A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects.

AIM: The trial (NCT04016974) investigated the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide, the first orally administered glucagon-like peptide-1 analogue for type 2 diabetes, in healthy Chinese subjects. MATERIALS AND METHODS: This single-centre, multiple-dose, placebo-controlled trial randomized 32 healthy Chinese adults to once-daily oral semaglutide (3 mg escalating to 14 mg) or placebo for 12 weeks. Blood samples were collected regularly during treatment and follow-up. The primary endpoint was the area under the semaglutide concentration-time curve over a dosing interval (0-24 h) at steady state (AUC0-24h,sema,SS). Secondary pharmacokinetic endpoints included the maximum observed semaglutide plasma concentration at steady state (Cmax,sema,SS). Supportive secondary pharmacodynamics endpoints included changes in body weight and fasting plasma glucose. RESULTS: Treatment with all oral semaglutide doses showed dose-dependent increases in semaglutide exposure in healthy Chinese subjects at steady state, determined by AUC0-24h,sema,SS (233, 552 and 1288 h·nmol/L for 3, 7 and 14 mg of oral semaglutide, respectively) and Cmax,sema,SS. Oral semaglutide treatment was associated with significant reductions in body weight (p = .0001) and fasting plasma glucose (p = .0011) versus placebo at the end of treatment. The safety and tolerability of oral semaglutide were consistent with the known profile of glucagon-like peptide-1 receptor agonists, with no severe or blood-glucose-confirmed symptomatic hypoglycaemic events, serious adverse events or deaths. The most frequent adverse events were gastrointestinal disorders. CONCLUSIONS: At steady state, oral semaglutide exposure was dose dependent and close to dose proportionality in healthy Chinese subjects. This is consistent with previous clinical pharmacology results for oral semaglutide.

Use of once-daily oral semaglutide and associated clinical outcomes among adults with type 2 diabetes in routine clinical practice in Canada: A multicentre, prospective real-world study (PIONEER REAL Canada).

AIM: PIONEER REAL Canada examined real-world clinical outcomes associated with the use of once-daily oral semaglutide in adults with type 2 diabetes. MATERIALS AND METHODS: This was a 34- to 44-week, multicentre, prospective, open-label, non-interventional study in adults who were treatment-naive to injectable glucose-lowering medication and initiated oral semaglutide in routine clinical practice. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to the end of the study (EoS). Secondary endpoints assessed at EoS were change from baseline in body weight (BW); the proportion of participants reaching HbA1c levels <7% and the composite endpoints, HbA1c reduction ≥1% point with BW reduction ≥3% and ≥5%; and treatment satisfaction measured using Diabetes Treatment Satisfaction Questionnaires (DTSQ) status and change. Primary analyses were based on the in-study observation period. RESULTS: In total, 182 participants initiated oral semaglutide (mean age, 58.6 years; HbA1c, 8.0%; BW, 93.7 kg). The estimated changes (95% confidence interval) from baseline to EoS in HbA1c and BW were -1.09% points (-1.24, -0.94; p < .0001) and -7.17% (-8.24, -6.11; p < .0001), respectively. At EoS, 53.7% of participants had HbA1c levels <7%; 39.3% and 31.6% reached HbA1c reduction ≥1% point plus BW reduction ≥3% and ≥5%, respectively. Treatment satisfaction significantly increased (DTSQ status, +4.47 points; DTSQ change, 11.83 points; both p < .0001). At EoS, 75.3% of participants remained on oral semaglutide (55.5% received oral semaglutide 14 mg). No new safety signals were identified for oral semaglutide. CONCLUSIONS: In PIONEER REAL Canada, participants treated with oral semaglutide in routine clinical practice experienced clinically relevant reductions in HbA1c and BW and increased treatment satisfaction.

Short-term effects of semaglutide among patients with obesity with and without food addiction: an observational study.

