Network meta-analysis of the risk of dyspepsia and anorexia in patients with type 2 diabetes mellitus induced by glucagon-like peptide 1 receptor agonist hypoglycemic drugs.

OBJECTIVE: The aim of this study was to investigate and evaluate the risk of dyspepsia and anorexia in patients with type 2 diabetes mellitus (T2DM) induced by glucagon-like peptide 1 receptor agonist (GLP-1 RA) hypoglycemic drugs. MATERIALS AND METHODS: We searched papers in PubMed, Web of Science, Cochrane Library, Google Scholar, CNKI, Wanfang, Embase, and VIP databases, and the retrieval time limit was set from the establishment of the database to May 2023. Randomized Controlled Trials (RCTs) were collected in which the subjects were T2DM patients, the intervention was GLP-1RA compared with placebo or traditional hypoglycemic drugs, and the outcome indicators included dyspepsia and anorexia. A meta-analysis and a network meta-analysis were performed. RESULTS: The results of the traditional meta-analysis showed that the risk of dyspepsia and anorexia of total GLP-1 RA was 3.01 and 2.56 times that of placebo, respectively. All types of GLP-1RA were compared with placebo and the results also showed a trend towards increased risk of digestive system adverse events (DSAEs). Among all interventions included, liraglutide was the one with the highest risk of dyspepsia in patients with T2DM, and dulaglutide was the one with the highest risk of anorexia. CONCLUSIONS: The results of the two meta-analyses are consistent, and both clearly show that GLP-1RA can increase the risk of dyspepsia and anorexia in T2DM patients.

Case report: GLP1RA for the treatment of diabetes in liver transplanted people. Do they increase the risk of pancreatitis?

The incidence of acute pancreatitis (AP) in liver transplanted people is reported to be 1.5-8%. On the other hand, the evidence for a causal relationship between glucagon-like peptide 1 receptor agonists (GLP1RAs) and pancreatitis in people with type 2 diabetes is still weak. In addition, there are currently no data on a possible increased risk of AP in liver-transplanted individuals with diabetes treated with GLP1RAs. In a population of liver-transplanted individuals with diabetes receiving GLP1RA-based therapy, we reported an incidence of AP of 3.0% (two subjects). No cases were reported in liver-transplanted individuals with diabetes receiving SGLT2 inhibitors, insulin or metformin, neither in kidney or lung-transplanted patients treated with GLP1RAs. In both patients with AP, the only additional risk factor for its development was a history of re-transplantation (liver or combined kidney/liver). For this reason, we suggest particular caution when considering GLP1RAs-based therapies in liver transplanted patients with multiple risk factors for AP, such as a history of repeated and complex abdominal surgery.

Gastrointestinal safety evaluation of semaglutide for the treatment of type 2 diabetes mellitus: A meta-analysis.

BACKGROUND: Semaglutide, as an innovative weekly formulation, has attracted much attention. Nevertheless, the predominant occurrence of gastrointestinal adverse events (GIAEs) poses a noteworthy challenge linked to the use of this medication, substantially affecting its clinical applicability and the overall well-being of patients. Therefore, this systematic review aims to comprehensively discuss the GIAEs, providing a basis for clinical therapeutic decisions. METHODS: We systematically searched 4 independent databases for randomized controlled trials investigating the application of semaglutide in managing type 2 diabetes mellitus. The search period spanned from the inception of the databases to December 2023. We conducted a comprehensive meta-analysis, employing Review Manager 5.4.1 software, to systematically analyze and evaluate potential biases. Our primary emphasis was on assessing the gastrointestinal safety profile of semaglutide. RESULTS: The outcomes unveiled a noteworthy rise in the collective occurrence of GIAEs across all dosage groups of semaglutide in comparison with the control group (P < .05). Upon further analysis, it was observed that semaglutide showed a heightened occurrence of GIAEs in contrast to the placebo. However, statistically significant distinction was not observed when compared to the reduction of conventional doses or the transition to other types of glucagon-like peptide-1 receptor agonist. Additionally, an extended treatment duration with semaglutide (>30 weeks) demonstrated an association with a certain degree of decrease in the incidence of gastrointestinal events. Funnel plot assessment for publication bias demonstrated high-quality inclusion of studies with no apparent publication bias. CONCLUSION: The frequency of GIAEs in using semaglutide was observed to be elevated in comparison to the control group. However, it was comparable to other glucagon-like peptide-1 receptor agonist or low-dose treatment regimens. Additionally, an extended treatment duration played a role in decreasing the frequency of GIAEs. These findings provide valuable insights for clinical practice. Nonetheless, further research is crucial to explore supplementary data indicators, informing clinical practices and better serving the interests of patients.

