Aim To investigate the effectiveness of metformin in delaying or preventing progression to diabetes in a Chinese population with impaired glucose regulation (IGR). Materials and methods This multicentre, randomized, open-label, controlled study (NCT03441750) will assess the efficacy of metformin in preventing diabetes over >= 2 years. Eligible participants will be randomly assigned (1:1) to lifestyle intervention (LSI) or metformin plus LSI, with stratification based on blood pressure, anti-hypertensive medication use and isolated/non-isolated impaired fasting glucose. All participants will receive LSI advice. Participants in the metformin plus LSI group will receive metformin 850 mg once daily for the first 2 weeks, and twice daily thereafter, according to tolerability. Results The primary objective is to compare rates of newly diagnosed diabetes in the two intervention groups. Changes in glycaemia, blood pressure, body weight, insulin resistance, and safety outcomes will also be evaluated. Conclusions This large clinical trial in a Chinese population with IGR aims to provide critical information to guide clinical decision-making in order to alleviate the current diabetes epidemic.
Aims To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of rongliflozin in a cohort of healthy Chinese people and people with type 2 diabetes mellitus (T2DM). Materials and methods We examined the effects of a single ascending dose (SAD) of rongliflozin (10-200 mg) in combination with food (20 mg) in 50 healthy people, and a multiple ascending dose (MAD) of rongliflozin (10-50 mg once daily for 12 days) in 36 people with T2DM. Results No serious adverse events (AEs) or discontinuations as a result of AEs (related to rongliflozin) occurred in either study. In healthy participants and those with T2DM, rongliflozin was rapidly absorbed, with a time to maximum plasma concentration of 0.63 to 1.75 hours. Systemic exposure (maximum observed serum concentration and area under the curve) to rongliflozin and its inactive major metabolites (T1444, T1454 and T1830) increased in proportion to dose. In the SAD and MAD studies, there was a dose-related increase in urinary glucose excretion (UGE) ranging from 10 to 50 mg rongliflozin. This increase in UGE was associated with dose-related decreases in serum glucose values in people with T2DM in the MAD group. In the SAD group, UGE plateaued at 50 to 200 mg. Conclusions Rongliflozin was well tolerated in all participants. The PK and PD measurements obtained for rongliflozin demonstrate a dose-response relationship when the drug is administered at doses ranging from 10 to 50 mg in healthy people and in people with T2DM.
Aim To evaluate the long-term cost-effectiveness of a Patient Empowerment Programme (PEP) for type 2 diabetes mellitus (DM) in primary care. Materials and Methods PEP participants were subjects with type 2 DM who enrolled into PEP in addition to enrolment in the Risk Assessment and Management Programme for DM (RAMP-DM) at primary care level. The comparison group was subjects who only enrolled into RAMP-DM without participating in PEP (non-PEP). A cost-effectiveness analysis was conducted using a patient-level simulation model (with fixed-time increments) from a societal perspective. We incorporated the empirical data from a matched cohort of PEP and non-PEP groups to simulate lifetime costs and outcomes for subjects with DM with or without PEP. Incremental cost-effectiveness ratios (ICER) in terms of cost per quality adjusted life year (QALY) gained were calculated. Probabilistic sensitivity analysis was conducted with results presented as a cost-effectiveness acceptability curve. Results With an assumption that the PEP effect would last for 5 years as shown by the empirical data, the incremental cost per subject was US $197 and the incremental QALYs gained were 0.06 per subject, which resulted in an ICER of US $3290 per QALY gained compared with no PEP across the lifetime. Probabilistic sensitivity analysis showed 66% likelihood that PEP is cost-effective compared with non-PEP when willingness-to-pay for a QALY is >= US $46 153 (based on per capita GDP 2017). Conclusions Based on this carefully measured cost of PEP and its potentially large benefits, PEP could be highly cost-effective from a societal perspective as an adjunct intervention for patients with DM.
