抵抗素、超敏C反应蛋白及血脂水平与2型糖尿病并发心血管病变的相关性研究

目的观察血清抵抗素、超敏C反应蛋白(hs-CRP)及血脂在2型糖尿病(T2DM)并发心血管病变患者中水平的变化及其相关关系。方法选择单纯T2DM组50例,T2DM合并心血管病变组50例,分别测定血清抵抗素、hs-CRP及血脂等指标,以5 0名健康人作正常对照。结果 T2 DM合并心血管病变组血清抵抗素和hs-CRP水平分别为(1 6.9 9±7.1 3)ng/mL、(4.9 7±2.88)mg/L,高于单纯T2DM组的(12.98±6.15)ng/mL、(3.61±1.49)mg/L,且均明显高于对照组的(9.32±4.46)ng/mL及(1.34±0.95)mg/L,3组两两比较差异有统计学意义(P<0.01)。T2DM组血脂水平除高密度脂蛋白胆固醇降低外,其余均比对照组明显升高(P<0.01),而T2DM组之间比较无统计学意义(P>0.05)。T2DM合并心血管病变组血清抵抗素水平与hs-CRP呈正相关(r=0.304,P<0.05),而与血脂水平无相关性(P>0.05)。结论血清抵抗素及hs-CRP可能作为炎症因子参与T2DM并发心血管病变发病机制,动态检测及时干预,可能有助于控制血管并发症的发生、发展。     

Rates of myocardial infarction and stroke in patients initiating treatment with SGLT2‐inhibitors versus other glucose‐lowering agents in real‐world clinical practice: Results from the CVD‐REAL study

The multinational, observational CVD‐REAL study recently showed that initiation of sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2i) was associated with significantly lower rates of death and heart failure vs other glucose‐lowering drugs (oGLDs). This sub‐analysis of the CVD‐REAL study sought to determine the association between initiation of SGLT‐2i vs oGLDs and rates of myocardial infarction (MI) and stroke. Medical records, claims and national registers from the USA, Sweden, Norway and Denmark were used to identify patients with T2D who newly initiated treatment with SGLT‐2i (canagliflozin, dapagliflozin or empagliflozin) or oGLDs. A non‐parsimonious propensity score was developed within each country to predict initiation of SGLT‐2i, and patients were matched 1:1 in the treatment groups. Pooled hazard ratios (HRs) and 95% CIs were generated using Cox regression models. Overall, 205 160 patients were included. In the intent‐to‐treat analysis, over 188 551 and 188 678 person‐years of follow‐up (MI and stroke, respectively), there were 1077 MI and 968 stroke events. Initiation of SGLT‐2i vs oGLD was associated with a modestly lower risk of MI and stroke (MI: HR, 0.85; 95%CI, 0.72‐1.00; P = .05; Stroke: HR, 0.83; 95% CI, 0.71‐0.97; P = .02). These findings complement the results of the cardiovascular outcomes trials, and offer additional reassurance with regard to the cardiovascular effects of SGLT‐2i, specifically as it relates to ischaemic events.     

Safety and tolerability of dapagliflozin,saxagliptin and metformin in combination: Post‐hoc analysis of concomitant add‐on versus sequential add‐on to metformin and of triple versus dual therapy with metformin

The safety of triple oral therapy with dapagliflozin plus saxagliptin plus metformin versus dual therapy with dapagliflozin or saxagliptin plus metformin was compared in a post‐hoc analysis of 3 randomized trials of sequential or concomitant add‐on of dapagliflozin and saxagliptin to metformin. In the concomitant add‐on trial, patients with type 2 diabetes on stable metformin received dapagliflozin 10 mg/d plus saxagliptin 5 mg/d. In sequential add‐on trials, patients on metformin plus either saxagliptin 5 mg/d or dapagliflozin 10 mg/d received dapagliflozin 10 mg/d or saxagliptin 5 mg/d, respectively, as add‐on therapy. After 24 weeks, incidences of adverse events and serious adverse events were similar between triple and dual therapy and between concomitant and sequential add‐on regimens. Urinary tract infections were more common with sequential than with concomitant add‐on therapy; genital infections were reported only with sequential add‐on of dapagliflozin to saxagliptin plus metformin. Hypoglycaemia incidence was <2.0% across all analysis groups. In conclusion, the safety and tolerability of triple therapy with dapagliflozin, saxagliptin and metformin, as either concomitant or sequential add‐on, were similar to dual therapy with either agent added to metformin.     

Increased Arterial Augmentation and Augmentation Index as Surrogate Parameters for Arteriosclerosis in Subjects with Diabetes Mellitus and Nondiabetic Subjects with Cardiovascular Disease

Background

Arterial augmentation (AP) and the augmentation index (Aix) are surrogate parameters of arterial stiffness and are commonly used as predictors for cardiovascular risk. The aim of this study is to compare these parameters in diabetic subjects and nondiabetic cardiovascular risk subjects with healthy control subjects.

