Comparison between different types of exercise training in patients with type 2 diabetes mellitus: A systematic review and network metanalysis of randomized controlled trials

AimAim of the present meta-analysis and network metanalysis (NMA) is the assessment of the effects of physical exercise on glucose control and cardiovascular risk factors in type 2 diabetes.Data synthesisThis metanalysis includes all available trials exploring the effects of different exercise modalities in type 2 diabetes, with a duration of ≥3 months. The standardized difference in means (SDM) with 95% Confidence Intervals were calculated. Data were analyzed using MetaXL and Rev Man 5.0. Primary endpoint was the effect of exercise versus no exercise on HbA1c and fasting plasma glucose (FPG) at endpoint. Secondary endpoints were body weight and fat, waist circumference, and blood pressure. A comparison of different exercise training modalities (aerobic, resistance and combined) for the same endpoints was also performed, choosing ‘no exercise’ as the reference for indirect comparisons. We included 25 trials fulfilling all inclusion criteria. Physical exercise versus no exercise produced a small, but significant, improvement of HbA1c, body fat, and systolic blood pressure at endpoint (?0.3 [-0.1;-0.4]%, ?1.44 [-2.22, ?0.66]%, and ?5.6 [-9.5, ?1.6] mmHg, respectively). Combined, supervised aerobic and resistance exercise were associated with a significantly greater reduction of HbA1c (SDM, ?0.4 [-0.6;-0.3], ?0.2 [-0.4;-0.1], and ?0.2 [-0.3;-0.1]%, respectively), but not of FPG, in comparison with no exercise.ConclusionsPhysical exercise produces small, but detectable, advantages on glycemic control and cardiovascular risk factors and should be suggested in type 2 diabetes. Combined aerobic/resistance training seems to be superior to aerobic training alone, but differences are small and the reliability of supporting evidence limited.     

Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin

BACKGROUND: In two placebo-controlled 30-week trials, treatment with exenatide reduced HbA(1c) and body weight in patients with type 2 diabetes in the context of sulphonylurea (SU) or SU plus metformin (MET) as background treatment. This analysis examines the effects of 82 weeks of exenatide treatment for participants in these earlier 30-week trials. METHODS: Data were pooled from the two pivotal trials of exenatide added to SU or SU plus MET. Both 30-week, placebo-controlled trials of 5 microg or 10 microg exenatide b.i.d. were followed by 52-week open-label, uncontrolled extension studies in which all participants received 10 microg exenatide b.i.d. and continued prior oral therapies. This interim analysis includes data for 222 patients who completed 82 weeks of exenatide treatment (61% M, age 57 +/- 10 y, weight 99 +/- 21 kg, BMI 34 +/- 6 kg/m(2), HbA(1c)8.4 +/- 1.0% [mean +/- SD]). RESULTS: Reduction in HbA(1c) from baseline to week 30 (-0.8 +/- 0.1% and -1.0 +/- 0.1% for 5 microg b.i.d. and 10 microg b.i.d., respectively [mean +/- SE]) was sustained up to week 82 (-1.0 +/- 0.1%). Of 207 patients with baseline HbA(1c) > 7%, 44% achieved HbA(1c) < or = 7% at week 82. Reduction of body weight from baseline to week 30 (-1.4 +/- 0.3 kg and -2.1 +/- 0.3 kg for 5 microg b.i.d. and 10 microg b.i.d., respectively) was progressive up to week 82 (-4.0 +/- 0.3 kg). The most frequent adverse events were nausea and hypoglycaemia, both generally mild to moderate in intensity. CONCLUSIONS: Exenatide added to maximally effective doses of SU or SU plus MET resulted in a sustained reduction in HbA(1c) and a progressive reduction in weight over 1 1/2 years.     

Meta-analysis of seven heterogeneous studies on liraglutide add-on therapy in patients with type 2 diabetes mellitus treated with insulin