INTRODUCTION: Food addiction (FA) is highly prevalent among people with obesity (PwO) and may constitute a key factor in weight loss failure or weight regain. GLP-1 analogues have been shown to act on the mesolimbic system, which is related to hedonic overeating and substance abuse. We aimed to study the effects of low doses of semaglutide on FA symptomatology and to evaluate whether the presence of FA have a negative impact on weight loss despite treatment with semaglutide. METHODS: One hundred and thirteen PwO (45.5 ± 10.2 years) were evaluated anthropometrically baseline and after four months of treatment with semaglutide. PwO were evaluated for the presence of FA by completing The Spanish version of the Yale Food Addiction Scale 2.0 questionnaire (YFAS 2.0). RESULTS: Baseline BMI and fat mass (%) were greater among PwO with FA (35.8 ± 4.5 vs 33 ± 3.9 kg/m2and 44.2 ± 6.5 vs 40.1 ± 7.9%; p = .01). After four months of treatment with semaglutide, the prevalence of FA diminished from 57.5% to 4.2% (p < .001). The percentage of weight loss (6.9 ± 12.7 vs 5.3 ± 4.6%; p = .4) and the proportion of fat mass loss (2 ± 9 vs 1.6 ± 3.1%; p = .7) were comparable between PwO with and without FA. No differences regarding side effects and treatment discontinuations were seen between the two groups. CONCLUSION: Semaglutide is an effective tool for the amelioration of FA symptomatology among PwO. Despite PwO with FA had greater basal BMI and fat mass, semaglutide showed similar results compared to PwO without FA in terms of weight and fat mass loss at short term.

Effect of albiglutide on cardiovascular outcomes in older adults: A post hoc analysis of a randomized controlled trial.

AIM: To analyse the effects of albiglutide, a glucagon-like peptide 1 receptor agonist, on cardiovascular outcomes in older adults aged ≥65 years with type 2 diabetes and cardiovascular disease who participated in the Harmony Outcomes trial (NCT02465515). MATERIALS AND METHODS: We conducted a post hoc analysis of the primary endpoint of the Harmony Outcomes trial-time to first occurrence of a major adverse cardiovascular event-in subgroups of participants aged <65 and ≥65 years and <75 and ≥75 years at baseline. Hazard ratios and 95% confidence intervals (CIs) were generated using Cox proportional hazards regression. RESULTS: The analysis population included 9462 Harmony Outcomes participants, including 4748 patients ≥65 and 1140 patients ≥75 years at baseline. Hazard ratios for the prevention of major adverse cardiovascular events were 0.66 (95% CI, 0.53-0.82) in persons <65 and 0.86 (95% CI, 0.71-1.04) in those ≥65 years (age interaction p = .07), and 0.78 (95% CI, 0.67-0.91) in <75 and 0.70 (95% CI, 0.48-1.01) in ≥75 year age groups (interaction p = .6). When analysed as a continuous variable, age did not modify the effect of albiglutide on the primary endpoint. CONCLUSIONS: This post hoc analysis adds to the body of literature showing that glucagon-like peptide 1 receptor agonists added to standard type 2 diabetes therapy safely reduce the incidence of cardiovascular events in older adults with established cardiovascular disease. In this analysis, the risk-benefit profile was similar between younger and older age groups treated with albiglutide.

Separate and combined effects of empagliflozin and semaglutide on vascular function: A 32-week randomized trial.

AIM: Despite the increasing use of combination treatment with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, data are limited on the effects of combination treatment on markers of cardiovascular disease. This study aimed to investigate the effect of empagliflozin, semaglutide, and their combination on vascular function. MATERIALS AND METHODS: In total, 120 patients with type 2 diabetes were randomized into four groups (n = 30 in each) for 32 weeks: placebo, semaglutide, empagliflozin, and their combination. The study had two co-primary outcomes: change in arterial stiffness and kidney oxygenation. This paper reports on arterial stiffness assessed as carotid-femoral pulse wave velocity. Secondary outcomes included 24-h blood pressure (BP), 24-h central BP, urinary albumin to creatinine ratio and glycaemic control assessed by both continuous glucose monitoring and glycated haemoglobin. RESULTS: The carotid-femoral pulse wave velocity did not change significantly in any of the groups compared with placebo. Twenty-four-hour systolic BP was reduced by 10 mmHg (95% CI 6-14), p < .001 in the combination group, significantly superior to both placebo and monotherapy (p < .05). Combination treatment increased glycaemic time in range from 72% at baseline to 91% at week 32, p < .001, without increasing time below range. The urinary albumin to creatinine ratio decreased by 36% (95% CI 4-57), p = .03 in the combination group compared with placebo. CONCLUSIONS: Empagliflozin, semaglutide, or their combination did not reduce arterial stiffness. Combination treatment showed a substantial and clinically important reduction in 24-h systolic BP compared with either treatment alone. Combination treatment increased glycaemic time in range without increasing the risk of hypoglycaemia.