To improve understanding of the safety and efficacy of adding sitagliptin to treatment of patients with type 2 diabetes taking premixed insulin, data from patients using premixed insulin +/- metformin (screening HbA1c >= 7.5% and <= 11%) in either of two clinical trials in which sitagliptin 100 mg once-daily or placebo was added to various formulations of insulin treatment, were analysed. In both trials, insulin doses were to remain stable throughout the 24-week trial period. At week 24, the between-group difference (sitagliptin - placebo) in the least squares mean (95% confidence intervals) change from baseline in HbA1c in patients using premixed insulin was -0.43% (-0.58, -0.28), P <0.001. Adverse events were generally similar between the treatment groups. The incidence of symptomatic hypoglycaemia was slightly higher with sitagliptin, and the incidence of hypoglycaemia requiring medical attention was slightly higher with placebo; in both cases the difference was not statistically significant. The data from this pooled analysis confirm the utility of sitagliptin used in combination with premixed insulin in patients with type 2 diabetes.
Aim To compare the efficacy and safety of once-weekly dulaglutide with that of insulin glargine in combination with metformin and/or a sulphonylurea in mainly Asian patients with type 2 diabetes mellitus (T2DM). Materials and Methods In this 52-week, randomized, parallel-arm open-label study, we enrolled patients aged >= 18 years with T2DM for at least 6 months and a glycated haemoglobin (HbA1c) concentration >= 53.0 mmol/mol (7.0%) and <= 96.7 mmol/mol (11.0%). The primary outcome was change in HbA1c from baseline to week 26 to determine non-inferiority of dulaglutide 1.5 mg versus glargine. Results A total of 774 patients from China, South Korea, Mexico and Russia were randomly assigned (1:1:1) to dulaglutide 1.5 mg, dulaglutide 0.75 mg or glargine treatment groups. The patients' mean age was 55 years and the average T2DM duration was similar to 8 years. The least squares mean (SE) changes from baseline in HbA1c at 26 weeks were - 18.9 (0.73) mmol/mol (-1.73 [0.067]%) for dulaglutide 1.5 mg and -14.5 (0.73) mmol/mol (-1.33 [0.067]%) for dulaglutide 0.75 mg, compared with -12.7 (0.73) mmol/mol (-1.16 [0.067]%) for glargine. Statistical criteria for superiority were met with both dulaglutide 1.5 mg and dulaglutide 0.75 mg. More patients in the dulaglutide 1.5 and 0.75 mg groups achieved HbA1c target <53.0 mmol/mol (<7.0%) than in the glargine group at week 26 (P < 0.001 and P = 0.004, respectively). Body weight decreased with dulaglutide and increased with glargine. The incidence and rate of total hypoglycaemia were lower with dulaglutide versus glargine. Gastrointestinal adverse events, including diarrhoea and nausea, were the most frequently reported for patients taking dulaglutide. Conclusions Once-weekly dulaglutide provides greater improvement in HbA1c, with weight loss and less hypoglycaemia, than once-daily insulin glargine in a population of mainly Asian patients with T2DM who had failed to achieve optimal glycaemic control on metformin and/or a sulphonylurea.
Aims The aim of this study was to assess the effect of FGF21 on food intake, body weight, body composition, glucose homeostasis, bone mineral density (BMD), cortisol and growth hormone (GH) in obese minipigs. The pig is a unique model for studying FGF21 pharmacology as it does not express UCP1, unlike mice and humans. Methods Twelve obese Gottingen minipigs with a mean body weight of 91.6 +/- 6.7 kg (mean +/- SD) received subcutaneously either vehicle (n = 6) or recombinant human FGF21 (n = 6) once daily for 14 weeks (0.1 mg/kg for 9.5 weeks and 0.3 mg/kg for 4.5 weeks). Results Treatment of obese minipigs with FGF21 led to a 50% reduction in food intake and a body weight loss of, on average, 18 kg compared to the vehicle group after 14 weeks of dosing. Glucose tolerance and insulin sensitivity, evaluated by intravenous glucose tolerance test, were significantly improved in the FGF21 group compared to the vehicle group at the end of the study. The plasma cortisol profile was unaffected by FGF21, whereas a small decrease in peak GH values was observed in the FGF21-treated animals after 7 to 9.5 weeks of treatment compared to the vehicle group. Whole-body BMD was not affected by 13 weeks of FGF21 dosing. Conclusion Despite a lack of UCP-1 in obese minipigs, FGF21 treatment induced a significant weight loss, primarily a result of reduction in food intake, with no adverse effect on BMD or plasma cortisol.