Background and aimsClinical trials indicate the efficacy of add-on therapy using incretin-related drugs to treat type 2 diabetes mellitus (DM) inadequately controlled by insulin. However, heterogeneity exists among these studies. Baseline body mass index (BMI) accounts for the heterogeneity of add-on therapy with dipeptidyl peptidase-4 (DPP-4) inhibitors and the associated higher BMI with a lower efficacy. The efficacy of add-on therapy with glucagon-like peptide-1 (GLP-1) receptor agonists remains unclear.MethodsWe performed a meta-analysis of randomized controlled trials of ≥12 weeks reporting the endpoint of adjusted mean change in hemoglobin A1c levels (AMΔHbA1c) or hypoglycemia incidence. Patients with type 2 DM treated with insulin alone or with metformin for at least 8 weeks before the study treatment were included. The intervention group received liraglutide co-administered with insulin or a fixed-dose combination. The control group received a placebo or insulin. Covariates included five baseline parameters (HbA1c, fasting plasma glucose, BMI, type 2 DM duration, and treatment duration).ResultsSeven studies (2067 patients) were selected. AMΔHbA1c was ?1.00% (95% confidence interval [CI]: ?1.21 to ?0.78, I² = 74.7%). The odds ratio for hypoglycemia incidence was 0.97 (95% CI: 0.50–1.87, I² = 81.9%). Covariates did not account for the heterogeneity in AMΔHbA1c or hypoglycemia incidence.ConclusionsLiraglutide add-on therapy reduced HbA1c levels without increasing hypoglycemia incidence, independent of BMI, in insulin non-responders with type 2 DM. GLP-1 receptor agonists may be more suitable than DPP-4 inhibitors for add-on therapy in patients with high BMI. Registration number. PROSPERO #CRD42021178888.     

Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial

PURPOSE: To assess the efficacy and safety of adding rosiglitazone to an established regimen of glyburide/metformin in patients with type 2 diabetes who had not achieved adequate glycemic control (glycosylated hemoglobin [HbA1C] levels >7.0% and < or =10.0%). METHODS: Following an open-label, lead-in phase to optimize the dosing of glyburide/metformin tablets, 365 patients randomly received additive therapy comprising rosiglitazone (4 mg once daily) or placebo for 24 weeks. Based on glycemic response, rosiglitazone dose was maintained or increased to 4 mg twice daily. Glyburide/metformin dose was maintained or reduced by 2.5/500 mg for symptomatic hypoglycemia. The primary endpoint was the change in HbA1C level from baseline to week 24. The proportions of patients achieving HbA1C levels <7% and a fasting plasma glucose level <126 mg/dL were also assessed. RESULTS: After 24 weeks, therapy with glyburide/metformin plus rosiglitazone resulted in a greater reduction in HbA1C levels (-1.0%, P<0.001) compared with combination therapy that included placebo, and in a larger proportion of patients (42% vs. 14%) who attained levels <7%. The difference in fasting plasma glucose levels between groups was -48 mg/dL (P<0.001), favoring glyburide/metformin plus rosiglitazone. The adverse event profile in the rosiglitazone-treated group included mild-to-moderate edema (8%), hypoglycemia (22%), and weight gain of 3 kg. No patient experienced hypoglycemia requiring third-party assistance. CONCLUSION: In patients with inadequate glycemic control despite established glyburide/metformin therapy, the addition of rosiglitazone improves glycemic control, allowing more patients to achieve an HbA1C level <7% and perhaps delaying the need for insulin treatment.     

Nateglinide or gliclazide in combination with metformin for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone: 1-year trial results

AIM: To compare long-term efficacy and safety of nateglinide plus metformin with those of gliclazide plus metformin in patients with type 2 diabetes not adequately controlled with metformin monotherapy. METHODS: Double-blind, double-dummy, multicentre study extended to a total of 52 weeks. Patients with inadequate glucose control on maximal doses of metformin were randomized to nateglinide (N = 133) or gliclazide (N = 129) add-on treatment. After the initial 6-month study, the majority of patients in the nateglinide group [n = 112 (93.3%)] and in the gliclazide group [n = 101 (92.7%)] entered a 6-month, double-blind, extension study. RESULTS: There was no significant difference between treatment regimens in haemoglobin Alc (HbA1c) change from baseline to 52 weeks (-0.14% for nateglinide vs. -0.27% for gliclazide; p = 0.396). Proportions of patients achieving an endpoint HbA1c of <7% were similar (40 vs. 47.4%) for nateglinide and gliclazide groups. There was no significant between-treatment difference in fasting plasma glucose change from baseline to 52 weeks (nateglinide: -0.2 mmol/l and gliclazide: -0.7 mmol/l; p = 0.096). The decreases in prandial plasma glucose area under the curve(0-4 h) from baseline were -3.26 and -1.86 h x mmol/l in the nateglinide and the gliclazide groups respectively, and the change was statistically significant in the nateglinide group only (p = 0.006). Initial insulin response to a meal was augmented with nateglinide treatment only, without between-treatment difference in 2-h insulin response. The overall rate of hypoglycaemic events was similar with nateglinide and gliclazide combinations with metformin. Nateglinide plus metformin treatment was not associated with weight gain. CONCLUSIONS: No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in terms of HbA1c. Treatment with nateglinide plus metformin for up to 12 months was not associated with weight gain.     