Role of Novel Glucagon-like Peptide-1 Receptor Analogue Polyethylene Glycol Loxenatide in Type 2 Diabetes: A Systematic Review and Meta-analysis.

Background: Polyethylene glycol loxenatide (peg-loxenatide) is a novel glucagon-like peptide-1 receptor agonist developed and available for clinical use in China. This meta-analysis was performed as no meta-analysis has analysed the efficacy and safety of peg-loxenatide in type 2 diabetes (T2DM). Methods: Electronic databases were systematically reviewed for RCTs having patients living with T2DM receiving peg-loxenatide in treatment arm and placebo/any other diabetes medicine in control arm. The primary outcome was to evaluate changes in glycated haemoglobin. The secondary outcomes were to evaluate alterations in weight, blood pressure, fasting glucose, prandial glucose, lipids, and adverse events. Results: Data from four trials (718 patients) were analysed. Over 12-24 weeks of clinical use, HbA1c was significantly lower in patients receiving standard-dose peg-loxenatide (100 mcg/week) {MD -0.95% [95% confidence interval (CI): -1.19 to -0.71]; P < 0.01; I2 = 76%} and high-dose peg-loxenatide (200 mcg/week) [MD -1.15% (95% CI: -1.47 to -0.82); P < 0.01; I2 = 90%], as compared to placebo. Standard-dose peg-loxenatide was not associated with increased occurrence of nausea [RR 2.87 (95% CI: 0.56 to 14.72); P = 0.21; I2 = 10%], vomiting [RR 4.73 (95% CI: 0.53 to 41.88); P = 0.16; I2 = 0%], and anorexia [RR 0.78 (95% CI: 0.18 to 3.28); P = 0.73; I2 = 0%]. Occurrence of nausea [RR 16.85 (95% CI: 3.89 to 72.92); P < 0.01; I2 = 10%], vomiting [RR 15.90 (95% CI: 2.99 to 84.55); P < 0.01; I2 = 0%], and anorexia [RR 3.85 (95% CI: 1.24 to 11.88); P = 0.02; I2 = 0%] was significantly higher with high-dose peg-loxenatide, as compared to placebo. Conclusion: Peg-loxenatide (100 mcg/week) is the most appropriate dose for clinical use as it is associated with good glycaemic efficacy with minimal gastro-intestinal side effects.

Management of hyperglycaemia in people with obesity.

Diabetes and obesity are closely interlinked. Obesity is a major risk factor for the development of type 2 diabetes mellitus and appears to be an important risk factor for diabetic micro- and macrovascular complications. Management of hyperglycaemia in people with diabetes is important to reduce diabetes-related complications. Previously, there was a significant tension between management of hyperglycaemia and mitigating weight gain. Older drugs, such as sulfonylureas, glitazones, and insulin, although effective antihyperglycaemic agents, tend to induce weight gain. There is now an increasing recognition in people with obesity and diabetes that the focus should be on aiding weight loss, initially with improvements in diet and physical activity, possibly with the use of low-calorie diet programmes. Subsequent addition of metformin and newer agents, such as sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogues, will aid glucose control and weight reduction, and offer cardiovascular and renal protection. These drugs are now much higher in the therapeutic pathway in many national and international guidelines. Bariatric surgery may also be an effective way to manage hyperglycaemia or induce remission in individuals with both obesity and diabetes.

Greater Combined Reductions of HbA1c ≥ 1.0% and Body Weight Loss ≥ 5.0% or ≥ 10.0% with Orally Administered Semaglutide Versus Comparators.