Methods

One hundred sixty-six nonsmoking subjects aged between 35 and 70 years were included in the study, which included 100 subjects with cardiovascular disease but not diabetes (mean age 62.73±8.75 years), 33 subjects with type 2 diabetes (66.58±2.69 years), and 33 healthy controls (51.89±8.91 years). In these subjects, arterial stiffness was measured by the difference between the second and the first systolic peak of the central pressure waveform, and the Aix was calculated as the percentage of Aix from pulse pressure.

Results

Arterial augmentation was increased in subjects with diabetes (DM) with 10.21±6.97 mm Hg and in subjects with cardiovascular disease but not diabetes (CV) with 10.74±5.29 mm Hg in comparison to healthy controls (C) with 6.59±3.97 mm Hg (p < 0.0005 DM vs C; p < 0.00005 CV vs C). Moreover, Aix was increased with 26.00±9.91% in CV subjects compared to healthy controls with 19.84±9.37% (p < 0.02 CV vs C). The augmentation index was increased with 21.12±11.21% in subjects with type 2 diabetes mellitus compared to controls, but failed to be statistically significant. There was no statistical significance in arterial augmentation or the augmentation index between CV and diabetic subjects.

Conclusion

The results of our study revealed a comparable increased augmentation index as a surrogate measure of arterial stiffness and arteriosclerosis in subjects with diabetes mellitus and in nondiabetic subjects with cardiovascular disease.     

Effects of exenatide once weekly plus dapagliflozin,exenatide once weekly,or dapagliflozin,added to metformin monotherapy,on body weight,systolic blood pressure,and triglycerides in patients with type 2 diabetes in the DURATION‐8 study

This post hoc analysis assessed the effects on cardiovascular risk factors of body weight, systolic blood pressure (SBP) and triglycerides after 28 weeks’ treatment with exenatide once weekly plus dapagliflozin, as compared with exenatide once weekly or dapagliflozin, in patient subpopulations from the DURATION‐8 trial of patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin alone. Subgroups of patients were stratified according to their baseline body weight, SBP and triglyceride levels. Body weight, SBP and triglyceride levels were reduced across most respective subgroups, with no significant subgroup‐by‐treatment interactions. For each treatment, weight loss was numerically greater as baseline body mass index increased. SBP reductions were greater among patients with SBP ≥140 vs <140 mm Hg for exenatide once weekly plus dapagliflozin and exenatide once weekly. Reductions in triglyceride levels were greater among patients with baseline triglycerides <1.69 vs ≥1.69 mmol/L for each treatment. The combination of exenatide once weekly plus dapagliflozin reduced cardiovascular risk factors across baseline subgroups for each variable to a greater extent than did either individual drug; the greatest effects were observed in the high baseline subgroups for body weight and SBP.     

Effects of exenatide once weekly plus dapagliflozin,exenatide once weekly alone,or dapagliflozin alone added to metformin monotherapy in subgroups of patients with type 2 diabetes in the DURATION‐8 randomized controlled trial

This analysis assessed whether responses with exenatide once weekly plus dapagliflozin (n = 231), exenatide once weekly alone (n = 230), or dapagliflozin alone (n = 233) differed in key patient subpopulations of the DURATION‐8 trial. Potential treatment‐by‐subgroup interactions for changes in glycated haemoglobin (HbA1c) and body weight after 28 weeks were evaluated among subgroups determined by baseline HbA1c, age, sex, body mass index, type 2 diabetes duration, race, ethnicity and estimated glomerular filtration rate (eGFR). Exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all subgroups: least‐squares mean reductions ranged from ?8.4 to ?26.1 mmol/mol (?0.77% to ?2.39%) for HbA1c and from ?2.07 to ?4.55 kg for body weight. Potential treatment‐by‐subgroup interactions (P < .10) were found for HbA1c change by age (P = .016) and eGFR (P = .097). Age subgroup analysis findings were not consistent with expected mechanistic effects, with the small number of patients aged ≥65 years (n = 74 vs n = 499 for patients aged <65 years) limiting the interpretability of the interaction term. In the exenatide once weekly plus dapagliflozin and dapagliflozin groups, but not the exenatide once weekly group, HbA1c reductions were greater among patients with eGFR ≥90 vs ≥60 to <90 mL/min/1.73 m² (least‐squares mean reductions of ?23.6 vs ?19.0 mmol/mol [?2.16% vs ?1.74%], ?17.3 vs ?12.0 mmol/mol [?1.58% vs ?1.10%], and ?17.7 vs ?16.9 mmol/mol [?1.62% vs ?1.55%] for the respective treatments); this was consistent with the mechanism of action of dapagliflozin. A potential treatment‐by‐subgroup interaction was observed for change in body weight by sex (P = .099), with greater weight loss for women vs men across all treatments (range ?2.56 to ?3.98 kg vs ?0.56 to ?2.99 kg). In conclusion, treatment with exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all patient subgroups and was more effective than exenatide once weekly or dapagliflozin alone in all adequately sized subgroups.     