A double-blind randomized study comparing the effects of continuing or not continuing rosiglitazone + metformin therapy when starting insulin therapy in people with Type 2 diabetes.

AIMS: To compare the efficacy and safety of either continuing or discontinuing rosiglitazone + metformin fixed-dose combination when starting insulin therapy in people with Type 2 diabetes inadequately controlled on oral therapy. METHODS: In this 24-week double-blind study, 324 individuals with Type 2 diabetes inadequately controlled on maximum dose rosiglitazone + metformin therapy were randomly assigned to twice-daily premix insulin therapy (target pre-breakfast and pre-evening meal glucose < or = 6.5 mmol/l) in addition to either rosiglitazone + metformin (8/2000 mg) or placebo. RESULTS: Insulin dose at week 24 was significantly lower with rosiglitazone + metformin (33.5 +/- 1.5 U/day, mean +/- se) compared with placebo [59.0 +/- 3.0 U/day; model-adjusted difference -26.6 (95% CI -37.7, -15,5) U/day, P < 0.001]. Despite this, there was greater improvement in glycaemic control [HbA(1c) rosiglitazone + metformin vs. placebo 6.8 +/- 0.1 vs. 7.5 +/- 0.1%; difference -0.7 (-0.8, -0.5)%, P < 0.001] and more individuals achieved glycaemic targets (HbA(1c) < 7.0% 70 vs. 34%, P < 0.001). The proportion of individuals reporting at least one hypoglycaemic event during the last 12 weeks of treatment was similar in the two groups (rosiglitazone + metformin vs. placebo 25 vs. 27%). People receiving rosiglitazone + metformin in addition to insulin reported greater treatment satisfaction than those receiving insulin alone. Both treatment regimens were well tolerated but more participants had oedema [12 (7%) vs. 4 (3%)] and there was more weight gain [3.7 vs. 2.6 kg; difference 1.1 (0.2, 2.1) kg, P = 0.02] with rosiglitazone + metformin. CONCLUSIONS: Addition of insulin to rosiglitazone + metformin enabled more people to reach glycaemic targets with less insulin, and was generally well tolerated.     

Continuing metformin when starting insulin in patients with Type 2 diabetes: a double-blind randomized placebo-controlled trial.

AIMS: To test the effect of continuing metformin on weight gain and glycaemic control in patients with poorly controlled Type 2 diabetes who need to start insulin. METHODS: Patients with Type 2 diabetes on maximum tolerated oral agents referred for insulin conversion were recruited from hospital diabetes clinics into a double-blind randomized placebo-controlled trial. The 183 participants received metformin or placebo, titrated up to 2 g a day or maximum tolerated dose, with insulin started according to local practice. The main outcome measures were weight change over 12 months, HbA1c, insulin dose, frequency of hypoglycaemia, treatment satisfaction, and well-being. RESULTS: Over 12 months, metformin was associated with less weight gain than placebo [mean 6.1 kg vs. 7.6 kg; adjusted difference 1.5 kg (95% confidence interval 0.2-2.9); P=0.02], a greater reduction in HbA1c[1.5% vs. 1.3%; adjusted difference 0.5% (0.1-0.9); P=0.02] and a lower insulin requirement [62 units vs. 86; adjusted difference 25 units (15-34); P<0.001], but also more hypoglycaemia [relative risk of any episode 1.24 (1.02-1.1); P=0.03]. Treatment satisfaction improved more in patients on metformin than on placebo (P<0.001), as did the positive well-being score (P=0.02). CONCLUSIONS: Metformin decreases weight gain, lowers insulin requirement, and improves glycaemic control, and should be continued in patients with Type 2 diabetes who transfer to insulin.     

Efficacy and safety of sitagliptin as compared with glimepiride in Japanese patients with type 2 diabetes mellitus aged ≥ 60 years (START‐J trial)

The aim of this study was to evaluate the efficacy and safety of sitagliptin administered to elderly patients with type 2 diabetes mellitus (T2DM) for 1 year as compared with glimepiride. Patients aged ≥60 years with T2DM and inadequately controlled blood glucose were randomly assigned to sitagliptin 50 mg once daily or glimepiride 0.5 mg once daily for 52 weeks. The primary efficacy endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 52. Secondary efficacy endpoints included self‐monitored blood glucose and weight. Safety endpoints were adverse events including hypoglycaemia. Administration of sitagliptin or glimepiride to elderly patients with T2DM resulted in a significant decrease in HbA1c change from baseline. At 52 weeks, the least squares mean difference between the treatments was 0.11% (95% confidence interval [CI] ?0.02 to 0.24; P = .087) (1.2 mmol/mol [?0.2 to 2.6]). The upper limit of the CI was below the predefined non‐inferiority margin (0.3% [3.3 mmol/mol]), demonstrating non‐inferiority of sitagliptin to glimepiride for the primary endpoint. Sitagliptin resulted in a significantly lower incidence rate of non‐serious hypoglycaemia than glimepiride during the 52 weeks (4.7% vs 16.1%; P = .002); thus, sitagliptin is a useful therapeutic option for elderly patients with T2DM.     