INTRODUCTION: A post hoc analysis of the PIONEER 1-5 and 8 trials assessed the clinically relevant composite endpoints of HbA1c (glycated haemoglobin) reduction ≥ 1% and body weight loss of ≥ 5% or ≥ 10% with orally administered semaglutide versus comparators. METHODS: In the PIONEER trials, people with type 2 diabetes were randomised to orally administered semaglutide versus placebo (PIONEER 1, 4, 5 and 8), empagliflozin (PIONEER 2), sitagliptin (PIONEER 3) and liraglutide (PIONEER 4) for 26-78 weeks. This analysis assessed the proportion of people achieving an HbA1c reduction of ≥ 1% and body weight loss of ≥ 5% at week 26 and at end of treatment, and the proportion of people achieving an HbA1c reduction of ≥ 1% and body weight loss of ≥ 10% at end of treatment. RESULTS: Overall, 3506 people in PIONEER 1-5 and 8 were included. At week 26 and at end of treatment, odds of achieving the composite endpoint of an HbA1c reduction of ≥ 1% and body weight loss of ≥ 5% were significantly greater with orally administered semaglutide 14 mg than with placebo (PIONEER 1, 4, 5 and 8; all p < 0.0001), empagliflozin 25 mg (PIONEER 2, p < 0.0001), sitagliptin 100 mg (PIONEER 3, p < 0.0001) and liraglutide 1.8 mg (PIONEER 4, p < 0.0001). Odds of achieving the composite endpoint of HbA1c reduction of ≥ 1% and body weight loss of ≥ 10% at end of treatment were also significantly greater with orally administered semaglutide versus comparators. CONCLUSION: In PIONEER 1-5 and 8, odds of achieving clinically relevant reductions in both HbA1c and body weight were significantly greater with orally administered semaglutide versus comparators.

Long-Term Cost-Effectiveness of Subcutaneous Once-Weekly Semaglutide Versus Polyethylene Glycol Loxenatide for Treatment of Type 2 Diabetes Mellitus in China.

OBJECTIVE: This study aimed to evaluate the long-term cost-effectiveness of once-weekly subcutaneous semaglutide versus polyethylene glycol loxenatide (PEG-loxenatide) in patients with type 2 diabetes uncontrolled on metformin, from a Chinese healthcare systems perspective. METHODS: The study applied the Swedish Institute of Health Economics Diabetes Cohort Model to evaluate the long-term clinical and economic outcomes of once-weekly treatment of semaglutide at 0.5 mg and 1.0 mg, respectively, versus PEG-loxenatide 0.2 mg, over a 40-year time horizon. Baseline cohort characteristics were collected from the SUSTAIN China trial. A network meta-analysis was conducted to obtain comparative treatment effects of once-weekly semaglutide and PEG-loxenatide based on two phase 3a clinical trials. Drug costs were sourced from the national bidding price of China. Outcomes were discounted at 5.0% per annum. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to assess the uncertainty of the base-case results. RESULTS: When compared with PEG-loxenatide 0.2 mg, the projections of outcomes over the 40-year time horizon in patients with type 2 diabetes uncontrolled on metformin showed that treatment with once-weekly semaglutide 0.5 mg and 1.0 mg were associated with improved discounted life expectancy by 0.08 and 0.12 years, and improved discounted quality-adjusted life expectancy by 0.16 and 0.22 quality-adjusted life-years, respectively. Once-weekly semaglutide 0.5 mg and 1.0 mg were achieved at lifetime cost savings of 19,309 China Yuan (CNY) and 10,179 CNY, respectively. Sensitivity analyses verified the robustness of the results. CONCLUSION: From the perspective of Chinese healthcare systems, treatment with once-weekly subcutaneous semaglutide represents a dominant option versus PEG-loxenatide for patients with type 2 diabetes uncontrolled on metformin.

iGlarLixi versus basal plus Rapid-Acting insulin in adults with type 2 diabetes advancing from basal insulin therapy: The SoliSimplify Real-World study.