Prediction of Five-Year Cardiovascular Disease Risk in People with Type 2 Diabetes Mellitus: Derivation in Nanjing,China and External Validation in Scotland,UK

Background:To use routinely collected data to develop a five-year cardiovascular disease (CVD) risk prediction model for Chinese adults with type 2 diabetes with validation of its performance in a population of European ancestry.Methods:People with incident type 2 diabetes and no history of CVD at diagnosis of diabetes between 2008 and 2017 were included in derivation and validation cohorts. The derivation cohort was identified from a pseudonymized research extract of data from the First Affiliated Hospital of Nanjing Medical University (NMU). Five-year risk of CVD was estimated using basic and extended Cox proportional hazards regression models including 6 and 11 predictors respectively. The risk prediction models were internally validated and externally validated in a Scottish population–based cohort with CVD events identified from linked hospital records. Discrimination and calibration were assessed using Harrell’s C-statistic and calibration plots, respectively.Results:Mean age of the derivation and validation cohorts were 58.4 and 59.2 years, respectively, with 53.5% and 56.9% men. During a median follow-up time of 4.75 [2.67, 7.42] years, 18,827 (22.25%) of the 84,630 people in the NMU-Diabetes cohort and 8,763 (7.31%) of the Scottish cohort of 119,891 people developed CVD. The extended model had a C-statistic of 0.723 [0.721–0.724] in internal validation and 0.716 [0.713–0.719] in external validation.Conclusions:It is possible to generate a risk prediction model with moderate discriminative power in internal and external validation derived from routinely collected Chinese hospital data. The proposed risk score could be used to improve CVD prevention in people with diabetes.     

Efficacy and safety of triple therapy with dapagliflozin add‐on to saxagliptin plus metformin over 52 weeks in patients with type 2 diabetes

We previously reported that dapagliflozin versus placebo as add‐on to saxagliptin plus metformin resulted in greater reductions in glycated haemoglobin (A1C), fasting plasma glucose (FPG) and body weight (BW) after 24 weeks of treatment in patients with type 2 diabetes (T2D). Here we report results after 52 weeks of treatment. Patients stabilized on open‐label metformin and saxagliptin 5 mg/day for 8‐16 weeks were randomized to placebo or dapagliflozin 10 mg/day plus open‐label saxagliptin plus metformin for 52 weeks. Changes from baseline to week 52 were greater with dapagliflozin versus placebo in A1C (?0.74% vs. 0.07%), FPG (?27 vs. 10 mg/dL) and BW (?2.1 vs. ?0.4 kg). More patients achieved A1C <7% with dapagliflozin (29.4%) versus placebo (12.6%). Adverse events were similar with dapagliflozin (66%) and placebo (71%), and hypoglycaemia was rare (≤2%). Genital infections occurred more often with dapagliflozin (6%) than with placebo (1%); frequency of urinary tract infections was similar between the two groups (9% vs. 10%). Triple therapy with dapagliflozin add‐on to saxagliptin plus metformin is a durable, effective and well‐tolerated intervention for the treatment of T2D.     

Effects of dapagliflozin on insulin‐requirement,glucose excretion and ß‐hydroxybutyrate levels are not related to baseline HbA1c in youth with type 1 diabetes

Youth with type 1 diabetes (T1D) infrequently achieve HbA1c targets. Therefore, this placebo‐controlled, randomized, crossover study was set up to assess the safety, effect and pharmacokinetics of a single dose of 10 mg dapagliflozin (DAPA) as add‐on to insulin in relationship to HbA1c in youth. A total of 33 youths (14 males, median age 16 years, diabetes duration 8 years) were included and stratified into 3 baseline HbA1c categories (<7.5%, 7.5%‐9.0% or >9.0; n = 11 each). During the study period of 24 hours, intravenous insulin administration and glucose‐infusion kept blood glucose levels at 160 to 220 mg/dL. DAPA reduced mean insulin dose by 13.6% ( P < .0001 by ANOVA) and increased urinary glucose excretion by 610% (143.4 vs 22.4 g/24 h; P < .0001), both irrespective of baseline HbA1c. Six independent episodes in 6 patients with plasma ß‐hydroxybutyrate levels between ≥0.6 and <1.0 mmol/L were observed after liquid meal challenges, 5 episodes in the DAPA group and 1 in the placebo group. This study provides a proof‐of‐concept, irrespective of preexisting HbA1c levels, for adjunct SGLT2‐inhibitor therapy in the paediatric age group by lowering insulin dose and increasing glucose excretion.