Aims We undertook a systematic review and meta-analysis to assess the efficacy and safety of sodium-glucose cotransporter 2 inhibitors (SGLT2is) concerning kidney outcomes in patients with type 2 diabetes mellitus (T2DM), with or without prevalent kidney disease. Materials and Methods PubMed, Web of science, Embase and the Cochrane Library were systematically searched for randomized controlled trials (RCTs) to assess the efficacy and safety of treatment with SGLT2is versus placebo in patients with T2DM. The weighted mean difference (WMD) and its 95% confidence interval (CI) were applied for continuous variables, and the risk ratio (RR) and corresponding 95% CI were used for dichotomous outcomes. Patients were categorized according to whether the baseline mean estimated glomerular filtration rate (eGFR) was less or was more than 60 mL/min/1.73 m(2). Results A total of 25 eligible studies with 43 721 participants were included. There was an initial and small decrease in eGFR during the early treatment period (WMD, -4.63; 95% CI, -6.08 to -3.19 mL/min/1.73 m(2)), which was noted at 1-6 weeks and gradually narrowed over time, with a decline in protection from eGFR in the long term (WMD, 3.82; 95% CI, 2.80-4.85 mL/min/1.73 m(2)). SGLT2is significantly delayed albuminuria progression (RR, 0.71; 95% CI, 0.66-0.76), promoted albuminuria regression (RR,1.71; 95% CI, 1.54-1.90), improved the composite of >= 40% decrease in eGFR, in the need for renal-replacement and in death from renal causes (RR, 0.57; 95% CI, 0.49-0.66), and reduced all-cause mortality (RR, 0.84; 95% CI, 0.75-0.94). At the same time, they significantly increased the risk of genital infection (RR, 3.43; 95% CI, 2.87-4.10) vs placebo in patients with T2DM. Meta-regression analyses showed that eGFR-preservation effects were not significantly associated with basic patient characteristics (age, BMI, HbA1c, eGFR level), but were influenced by drug administration (treatment duration, type, dosage of SGLT2is). Subgroup analyses showed that the relative effects on renal outcomes of SGLT2is vs placebo were similar across eGFR subgroups (P heterogeneity >0.05). Conclusions SGLT2is slowed eGFR decline, lowered albuminuria progression, improved adverse renal endpoints and reduced all-cause mortality, but increased risk of genital infections vs placebo in patients with T2DM. The indication of consistent renal benefits across categories of baseline eGFR levels may allow additional individuals to benefit from SGLT2is therapy.
Aim To evaluate the comparative effects of incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is), on beta-cell function and insulin resistance in patients with type 2 diabetes mellitus (T2DM). Materials and Methods Medline, Embase, the Cochrane Library and were searched for randomized controlled trials (RCTs) with a duration of at least 4 weeks. Network meta-analysis was performed, followed by subgroup analysis and meta-regression. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the quality of evidence. Outcomes of interest include homeostasis model assessment for beta cell function (HOMA-beta) and insulin resistance (HOMA-IR), fasting C-peptide and fasting plasma glucose (FPG). Weighted mean difference (WMD) with 95% confidence interval (CI) was calculated as the measure of effect size. Results A total of 360 RCTs (74% at least double-blinded) with 157 696 patients were included. Incretin-based therapies were compared with six other classes of glucose-lowering drugs or with placebo. Compared with placebo, a significant increase in HOMA-beta and fasting C-peptide was detected for GLP-1RAs (WMD = 20.31 [95% CI, 16.34-24.39] with low quality; WMD = 0.16 ng/mL [95% CI, 0.03-0.29] with low quality) and for DPP-4Is (WMD = 9.90 [95% CI, 8.27-11.61] with moderate quality; WMD = 0.09 ng/mL [95% CI, 0.04-0.14] with moderate quality) separately, while a significant reduction in HOMA-IR and FPG were found in favour of GLP-1RAs (WMD = -0.67 [95% CI, -1.08 to -0.27] with low quality; WMD = -1.04 mmol/L [95% CI, -1.26 to -0.83] with moderate quality) and DPP-4Is (WMD = -0.23 [95% CI, -0.38 to -0.08] with low quality; WMD = -0.77 mmol/L [95% CI, -0.98 to -0.57] with moderate quality), respectively. Conclusions Incretin-based therapies not only show an increase in HOMA-beta and fasting C-peptide level, but also achieve a reduction in HOMA-IR and FPG in comparison with placebo. Although GRADE scores indicate low to moderate for most comparisons, incretin-based therapies seem to be an advisable option for long-term treatment to preserve beta-cell function.