AIM: For people with suboptimally controlled type 2 diabetes (T2D) on basal insulin (BI), guidelines recommend several treatment advancement options. This study compared the clinical effectiveness of once-daily iGlarLixi versus a multiple-injection BI + rapid acting insulin (RAI) regimen in adults with T2D advancing from BI therapy in real-world clinical practice. MATERIALS AND METHODS: Electronic medical records from the Observational Medical Outcomes Partnership (OMOP) database were analysed retrospectively using propensity score matching to compare therapy advancement with iGlarLixi or BI + RAI in US adults ≥18 years with T2D on BI who had ≥1 valid glycated haemoglobin (HbA1c) value at baseline and at the 6-month follow-up. The primary objective was non-inferiority of iGlarLixi to BI + RAI in HbA1c change from baseline to 6 months (margin 0.3%). RESULTS: Propensity score matching generated cohorts with balanced baseline characteristics (N = 814 in each group). HbA1c reduction from baseline to 6 months with iGlarLixi was non-inferior to BI + RAI [mean difference (95% confidence interval): 0.1 (-0.1, 0.2)%; one-sided p = .0032]. At 6 months, weight gain was significantly lower with iGlarLixi than with BI + RAI [-0.8 (-1.3, -0.2) kg; two-sided p = .0069]. Achievement of HbA1c <7% without hypoglycaemia and weight gain were similar between groups [odds ratio (95% confidence interval): 1.15 (0.81, 1.63); p = .4280]. Hypoglycaemia was low in both groups, probably because of underreporting. CONCLUSIONS: In real-world clinical practice, glycaemic outcomes 6 months after treatment advancement from BI are similar for people with T2D using iGlarLixi versus BI + RAI, with iGlarLixi leading to less weight gain.

A Significant Effect of Oral Semaglutide on Cardiovascular Risk Factors in Patients With Type 2 Diabetes.

Background: The once-daily glucagon-like peptide 1 (GLP-1) analogue, liraglutide has been shown to reduce major adverse cardiovascular events (MACE) and progression of chronic kidney disease (CKD). The once-weekly GLP-1 analogue, semaglutide also reduced MACE and renal events. Based on the evidence for GLP-1 analogues on MACE and renal events, the guideline recommended to treat high-risk diabetic individuals with GLP-1 analogues to reduce MACE and CKD progression. Recently, a once-daily oral semaglutide was developed and shown to reduce MACE. However, its effects on renal outcome and cardiovascular metabolic risk factors remain unknown. Methods: We retrospectively picked up patients who had taken oral semaglutide from March 2021 to June 2022 and compared metabolic parameters at baseline with the data at 3, 6 months after the start of oral semaglutide. Results: We found 47 patients who had taken oral semaglutide. Body weight significantly decreased at 3 and 6 months after the start of oral semaglutide, and systolic blood pressure significantly decreased after 6 months. Hemoglobin A1c (HbA1c) tended to decrease after 3 months and significantly deceased after 6 months. Serum low-density lipoprotein cholesterol (LDL-C) levels significantly decreased after 6 months and non-high-density lipoprotein-cholesterol (non-HDL-C) levels tended to decrease after 6 months. Urinary albumin to creatinine ratio (UACR) tended to decrease after 3 and 6 months. Such favorable metabolic changes by oral semaglutide were observed more prominently in patients who had not ever used GLP-1 analogues than in patients who switched from subcutaneous GLP-1 analogues. Conclusions: Our study showed that oral semaglutide improved body weight, blood pressure, HbA1c, LDL-C, non-HDL-C and UACR, in type 2 diabetic obese patients, especially, in patients who had not ever used GLP-1 analogues.

INnoVative trial design for testing the Efficacy, Safety and Tolerability of 6-month treatment with incretin-based therapy to prevent type 1 DIAbetes in autoantibody positive participants: A protocol for three parallel double-blind, randomised controlled trials (INVESTDIA).

AIMS: ß-cell stress and dysfunction may contribute to islet autoimmunity and progression to clinical type 1 diabetes. We present a protocol of three randomised controlled trials assessing the effects of glucagon-like peptide 1 (GLP - 1) analogue liraglutide in three early stages of type 1 diabetes. METHODS: We will test 10- to 30-year-old people with multiple islet autoantibodies for their glucose metabolism and randomise participants with stage 1 (multiple islet autoantibodies and normoglycaemia), stage 2 (multiple islet autoantibodies and dysglycaemia) and early stage 3 (clinical diagnosis) type 1 diabetes, 10-14 persons in each, to a 6-month intervention with liraglutide or placebo with 6-month follow-up in the stage 2 and stage 3 trials and 18-month follow-up in the stage 1 trial. Primary efficacy outcome in the stage 1 and stage 2 trials is a first-phase insulin response in an intravenous glucose tolerance test and C-peptide area under the curve in a 2-h mixed-meal tolerance test in the stage 3 trial. In addition, safety and tolerability of liraglutide treatment will be assessed. CONCLUSIONS: Most prevention trials of type 1 diabetes have targeted the immune system. Treatment with GLP-1 analogue liraglutide supports the pancreatic ß-cells, which should likewise attenuate islet autoimmunity. Our innovative study design allows simultaneous investigation of an intervention in three groups of people who represent various early stages of type 1 diabetes and maximises the eligibility to participate. TRIAL REGISTRATION: NCT02611232 (stage 1 trial), NCT02898506 (stage 2 trial), NCT02908087 (stage 3 trial).