Rare cutaneous adverse reactions associated with GLP-1 agonists: a review of the published literature.

Glucagon-like-peptide-1 (GLP-1) agonists are an emerging class of medications used to manage type 2 diabetes mellitus (T2DM) and weight loss, with demonstrated efficacy in reducing hemoglobin A1c levels, body mass index, and adverse cardiovascular events. While previous studies have reviewed notable cutaneous adverse effects with other antidiabetic medications, little is known about GLP-1 agonist-induced cutaneous reactions. Nevertheless, rare but significant cutaneous adverse reactions have been reported, including but not limited to dermal hypersensitivity reactions, eosinophilic panniculitis, bullous pemphigoid, and morbilliform drug eruptions. As GLP-1 induced cutaneous reactions are diverse, diagnosis requires clinical suspicion, thorough history-taking, and supportive histopathological findings when available. Management involves cessation of the offending agent with a tailored regimen to address inflammatory and/or immunogenic etiologies as well as irritative symptoms. This review aims to consolidate available information from case reports and case series regarding rare skin-related adverse outcomes due to GLP-1 use, aiming to provide a comprehensive overview of the presentation, pathogenesis, and management for dermatologists and other clinicians.

Evaluating the efficacy and safety of empagliflozin addition to insulin and oral antidiabetic medication (OAD) regimen in poorly controlled type 2 diabetes and obese patients.

Insulin resistance complicates diabetes care. Its effectiveness and tolerability as an addition to metformin, DPP4 inhibitor and insulin treatment in type 2 diabetic patients will be examined in this research. Participants with type 2 diabetes from poor socio-economic backgrounds had HbA1c values ≥8.5% when using Insulin+Metformin+DPP-4 inhibitors. They received 10mg Empagliflozin daily for 12 weeks (n=143). The main outcome was change in HbA1c at 12th week from baseline. Secondary outcomes were baseline weight and week 12 FPG. Adjusted mean (SE) HbA1c increases at week 12 were: Mean ± SD 10.38 (6.8-17.0) vs. Mean±SD 9.05±1.77 (5.60-16.0) with empagliflozin 10mg. When added to the regimen, empagliflozin significantly reduced FPG, systolic and diastolic blood pressure. The mean (SE) BMI increases from baseline were 31.28±5.89 (16.0-66.0) and 29.73±5.47 (3.0-46.0) with 10mg empagliflozin. Two individuals experienced urinary tract infections as AEs, but no genital infections. Adding empagliflozin 10mg daily to metformin+DPP4 inhibitor+insulin improved glycemic control, body weight and blood pressure for 12 weeks. The intervention was well-tolerated, highlighting empagliflozin's therapeutic potential.

In type 2 diabetes, the effectiveness and side effects of GLP-1 RAs vary.

SOURCE CITATION: Yao H, Zhang A, Li D, et al. Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis. BMJ. 2024;384:e076410. 38286487.

Implementation research: a protocol for two three-arm pragmatic randomised controlled trials on continuous glucose monitoring devices in people with type 1 diabetes in South Africa and Kenya.

BACKGROUND: Self-monitoring of glucose is an essential component of type 1 diabetes (T1D) management. In recent years, continuous glucose monitoring (CGM) has provided an alternative to daily fingerstick testing for the optimisation of insulin dosing and general glucose management in people with T1D. While studies have been conducted to evaluate the impact of CGM on clinical outcomes in the US, Europe and Australia, there are limited data available for low- and middle-income countries (LMICs) and further empirical evidence is needed to inform policy decision around their use in these countries. METHODS: This trial was designed as a pragmatic, parallel-group, open-label, multicentre, three-arm, randomised (1:1:1) controlled trial of continuous or periodic CGM device use versus standard of care in people with T1D in South Africa and Kenya. The primary objective of this trial will be to assess the impact of continuous or periodic CGM device use on glycaemic control as measured by change from baseline glycosylated haemoglobin (HbA1c). Additional assessments will include clinical outcomes (glucose variation, time in/below/above range), safety (adverse events, hospitalisations), quality of life (EQ-5D, T1D distress score, Glucose Monitoring Satisfaction Survey for T1D), and health economic measures (incremental cost-effectiveness ratios, quality adjusted life years). DISCUSSION: This trial aims to address the substantial evidence gap on the impact of CGM device use on clinical outcomes in LMICs, specifically South Africa and Kenya. The trial results will provide evidence to inform policy and treatment decisions in these countries. TRIAL REGISTRATION: NCT05944731 (Kenya), July 6, 2023; NCT05944718 (South Africa), July 13, 2023.