Once-weekly dulaglutide versus insulin glargine in the early control of fasting serum glucose and HbA1c

AimsTo determine the early benefit:risk balance of dulaglutide versus insulin glargine in patients with type 2 diabetes mellitus (T2DM).MethodsThis post hoc analysis used data from a randomized, open-label study (AWARD-2; modified intention-to-treat group) in which suboptimally controlled metformin + glimepiride-treated patients received dulaglutide 1.5 mg (n = 273) or insulin glargine (n = 262). Two composite endpoints were used: for weeks 2–20, fasting serum glucose (FSG) <130 mg/dL (<7.2 mmol/L) without hypoglycemia (blood glucose ≤70 mg/dL [≤3.9 mmol/L] or severe hypoglycemia); at week 26, patients with glycated hemoglobin (HbA1c) <7.0% (<53.0 mmol/mol) or reduction from baseline ≥1.0% (≥10.9 mmol/mol), no hypoglycemia (as defined above) and no weight gain. Odds ratios (ORs) were generated using logistic regression analysis.ResultsThe probability of reaching the FSG target without hypoglycemia was higher with dulaglutide than with insulin glargine at weeks 4 (OR 1.78; 95% confidence interval [CI] 1.22–2.60) and 8 (OR 1.69; 95% CI 1.15–2.48). The proportion of patients achieving the 26-week endpoint was higher with dulaglutide (37.4% vs. 10.3%; OR 5.28; 95% CI 3.28–8.48).ConclusionsDulaglutide's balanced efficacy-to-safety profile compares favorably with that of insulin glargine and is apparent soon after treatment initiation and after 6 months of therapy.     

DUAL I China: Improved glycemic control with IDegLira versus its individual components in a randomized trial with Chinese participants with type 2 diabetes uncontrolled on oral antidiabetic drugs

BackgroundDUAL I China, one of the DUAL trials, assessed efficacy/safety of insulin degludec/liraglutide (IDegLira) in Chinese adults with type 2 diabetes (T2D) not controlled by oral antidiabetic drugs (OADs).MethodsThis phase 3a, treat‐to‐target multicenter trial randomized participants (glycated hemoglobin [HbA1c] 53.0‐85.8 mmol/mol; previous metformin ± another OAD) 2:1:1 to IDegLira (n = 361), degludec (n = 179), or liraglutide (n = 180). Primary endpoint was change in HbA1c after 26 weeks. Secondary endpoints included: HbA1c < 53.0 mmol/mol attainment, weight change, treatment‐emergent hypoglycemia, end‐of‐treatment insulin dose, and safety.ResultsAt 26 weeks, HbA1c had decreased by a mean 18.12 mmoL/moL (IDegLira), 12.37 mmoL/moL (degludec) (estimated treatment difference [ETD] −6.50 mmoL/moL; 95% confidence interval [CI] −7.96, −5.04; P < .0001), and 11.33 mmoL/moL (liraglutide) (ETD −6.87 mmoL/moL; 95% CI −8.33, −5.41; P < 0.0001), indicating noninferiority for IDegLira vs degludec and superiority vs liraglutide. HbA1c < 53.0 mmoL/moL attainment was 77.0% (IDegLira), 46.4% (degludec), and 48.3% (liraglutide). Mean weight change with IDegLira (0.1 kg) was superior to degludec (1.2 kg) (ETD −1.08 kg; 96% CI −1.55, −0.62; P < 0.0001). Severe or confirmed hypoglycemic event rates were 0.24 (IDegLira) and 0.17 (degludec) episodes/participant‐year (estimated rate ratio 1.46; 95% CI 0.71, 3.02; P = .3008, not significant). At the end of treatment, the IDegLira insulin dose was lower (24.5 U/d) vs degludec (30.3 U/d) (ETD −5.49 U; 95% CI −7.77, −3.21; P < 0.0001). No unexpected safety issues occurred.ConclusionsIDegLira is efficacious and well tolerated in Chinese adults with T2D not controlled by OADs.     

