glucose-lowering drugs admitted with myocardial infarction between 1997 and 2006 who underwent emergent percutaneous coronary intervention were identified from national registers. Multivariable Cox proportional hazards models were used to analyze the risk of cardiovascular mortality and morbidity associated with sulfonylureas.

Results

A total of 926 patients were included and 163 (17.6%) patients died during the first year of which 155 (16.7%) were cardiovascular deaths. The most common treatment was sulfonylureas which were received by 271 (29.3%) patients, and 129 (13.9%) received metformin. Cox proportional hazard regression analyses adjusted for age, sex, calendar year, comorbidity and concomitant pharmacotherapy showed an increased risk of cardiovascular mortality (hazard ratio [HR] 2.91, 95% confidence interval [CI] 1.26-6.72 ; p = 0.012), cardiovascular mortality and nonfatal myocardial infarction (HR 2.69 , 95% CI 1.21-6.00; p = 0.016), and all-cause mortality (HR 2.46, 95% CI 1.11-5.47; p = 0.027), respectively, with glyburide compared to metformin.

Conclusions

Glyburide is associated with increased cardiovascular mortality and morbidity in patients with diabetes mellitus undergoing emergent percutaneous coronary intervention after myocardial infarction. Early reperfusion therapy is the mainstay in modern treatment of myocardial infarction and the time may have come to discard glyburide in favour of sulfonylureas that do not appear to confer increased cardiovascular risk.     

Discontinuation of metformin in type 2 diabetes patients treated with insulin

BACKGROUND: Metformin added to insulin therapy in type 2 diabetic patients improves glycaemic control and decreases the required daily dose of insulin (DDI). Metformin should be discontinued if cardiac, hepatic or renal failure develops. We examined whether glycaemic control can be maintained after metformin cessation. METHODS: We included 45 type 2 diabetic patients treated with insulin plus metformin, and 45 matched controls treated with insulin only. After discontinuation of metformin in the first group, we aimed for tight fasting and postprandial blood glucose levels, 4-7 and 4-10 mmol/l, respectively, in both groups. During 12 weeks we assessed glycaemic control every two weeks and, if necessary, adjusted the insulin dosage. RESULTS: In the group in which metformin was discontinued, DDI increased from 67.9 +/- 22.9 to 92.2 +/- 29.4 IU (p < 0.001) leaving glycaemic control unchanged. In the controls, glycated haemoglobin (GHb) decreased by 0.93% (p < 0.001), while DDI increased slightly from 62.4 +/- 22.9 to 72.3 +/- 27.3 IU (p < 0.001). The increase in DDI was larger in patients in whom metformin was discontinued than in the controls (p < 0.001). CONCLUSIONS: In type 2 diabetic patients treated with insulin plus metformin, glycaemic control can be maintained after discontinuation of metformin by increasing the DDI substantially (20 to 36%) during application of an intensified treatment protocol.     

Effect of the combination of mitiglinide and metformin on glycemic control in patients with type 2 diabetes mellitus

Aims/Introduction: Mitiglinide is the newest drug in the meglitinide family. It increases the early‐phase insulin release through rapid association‐dissociation kinetics in the pancreatic β cells. The efficacy and safety of adding meglitinide to metformin monotherapy in patients with type 2 diabetes are unknown. Materials and Methods: We carried out a prospective, randomized, multicenter trial to assess the efficacy and safety of combined treatment with mitiglinide and metformin for patients with type 2 diabetes who showed inadequate glycemic control with metformin monotherapy. Subjects with glycated hemoglobin (HbA_1c) >7.0% after an 8‐week metformin run‐in phase were randomized to a 16‐week trial phase with metformin plus mitiglinide (Met + Mit) or metformin plus placebo (Met + Pcb). Results: Compared with the Met + Pcb group, the Met + Mit group showed a greater reduction in HbA_1c (?0.7 ± 0.6%vs?0.4 ± 0.7%, P = 0.002), fasting plasma glucose (?0.77 ± 1.76 mmol/L vs?0.05 ± 1.60 mmol/L, P = 0.015) and 2‐h postprandial glucose (?3.76 ± 3.57 mmol/L vs?0.84 ± 3.07 mmol/L, P < 0.0001). The proportion of the patients who achieved the target HbA_1c value of <7% at the end of the study was also higher in the Met + Mit group than the Met + Pcb group (49.3%vs 28.8%, P = 0.016). There were no differences in the adverse event rates between groups. Conclusions: Combination therapy with metformin and mitiglinide is effective and safe for the treatment of patients with type 2 diabetes who have inadequate glycemic control with metformin monotherapy. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00023.x, 2010)