Efficacy and safety of oral semaglutide by baseline age in Japanese patients with type 2 diabetes: A subgroup analysis of the PIONEER 9 and 10 Japan trials.

A post-hoc exploratory analysis of the PIONEER 9 and 10 trials evaluated the effect of baseline age (<65 and ≥65 years) on the efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes. In PIONEER 9 and 10, patients were randomized to once-daily oral semaglutide (3, 7 or 14 mg) or a comparator (placebo or once-daily subcutaneous liraglutide 0.9 mg [PIONEER 9]; once-weekly subcutaneous dulaglutide 0.75 mg [PIONEER 10]) for 52 weeks, with 5 weeks' follow-up. In total, 701 patients were included (PIONEER 9: N = 243; PIONEER 10: N = 458). Glycaemic efficacy of oral semaglutide was similar in Japanese patients aged <65 years compared with those ≥65 years, and there did not appear to be a clear pattern between age subgroup and body weight changes. Across treatment arms, adverse events generally occurred in greater proportions of patients aged ≥65 versus <65 years. There was generally a higher rate of premature trial product discontinuation because of adverse events in the older age group. These results indicate that oral semaglutide is efficacious in Japanese patients irrespective of age.

Glucagon-like peptide-1 analogs mitigate neuroinflammation in Alzheimer's disease by suppressing NLRP2 activation in astrocytes.

Neuroinflammation is closely linked to the pathogenesis of Alzheimer's disease (AD). Glucagon-like peptide-1 (GLP-1) analogs exhibit anti-inflammatory and neuroprotective effects; hence, we investigated whether they reduce cognitive impairment and protect astrocytes from oxidative stress. We found that 5 × FAD transgenic mice treated with the synthetic GLP-1 receptor agonist exenatide had improved cognitive function per the Morris water maze test. Immunohistochemistry, western blotting, and ELISAs used to detect inflammatory factors revealed reduced neuroinflammation in extracted piriform cortexes of exenatide-treated mice as well as lower amyloid ß1-42-induced oxidative stress and inflammation in astrocytes treated with exendin-4 (the natural analog of exenatide). Adenovirus-mediated overexpression of nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 2 (NLRP2) revealed that exenatide/exendin-4 function may be attributed to NLRP2 inflammasome inhibition. Collectively, our results indicate that GLP-1 analogs improve cognitive dysfunction in vivo and protect astrocytes in vitro, potentially via the downregulation of the NLRP2 inflammasome.

Towards Better Drug Repositioning: Targeted Immunoinflammatory Therapy for Diabetic Nephropathy.

Diabetic nephropathy (DN) is one of the most common and important microvascular complications of diabetes mellitus (DM). The main clinical features of DN are proteinuria and a progressive decline in renal function, which are associated with structural and functional changes in the kidney. The pathogenesis of DN is multifactorial, including genetic, metabolic, and haemodynamic factors, which can trigger a sequence of events. Controlling metabolic risks such as hyperglycaemia, hypertension, and dyslipidaemia is not enough to slow the progression of DN. Recent studies emphasized immunoinflammation as a critical pathogenic factor in the progression of DN. Therefore, targeting inflammation is considered a potential and novel treatment strategy for DN. In this review, we will briefly introduce the inflammatory process of DN and discuss the anti-inflammatory effects of antidiabetic drugs when treating DN.

Fixed-Ratio Combination of Insulin and GLP-1 RA in Patients with Longstanding Type 2 Diabetes: A Subanalysis of LixiLan-L.