Effect of metformin on all-cause mortality and major adverse cardiovascular events: An updated meta-analysis of randomized controlled trials

AimsThe Italian Society of Diabetology and the Italian Association of Clinical Diabetologists are developing new guidelines for drug treatment of type 2 diabetes. The effects of anti-hyperglycaemic drugs on all-cause mortality and major adverse cardiovascular events (MACEs) were included among the critical clinical outcomes. We have therefore carried out an updated meta-analysis on the effects of metformin on these outcomes.Data synthesisA MEDLINE and EMBASE search was performed to identify all randomized controlled trials (RCTs) with duration ≥52 weeks (published up to August 2020), in which metformin was compared with either placebo/no therapy or active comparators. MACEs (restricted for RCT reporting MACEs within their study endpoints) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified endpoints) were considered as the primary endpoints. Mantel-Haenszel odds ratio (MH–OR) with 95% confidence interval was calculated for all endpoints considered. Metformin was associated with a nonsignificant reduction of all-cause mortality (n = 13 RCTs; MH–OR 0.80 [95% CI 0.60, 1.07]). However, this association became statistically significant after excluding RCTs comparing metformin with sulfonylureas, SGLT-2 inhibitors or GLP-1 analogues (MH–OR 0.71 [0.51, 0.99]). Metformin was associated with a lower risk of MACEs compared with comparator treatments (n = 2 RCTs; MH–OR 0.52 [0.37, 0.73]), p < 0.001. Similar results were obtained in a post-hoc analysis including all RCTs fulfilling criteria for inclusion in the analysis (MH–OR: 0.57 [0.42, 0.76]).ConclusionsThis updated meta-analysis suggests that metfomin is significantly associated with lower risk of MACEs and tendentially lower all-cause mortality compared to placebo or other anti-hyperglycaemic drugs.     

Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo‐controlled randomized study

Aims

To assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin.

Materials and Methods

In this double‐blind randomized study ( Clinicaltrials.gov NCT02036515), patients (glycated haemoglobin [HbA1c] 7.0% to 10.5% [53‐91 mmol/mol] receiving metformin ≥1500 mg/d and sitagliptin 100 mg/d; estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m²) were randomized to ertugliflozin 5 mg once‐daily, 15 mg once‐daily or placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 26; treatment was continued until Week 52.

Results

A total of 464 patients were randomized (mean baseline HbA1c, 8.0% [64.3 mmol/mol]; eGFR, 87.9 mL/min/1.73 m²). After 26 weeks, placebo‐adjusted least squares (LS) mean changes in HbA1c from baseline were ?0.7% (?7.5 mmol/mol) and ?0.8% (?8.3 mmol/mol) for ertugliflozin 5 and 15 mg, respectively (both P < .001); 17.0%, 32.1% and 39.9% of patients receiving placebo, ertugliflozin 5 mg or ertugliflozin 15 mg, respectively, had HbA1c <7.0% (53 mmol/mol). Significant reductions in fasting plasma glucose, body weight (BW) and systolic blood pressure (SBP) were observed with ertugliflozin relative to placebo. The positive effects of ertugliflozin on glycaemic control, BW and SBP were maintained through Week 52. A higher incidence of genital mycotic infections was observed in male and female patients receiving ertugliflozin (3.7%‐14.1%) vs placebo (0%‐1.9%) through Week 52. The incidence of urinary tract infections, symptomatic hypoglycaemia and hypovolaemia adverse events were not meaningfully different across groups.

Conclusions

Ertugliflozin added to metformin and sitagliptin was well‐tolerated, and provided clinically meaningful, durable glycaemic control, BW and SBP reductions vs placebo over 52 weeks.     

Predictors of adverse in-hospital outcome and recovery in patients with diabetes mellitus and COVID-19 pneumonia in Iraq