Aims To compare the efficacy and safety of saxagliptin and glimepiride in type 2 diabetes (T2D) patients who are inadequately controlled with metformin monotherapy. Materials and methods In this 48-week, multi-centre, open-label, randomized, parallel trial (NCT02280486, ), a total of 388 T2D patients were randomized 1:1 to saxagliptin or glimepiride groups. The primary endpoint was achievement of HbA1c <7.0%, without hypoglycaemia, defined as blood glucose Results Over 48 weeks, a greater proportion of patients achieved the primary endpoint with saxagliptin compared with glimepiride (43.3% vs 31.3%; odds ratio, 1.38, 95% CI, 1.05-1.82; P = 0.019), especially among patients with baseline HbA1c <8.0%, duration <5 years or baseline BMI >= 25 kg/m(2). Mean reduction in HbA1c was similar in the two treatment groups at Week 48 (-0.94% with saxagliptin vs -0.98% with glimepiride; P = 0.439). Bodyweight decreased with saxagliptin, but increased with glimepiride over the treatment period, and the treatment difference was -1.6 kg (P < 0.001) at Week 48. The proportion of patients experiencing hypoglycaemia was much lower with saxagliptin vs glimepiride (3.1% vs 12.8%; P < 0.001). Conclusions This study provides evidence that, compared to glimepiride, saxagliptin more effectively achieves a composite endpoint of adequate glycaemic control without hypoglycaemia and without weight gain in T2D patients who are inadequately controlled with metformin monotherapy, especially in overweight patients with moderate hyperglycaemia and a relatively short duration of diabetes.
Aims To investigate the prevalence of adult-onset autoimmune diabetes (ADM) and predisposition to autoimmune diseases by quantifying serum organ-specific autoantibodies in people with phenotype of type 2 diabetes (T2D). Materials and methods We included a nationally representative sample of 46 239 adults aged >= 20 years from 14 provinces, of whom 4671 had diabetes, plus 1000 control subjects with normal glucose tolerance (NGT). Participants were screened centrally for autoantibodies to glutamic acid decarboxylase (GAD), islet antigen 2 (IA2) and zinc transporter isoform-8 (Znt8) and were defined as having ADM where positive for these antibodies. We then assayed thyroid peroxidase (TPO), tissue transglutaminase (tTG) and 21-hydroxylase (21-OH) autoantibodies in randomly selected participants with ADM and in age-matched, sex-matched and non-ADM controls with T2D plus controls with NGT. Results Post-normalization, the standardized prevalence rate of ADM was 6.0% (95% confidence interval [CI] 5.3-6.8) in initially non-insulin-requiring participants with ADM, corresponding to six million adults in China, in whom adjusted antibody positivity was: TPO autoantibodies 16.3% (95% CI 10.8-21.8), tTG autoantibodies 2.1% (95% CI 0.0-4.2), and 21-OH autoantibodies 1.8% (95% CI -0.2 to 3.8). Those participants with ADM who were GAD autoantibody-positive had high risk of TPO autoantibody positivity (odds ratio [OR] 2.39, P = 0.0031) and tTG autoantibody positivity (OR 6.98, P = 0.027), while those positive for IA2 autoantibodies had a high risk of tTG autoantibody positivity (OR 19.05, P = 0.001). Conclusions A proportion of people with phenotype of T2D in China have ADM, with diabetes-associated autoantibodies, and may be at risk of developing other organ-specific autoimmune diseases; therefore, it may be clinically relevant to consider screening such Chinese populations.