INTRODUCTION: With longer duration and progression of type 2 diabetes (T2D), ß-cell function deteriorates and insulin therapy often becomes necessary. Glucagon-like peptide-1 receptor agonists such as lixisenatide that do not rely only on ß-cell function and glucagon suppression primarily, but also lower glucose by other (insulin-independent) mechanisms such as delayed gastric emptying, may be appropriate adjuvant therapy to basal insulin in patients with longstanding T2D. METHODS: We assessed the efficacy and safety of insulin glargine (iGlar) versus iGlarLixi, a fixed-ratio combination of iGlar and lixisenatide, stratified by quartiles (Q) of T2D duration (≤ 7.305 [Q1], > 7.305 to ≤ 10.75 [Q2], > 10.75 to ≤ 15.67 [Q3], and > 15.67 years [Q4]) in the LixiLan-L trial (N = 736). RESULTS: Across all quartiles, the reduction in glycated haemoglobin was greater with iGlarLixi versus iGlar, and the difference was most pronounced in patients with the longest duration (Q4; least squares mean difference [standard error] - 0.62 [0.13], P < 0.0001). Additionally, hypoglycaemia rates were significantly lower with iGlarLixi versus iGlar in patients in Q4 (3.3 vs. 6.9 events/patient-year, P < 0.0001). CONCLUSION: iGlarLixi lowered glycated haemoglobin more versus iGlar regardless of T2D duration, with benefit retained even among patients with the longest T2D duration.

Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens.

AIM: To assess the efficacy and tolerability of tirzepatide treatment using three different dose-escalation regimens in patients with type 2 diabetes. MATERIALS AND METHODS: In this double-blind, placebo-controlled study, patients were randomized (1:1:1:1) to receive either once-weekly subcutaneous tirzepatide or placebo. The tirzepatide dose groups and dose-escalation regimens were: 12 mg (4 mg weeks 0-3; 8 mg weeks 4-7; 12 mg weeks 8-11), 15 mg-1 (2.5 mg weeks 0-1; 5 mg weeks 2-3; 10 mg weeks 4-7; 15 mg weeks 8-11) and 15 mg-2 (2.5 mg weeks 0-3; 7.5 mg weeks 4-7; 15 mg weeks 8-11). The primary objective was to compare tirzepatide with placebo in HbA1c change from baseline at 12 weeks. RESULTS: Overall, 111 patients were randomized: placebo, 26; tirzepatide 12 mg, 29; tirzepatide 15 mg-1, 28; tirzepatide 15 mg-2, 28. The mean age was 57.4 years, HbA1c 8.4% and body mass index 31.9 kg/m2 . At week 12, absolute HbA1c change from baseline (SE) was greater in the tirzepatide treatment groups compared with placebo (placebo, +0.2% [0.21]; 12 mg, -1.7% [0.19]; 15 mg-1, -2.0% [0.20]; 15 mg-2, -1.8% [0.19]). The incidence of nausea was: placebo, 7.7%; 12 mg group, 24.1%; 15 mg-1 group, 39.3%; 15 mg-2 group, 35.7%. Three patients discontinued the treatment because of adverse events, one from each of the placebo, 12 mg and 15 mg-1 groups. CONCLUSIONS: Tirzepatide treatment for 12 weeks resulted in clinically significant reductions in HbA1c. This suggests that lower starting doses and smaller dose increments are associated with a more favourable side effect profile.

Prediction and validation of exenatide risk marker effects on progression of renal disease: Insights from EXSCEL.

AIM: To assess whether the previously developed multivariable risk prediction framework (PRE score) could predict the renal effects observed in the EXSCEL cardiovascular outcomes trial using short-term changes in cardio-renal risk markers. MATERIALS AND METHODS: Changes from baseline to 6 months in HbA1c, systolic blood pressure (SBP), body mass index (BMI), haemoglobin, total cholesterol, and new micro- or macroalbuminuria were evaluated. The renal outcomes were defined as a composite of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD). Relationships between risk markers and long-term renal outcomes were determined in patients with type 2 diabetes from the ALTITUDE study using multivariable Cox regression analysis, and then applied to short-term changes in risk markers observed in EXSCEL to predict the exenatide-induced impact on renal outcomes. RESULTS: Compared with placebo, mean HbA1c, BMI, SBP and total cholesterol were lower at 6 months with exenatide, as was the incidence of new microalbuminuria. The PRE score predicted a relative risk reduction for the 30% eGFR decline + ESRD endpoint of 11.3% (HR 0.89; 95% CI 0.83-0.94), compared with 12.7% (HR 0.87; 0.77-0.99) observed risk reduction. For the 40% eGFR decline + ESRD endpoint, the predicted and observed risk reductions were 11.0% (HR 0.89; 0.82-0.97) and 13.7% (HR 0.86, 0.72-1.04), respectively. CONCLUSIONS: Integrating short-term risk marker changes into a multivariable risk score predicted the magnitude of renal risk reduction observed in EXSCEL.