Background and aimsThere is limited data about the prognosis and impact of COVID-19 pneumonia on patients with diabetes mellitus (DM). We aimed to assess blood indices, ECG markers of sudden death and malignant arrhythmias on admission, and diabetes lowering drugs as possible predictors of adverse in-hospital outcome and COVID-19 pneumonia recovery status.MethodsA retrospective study included patients with newly diagnosed COVID-19 pneumonia from August 20, to October 5, 2020.ResultsA total of 192 patients with COVID-19 pneumonia were included in the present study, of whom 67 patients had DM. Low lymphocytes % [0.4(0.1–0.9), P = .011] and QTc interval prolongation [0.4(0.1–0.8), P = .022] were associated with increased length of ICU stay. On the other hand, metformin use [0.3(0.2–4), P = .032] and DPP-4 inhibitors use [0.3(0.2–3), P = .040] were associated with decreased length of ICU stay. QTc interval prolongation [0.4(0.1–0.9), P = .017] was associated with increased length of hospital stay, while using metformin [0.4(0.2–3), P = .022] was associated with decreased length of hospital stay. Low lymphocytes % [0.5(0.4–1.6), P = .001], insulin use [0.4(0.3–5), P = .003], and old age [0.5(0.1–2.3), P = .025] were associated with extensive lung injury. The risk for in-hospital death was associated with high neutrophil% [1(1–1.4), P = .045], while metformin use was associated with decreased risk for in-hospital death [0.1(0.1–0.6), P = .025]. Insulin use [0.3(0.2–4), P = .013] was associated with partial recovery following acute COVID pneumonia.ConclusionsMetformin and DPP-4 inhibitors use were associated with favorable in-hospital outcomes, while insulin use was associated with extensive lung injury and post-acute COVID-19 pneumonia partial recovery.     

西格列汀联合二甲双胍治疗老年2型糖尿病疗效分析

目的探讨单服二甲双胍(metformin)治疗未达标的老年2型糖尿病患者(T2DM)加用西格列汀(sitagliptin)的有效性及安全性。方法入选2015年5月至2016年9月中关村医院内分泌科单服二甲双胍控制不佳的老年T2DM患者52例,其中男性30例,女性22例,年龄65~78(68.0±8.0)岁。随机分成西格列汀组和阿卡波糖(acarbose)组,每组26例(男性15例,女性11例)。西格列汀组患者口服西格列汀100 mg/次,1次/d,阿卡波糖组患者口服阿卡波糖50 mg/次,3次/d,两组患者同时口服二甲双胍500 mg/次,3次/d,连续治疗12周。观察两组患者服药12周后空腹血糖(FPG)、餐后2h血糖(2hPG)、糖化血红蛋白(HbA1c)等指标变化,并记录低血糖、胃肠道不良反应的发生情况。结果两组患者治疗前FPG、2hPG和HbA1c差异均无统计学意义(P0.05);治疗12周后,两组患者FPG、2hPG和HbA1c较治疗前均明显降低,并且西格列汀组较阿卡波糖组2hPG和HbA1c下降更显著,差异有统计学意义(P0.05)。治疗期间两组患者无低血糖发生,阿卡波糖组4例发生腹胀,排气增加,两组患者不良反应发生差异无统计学意义(P0.05)。结论西格列汀与二甲双胍联用治疗T2DM患者疗效显著且安全。     

Rosiglitazone RECORD study: glucose control outcomes at 18 months.

AIMS: To compare glucose control over 18 months between rosiglitazone oral combination therapy and combination metformin and sulphonylurea in people with Type 2 diabetes. METHODS: RECORD, a multicentre, parallel-group study of cardiovascular outcomes, enrolled people with an HbA(1c) of 7.1-9.0% on maximum doses of metformin or sulphonylurea. If on metformin they were randomized to add-on rosiglitazone or sulphonylurea (open label) and if on sulphonylurea to rosiglitazone or metformin. HbA(1c) was managed to < or = 7.0% by dose titration. A prospectively defined analysis of glycaemic control on the first 1122 participants is reported here, with a primary outcome assessed against a non-inferiority margin for HbA(1c) of 0.4%. RESULTS: At 18 months, HbA(1c) reduction on background metformin was similar with rosiglitazone and sulphonylurea [difference 0.07 (95% CI -0.09, 0.23)%], as was the change when rosiglitazone or metformin was added to sulphonylurea [0.06 (-0.09, 0.20)%]. At 6 months, the effect on HbA(1c) was greater with add-on sulphonylurea, but was similar whether sulphonylurea was added to rosiglitazone or metformin. Differences in fasting plasma glucose were not statistically significant at 18 months [rosiglitazone vs. sulphonylurea -0.36 (-0.74, 0.02) mmol/l, rosiglitazone vs. metformin -0.34 (-0.73, 0.05) mmol/l]. Increased homeostasis model assessment insulin sensitivity and reduced C-reactive protein were greater with rosiglitazone than metformin or sulphonylurea (all P < or = 0.001). Body weight was significantly increased with rosiglitazone compared with sulphonylurea [difference 1.2 (0.4, 2.0) kg, P = 0.003] and metformin [difference 4.3 (3.6, 5.1) kg, P < 0.001]. CONCLUSIONS: In people with diabetes, rosiglitazone in combination with metformin or sulphonylurea was demonstrated to be non-inferior to the standard combination of metformin + sulphonylurea in lowering HbA(1c) over 18 months, and produces greater improvements in C-reactive protein and basal insulin sensitivity but is also associated with greater weight gain.     