AimsThe potential effect of regenerating (Reg) proteins in the treatment of diabetes has been indicated in the past decade, but the clinical use of Reg proteins requires more advances in translational medicine. In the present study, we produced recombinant regenerating protein 2 (rReg2), to prove its protective effect against streptozocin (STZ)-induced diabetes in BALB/c mice. Materials and MethodsrReg2 was administrated in STZ-induced diabetic mice. Blood glucose, body weight, serum insulin and islet -cell loss were determined. However, Reg2 has also been reported to serve as an autoantigen that induces autoimmune attacks on islets and aggravates diabetic development in non-obese diabetic mice. To address this contradiction, complete Freund's adjuvant was injected to generate a model that was hypersensitive to Reg2. In this model, islet CD8 T-cell infiltration, serum Reg2 antibody and interleukin (IL)-4 and IL-10, and splenic CD4+/interferon (IFN)-+ T cells were determined. ResultsDirect rReg2 pretreatment preserved islet -cell mass against STZ and improved glycaemia, body weight and serum insulin content. The protection against cell death was further confirmed in cultured mouse islets and MIN6 cells. On the other hand, significant elevations of serum Reg2 antibody and splenic CD4+/IFN-+ T cells, and decreases in serum IL-4 and IL-10 were detected in rReg2-vaccinated mice, which may contribute to the accelerated diabetes. Interestingly, these mice, upon further rReg2 treatment, exhibited alleviated diabetic conditions with less islet CD8+ T-cell infiltration. ConclusionrReg2 treatment ameliorated STZ-induced diabetes in normal BALB/c mice. By contrast, rReg2 vaccination exacerbated, but further rReg2 treatment alleviated, the severity of STZ-induced diabetes. Thus, the protective effect of rReg2 is predominant over the autoantigenic -cell destruction, supporting the potential of rReg2 in the clinical treatment of diabetes.
AimsTo investigate the progression of obesity-related type 2 diabetes mellitus (T2DM) in rhesus monkeys, especially dynamic changes in insulin and glucagon. Materials and methodsWe followed a cohort of 52 rhesus monkeys for 7 years throughout the progression of obesity-related T2DM. Intravenous glucose tolerance tests were performed every 6 months to evaluate dynamic changes in glucose, insulin and glucagon levels. ResultsObesity in rhesus monkeys increased the overall mortality and T2DM morbidity. During the progression of T2DM, glucagon remained consistently elevated, while insulin initially increased in compensation but then dropped to below normal levels when the monkeys developed overt T2DM. After a glucose challenge, both the first and second phases of insulin secretion increased during the early stage of T2DM; in later stages the first phase was delayed and the second phase was diminished. ConclusionOur findings showed that, beside the decreased insulin level, hyperglucagonaemia also plays an important role in the development of T2DM.
AimsTo describe global patterns of insulin treatment and to assess the impact of patient, provider, health system and economic influences on treatment decisions for patients with insulin-treated type 2 diabetes (T2D). MethodsThis prospective cohort study of insulin-treated patients with T2D was conducted across 18 countries categorized as high, upper-middle or lower-middle income regions. Information collected from patients included knowledge of diabetes, experiences and interactions with their healthcare provider. Physician information included specialty, practice size, availability of diabetes support services, volume of diabetes patients treated and time spent per patient. Physicians determined an individualized haemoglobin A1c (HbA1c) target for each patient by the start of the study. Changes in T2D therapies and HbA1c were recorded for 2years. ResultsComplete treatment data were available for 2528 patients. Median age was 61years and median duration of diabetes was 11.4years. Changes to treatment regimen occurred in 90.0% of patients, but changes were less common in countries with a higher economic status (P<0.001). Most treatment changes involved insulin, with changes in dose the most common. Overall predictors of change in insulin therapy included younger age, use of any insulin regimen other than basal only, higher mean baseline HbA1c and longer duration of T2D. HbA1c levels remained constant regardless of regional economic status. At baseline, 20.6% of patients were at their HbA1c target; at 2years this was 26.8%. ConclusionsAmong insulin-treated patients with T2D, treatment changes were common; however, only approximately one-fourth of individuals achieved their HbA1c target.