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk.

AIM: To investigate the effects of semaglutide versus comparators on major adverse cardiovascular events (MACE: cardiovascular [CV] death, nonfatal myocardial infarction [MI] and nonfatal stroke) and hospitalization for heart failure (HF) in the SUSTAIN (subcutaneous semaglutide) and PIONEER (oral semaglutide) trials across subgroups of varying CV risk. METHODS: Post hoc analyses of individual patient-level data combined from SUSTAIN 6 and PIONEER 6 were performed to assess MACE and HF. MACE were analysed in subjects with and without: established CV disease and/or chronic kidney disease; prior MI or stroke; and prior HF. MACE in the SUSTAIN and PIONEER glycaemic efficacy trials were also assessed. RESULTS: In SUSTAIN 6 and PIONEER 6 combined, the hazard ratio (HR) for effect of semaglutide versus placebo on overall MACE was 0.76 (95% CI 0.62, 0.92), which was mainly driven by the effect on nonfatal stroke (HR 0.65 [95% CI 0.43, 0.97]). The HR for hospitalization for HF was 1.03 (95% CI 0.75, 1.40). The HRs for MACE were <1.0 in all subgroups, except for those with prior HF (HR 1.06 [95% CI 0.72, 1.57]); P-values for interaction of subgroup on treatment effect were >0.05, except for HF (0.046). In the combined glycaemic efficacy trials, the HR for effect of semaglutide versus comparators on MACE was 0.85 (95% CI 0.55, 1.33). CONCLUSIONS: In SUSTAIN and PIONEER combined, glucagon-like peptide-1 analogue semaglutide showed consistent effects on MACE versus comparators across varying CV risk. No effect of semaglutide on MACE was observed in subjects with prior HF.

Enrolment criteria for diabetes cardiovascular outcome trials do not inform on generalizability to clinical practice: The case of glucagon-like peptide-1 receptor agonists.

AIM: To evaluate the generalizability of cardiovascular outcome trials (CVOTs) on glucagon-like peptide-1 receptor agonists (GLP-1RAs), we assessed what proportion of real-world patients with type 2 diabetes (T2D) constitute true CVOT-like populations. MATERIALS AND METHODS: We applied inclusion/exclusion (I/E) criteria of each GLP-1RA CVOT to a cross-sectional database of 281 380 T2D patients from Italian diabetes outpatient clinics. We calculated the proportion of patients eligible for each CVOT and compared their clinical characteristics with those of trial patients. In addition, we used a Bayesian network-based method to sample the greatest subsets of real-world patients yielding true CVOT-like populations. RESULTS: Between 98 725 and 124 164 T2D patients could be evaluated for CVOT eligibility. After excluding patients who were already on GLP-1RAs and applying I/E criteria, 35.8% of patients would be eligible for REWIND, 34.1% for PIONEER-6, 13.4% for EXSCEL, 10.1% for SUSTAIN-6, 9.5% for HARMONY and 9.4% for LEADER. Overall, 45.4% of patients could be eligible for at least one of the CVOTs. These patients, however, were extremely different to trial patients in most of the clinical characteristics, including demographics, concomitant medications and complications. The greatest CVOT-like subsets of real-world patients were 0.5% for SUSTAIN-6, 1.0% for EXSCEL, 1.2% for LEADER, 1.8% for PIONEER-6 and 7.9% for REWIND. CONCLUSIONS: A very small proportion of real-world patients constitute true CVOT-like populations. These findings question whether any meaningful information can be drawn from applying trial enrolment criteria to real-world T2D patients.