Improvement of glycemic control in type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials

AimDifferent guidelines provide similar, but not identical, therapeutic targets for HbA1c in type 2 diabetes. These targets can also depend from the different pharmacological strategies adopted for intensifying glycemic control.Data synthesisThis meta-analysis includes randomized trials adopting any pharmacological regimen for intensifying glycemic control in T2DM (versus standard of care/placebo), with a trial duration ≥2 years and a between-group HbA1c difference≥0.5%. The primary outcome was to assess the effects of the improvement of glycemic control on major cardiovascular events (MACE), ocular and renal complications, and severe hypoglycemia. Mantel-Haenszel odds ratios (MH–OR) with 95% Confidence Intervals were calculated for all the outcomes considered.We included 13 trials fulfilling the inclusion criteria. The improvement of glycemic control was associated with a lower risk of MACE (MH–OR:0.89 [95%CI 0.85–0.94]) and renal adverse events (MH–OR 0.73 [0.65–0.82]), but not all-cause mortality (MH–OR 0.95 [0.88–1.01]) and ocular adverse complications (MH–OR 0.94 [0.72–1.22]). For glucose-lowering drugs inducing hypoglycemia, a protective effect on the risk of microvascular complications, but not of MACE and all-cause mortality, was observed only for HbA1c ≤ 48 mmol/mol, but with higher risk of severe hypoglycaemia (MH–OR 2.72 [1.79–4.13]). Drugs not inducing hypoglycaemia were associated with a reduction of MACE, renal adverse events, and all-cause mortality, for HbA1c< 7% (no data for lower targets).ConclusionsThe present meta-analysis show that the improvement of glycemic control with drugs not inducing hypoglycemia is associated with a reduction in the risk of long-term chronic vascular and renal complications, and all-cause mortality.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial

AIM: To compare the efficacy and safety of sitagliptin vs. glipizide in patients with type 2 diabetes and inadequate glycaemic control [haemoglobin A(1c) (HbA(1c)) > or = 6.5 and < or = 10%] on metformin monotherapy. METHODS: After a metformin dose titration/stabilization period (> or = 1500 mg/day), 1172 patients were randomized to the addition of sitagliptin 100 mg q.d. (N = 588) or glipizide 5 mg/day (uptitrated to a potential maximum 20 mg/day) (N = 584) for 52 weeks. The primary analysis assessed whether sitagliptin was non-inferior to glipizide regarding HbA(1c) changes from baseline at Week 52 using a per-protocol approach. RESULTS: From a mean baseline of 7.5%, HbA(1c) changes from baseline were -0.67% at Week 52 in both groups, confirming non-inferiority. The proportions achieving an HbA(1c) < 7% were 63% (sitagliptin) and 59% (glipizide). Fasting plasma glucose changes from baseline were -0.56 mmol/l (-10.0 mg/dl) and -0.42 mmol/l (-7.5 mg/dl) for sitagliptin and glipizide, respectively. The proportion of patients experiencing hypoglycaemia episodes was significantly (p < 0.001) higher with glipizide (32%) than with sitagliptin (5%), with 657 events in glipizide-treated patients compared with 50 events in sitagliptin-treated patients. Sitagliptin led to weight loss (change from baseline =-1.5 kg) compared with weight gain (+1.1 kg) with glipizide [between-treatment difference (95% confidence interval) =-2.5 kg (-3.1, -2.0); p < 0.001]. CONCLUSIONS: In this study, the addition of sitagliptin compared with glipizide provided similar HbA(1c)-lowering efficacy over 52 weeks in patients on ongoing metformin therapy. Sitagliptin was generally well tolerated, with a lower risk of hypoglycaemia relative to glipizide and with weight loss compared with weight gain with glipizide.     

Efficacy and safety of sotagliflozin in patients with type 2 diabetes and stage 3 chronic kidney disease

Aim

To assess the efficacy and safety of sotagliflozin, a dual inhibitor of sodium-glucose co-transporters 1 and 2, in adults with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD3).

Materials and Methods

This phase 3, randomized, placebo-controlled trial evaluated sotagliflozin 200 and 400 mg in 787 patients with T2D and an estimated glomerular filtration rate of 30-59 ml/min/1.73m². The primary objective was superiority of week 26 HbA1c reductions with sotagliflozin versus placebo. Secondary endpoints included changes in other glycaemic and renal endpoints overall and in CKD3 subgroups.