Aim Phase III, randomized, double-blind study evaluating the efficacy and safety of ertugliflozin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin, including evaluation in the China subpopulation. Materials and methods A 26-week, double-blind study of 506 Asian patients (80.2% from mainland China), randomized 1:1:1 to placebo, ertugliflozin 5- or 15 mg, was performed. Primary endpoint was change from baseline in HbA1c at week 26. Secondary endpoints were change from baseline at week 26 in fasting plasma glucose (FPG), body weight (BW), systolic/diastolic blood pressure (SBP/DBP), and proportion of patients with HbA1c <7.0%. Hypotheses for the primary endpoint and FPG and BW secondary endpoints were tested in the China subpopulation. Results At week 26, least squares mean (95% CI) change from baseline HbA1c was significantly greater with ertugliflozin 5- and 15 mg versus placebo: -1.0% (-1.1, -0.9), -0.9% (-1.0, -0.8), -0.2% (-0.3, -0.1), respectively. Ertugliflozin significantly reduced FPG, BW and SBP. Reductions in DBP with ertugliflozin were not significant. At week 26, 16.2%, 38.2% and 40.8% of patients had HbA1c <7.0% with placebo, ertugliflozin 5- and 15 mg, respectively. 59.3%, 56.5% and 53.3% of patients experienced adverse events with placebo, ertugliflozin 5- and 15 mg, respectively. Incidence of symptomatic hypoglycaemia was higher for ertugliflozin 15 mg vs placebo. Results in the China subpopulation were consistent. Conclusions Ertugliflozin significantly improved glycaemic control and reduced BW and SBP in Asian patients with T2DM. Ertugliflozin was generally well-tolerated. Results in the China subpopulation were consistent with the overall population. : NCT02630706.
Aim The aim of this study was to evaluate the efficacy and safety of evolocumab with background atorvastatin in Chinese patients with type 2 diabetes mellitus (T2DM) and hyperlipidaemia or mixed dyslipidaemia. Materials and methods This is a pre-specified analysis of patients in the BERSON study (, NCT02662569) in China. Patients initiated background atorvastatin 20 mg/d, after which they were randomized 2:2:1:1 to evolocumab 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) or to placebo Q2W or QM. Co-primary endpoints were percentage change in LDL cholesterol (LDL-C) from baseline to week 12 and from baseline to the mean of weeks 10 and 12. Additional endpoints included atherogenic lipids, glycaemic measures and adverse events (AEs). Results Among 453 patients randomized in China, 451 received at least one dose of study drug (evolocumab or placebo). Evolocumab significantly reduced LDL-C compared with placebo at week 12 (Q2W, -85.0%; QM, -74.8%) and at the mean of weeks 10 and 12 (Q2W, -80.4%; QM, -81.0%) (adjusted P < 0.0001 for all) when administered with background atorvastatin. Non-HDL-C, ApoB100, total cholesterol, Lp(a), triglycerides, HDL-C and VLDL-C significantly improved with evolocumab vs placebo. No new safety findings were observed with evolocumab. The incidence of diabetes AEs was higher with evolocumab compared with placebo. There were no differences over time between evolocumab and placebo in measures of glycaemic control. Conclusions In patients in China with T2DM and hyperlipidaemia or mixed dyslipidaemia receiving background atorvastatin, evolocumab significantly reduced LDL-C and other atherogenic lipids, was well tolerated, and had no notable impact on glycaemic measures.