Results

At 26 weeks, the placebo-adjusted mean change in HbA1c (from a baseline of 8.3% ± 1.0%) was –0.1% (95% CI: –0.2% to 0.05%; P = .2095) and –0.2% (–0.4% to –0.09%; P = .0021) in the sotagliflozin 200 and 400 mg groups, respectively. Significant reductions in fasting plasma glucose and body weight, but not systolic blood pressure, were observed. Among patients with at least A2 albuminuria at week 26, the urine albumin-creatinine ratio (UACR) was reduced with both sotagliflozin doses relative to placebo. At week 52, UACR was reduced with sotagliflozin 200 mg in the CKD3B group. Adverse events (AEs), including serious AEs, were similar between the treatment groups.

Conclusions

After 26 weeks, HbA1c was significantly reduced with sotagliflozin 400 but not 200 mg compared with placebo in this CKD3 cohort. UACR in patients with at least A2 albuminuria was reduced with each of the two doses at 26 weeks, but changes were not sustained at week 52. The safety findings were consistent with previous reports (NCT03242252).     

双时相门冬胰岛素30联合二甲双胍治疗基础胰岛素控制不佳的2型糖尿病患者:疗效及安全性评价

目的 评价既往基础胰岛素联合口服降糖药物(OAD)治疗血糖控制不佳的2型糖尿病患者转用双时相门冬胰岛素30(BIAsp30)联合二甲双胍治疗的疗效及安全性.方法 本试验为多中心、非随机、开放、单组治疗达标研究,包括2周筛选期、4周导入期和16周治疗期.既往使用基础胰岛素联合OAD治疗血糖控制不佳的2型糖尿病患者转用每日两次BIAsp30注射联合口服二甲双胍治疗.收集疗效及安全性数据进行统计学分析.结果 共293例患者(男154,女139)入选,平均年龄(54.0±9.6)岁,平均糖尿病病程(8.54±5.49)年,平均体重指数(24.89±3.28)kg/m2,HbA1c 8.16%±0.89%,122例既往使用基础胰岛素类似物,169例使用人中效胰岛素.经16周的治疗,平均HbA1C降幅达1.30%±0.96%(P＜0.01);HbA1C达到＜7.0%和≤6.5%的患者比例分别为60.4%和38.9%.患者8点血糖谱各点血糖值均有显著降低(P＜0.01),8点血糖均值由基线时的(10.53±2.58)mmol/L降至(7.79±1.58)mmol/L(P＜0.01),降幅为2.76 mmol/L.早餐和晚餐后血糖增幅显著下降,分别下降了1.73 mmol/L(P＜0.01)和1.28 mmol/L(P＜0.01),而午餐后的血糖增幅未发现显著性降低(-0.09 mmol/L,P=0.734 5).研究治疗中无严重不良事件和重度低血糖事件报告,总体低血糖发生率为2.68例/患者年;患者体重平均增加(0.76±0.14)kg(P＜0.01).结论 BIAsp30联合二甲双胍可显著改善基础胰岛素联合OAD血糖控制不佳的2型糖尿病患者的血糖控制,并具有良好的安全性.     

Metformin extended‐release versus immediate‐release: An international,randomized, double‐blind,head‐to‐head trial in pharmacotherapy‐naïve patients with type 2 diabetes

This international, randomized, double‐blind trial (NCT01864174) compared the efficacy and safety of metformin extended‐release (XR) and immediate‐release (IR) in patients with type 2 diabetes. After a 4‐week placebo lead‐in, pharmacotherapy‐naïve adults with glycated haemoglobin (HbA1c) at 7.0% to 9.2% were randomized (1:1) to receive once‐daily metformin XR 2000 mg or twice‐daily metformin IR 1000 mg for 24 weeks. The primary endpoint was change in HbA1c after 24 weeks. Secondary endpoints were change in fasting plasma glucose (FPG), mean daily glucose (MDG) and patients (%) with HbA1c <7.0% after 24 weeks. Overall, 539 patients were randomized (metformin XR, N = 268; metformin IR, N = 271). Adjusted mean changes in HbA1c, FPG, MDG and patients (%) with HbA1c <7.0% after 24 weeks were similar for XR and IR: ?0.93% vs ?0.96%; ?21.1 vs ?20.6 mg/dL (?1.2 vs ?1.1 mmol/L); ?24.7 vs ?27.1 mg/dL (?1.4 vs ?1.5 mmol/L); and 70.9% vs 72.0%, respectively. Adverse events were similar between groups and consistent with previous studies. Overall, metformin XR demonstrated efficacy and safety similar to that of metformin IR over 24 weeks, with the advantage of once‐daily dosing.