Randomized, Double-blind, Phase III Trial of Lobeglitazone Add-on to Metformin in Type 2 Diabetes (SENSITIZE INDIA).

BACKGROUND: The efficacy and safety of lobeglitazone sulfate has been reported only in the Korean population, and no study has been conducted in India. MATERIALS AND METHODS: In this 16-week randomized, double-blind, and multicenter study, the efficacy and safety of lobeglitazone sulfate 0.5 mg were evaluated with pioglitazone 15 mg. Type 2 diabetes mellitus (T2DM) patients with ≥7.5% glycated hemoglobin (HbA1c) ≤10.5% and on stable metformin dose were assigned to both treatment arms. The primary outcome was a mean change in HbA1c. Safety assessments included adverse events (AE), home-based glucose monitoring, vital parameters, electrocardiogram (ECG), and laboratory assessments. RESULTS: A total of 328 subjects were randomized equally in two groups. A statistically significant reduction in HbA1c at week 16 in the lobeglitazone group with the least square (LS) mean change: 1.01 [standard error (SE): 0.09] (p < 0.0001) was seen. The LS mean difference between the two groups was 0.05 (SE: 0.12) [95% confidence interval (CI): -0.18, 0.27], which was statistically significant (p = 0.0013). Statistically significant reductions were also observed in fasting and postprandial glucose. Treatment-emergent Aes (TEAE) were comparable between both groups. CONCLUSION: Lobeglitazone 0.5 mg once daily was found to be efficacious and safe in the treatment of T2DM in the Indian population. Lobeglitazone significantly improved glycemic parameters and was noninferior to pioglitazone; hence, it could be a promising insulin sensitizer in T2DM management in India.

Hyperglycemia in Cancer Patients.

Most of the cancer patients have multiple comorbid conditions, commonly diabetes mellitus, hypertension, and coronary vascular diseases. Cancer treatment involves a multidisciplinary approach targeting primary cancer-directed therapy along with optimal management of comorbid conditions as well. Hyperglycemia, which exists prior to cancer therapy initiation or if it develops during or after therapy, is associated with less desirable outcomes like treatment compromise due to increased adverse effects of therapy and higher mortality. Hence, prompt diagnoses and management of hyperglycemia become crucial during therapy. Healthcare providers working in an oncology setting, as well as primary care providers, should be aware of medications that are associated with hyperglycemia and diabetes. This paper will elucidate various cancer-directed therapies associated with hyperglycemia.

Association of RASGRP1 polymorphism with vascular complications in Chinese diabetic patients with glycemic control and antihypertensive treatment.

BACKGROUND: Studies have shown that RASGRP1 was potently associated with the onset of type 2 diabetes mellitus (T2DM), and RASGRP1 rs7403531 was significantly correlated with islet function in T2DM patients. However, the effect of RASGRP1 polymorphism on blood glucose and blood pressure in T2DM patients after continuous treatment has yet to be fully elucidated. OBJECTIVE: This study aimed to explore the association between RASGRP1 genetic polymorphism and cardiovascular complications in T2DM patients, so as to provide more evidence for the individualized treatment of T2DM patients. METHODS: We retrospectively analyzed a large-scale multicenter drug clinical study cohort that based on a 2 × 2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled design, with follow-up for 5 years. The major vascular endpoint events included cardiovascular death, non-fatal stroke, coronary heart disease, new-onset or worsening renal disease, and diabetic retinopathy. RASGRP1 rs12593201, rs56254815 and rs7403531 were finally selected as candidate single nucleotide polymorphisms. Mixed linear model and Cox hazard ratio (HR) model were used for data analysis with IBM SPSS (version 20.0 for windows; Chicago, IL). RESULTS: Our study enrolled 1357 patients with high-risk diabetes, with a mean follow-up duration of 4.8 years. RASGRP1 rs7403531 was associated with vascular events in hypoglycemic and antihypertensive therapy. Specifically, compared with CC carriers, patients with CT/TT genotype had fewer major microvascular events (HR = 0.41, 95% confidence interval (CI) 0.21-0.80, P = 0.009), and reduced the risk of major eye disease events (HR = 0.44, 95% CI 0.20-0.94, P = 0.03). For glucose lowering axis, CT/TT carriers had a lower risk of secondary nephropathy (HR = 0.48, 95% CI 0.25-0.92, P = 0.03) in patients with standard glycemic control. For blood pressure lowering axis, all cerebrovascular events (HR = 2.24, 95% CI 1.11-4.51, P = 0.025) and stroke events (HR = 2.07, 95% CI 1.03-4.15, P = 0.04) were increased in patients with CC genotype compared to those with CT/TT genotype in the placebo group, respectively. Furthermore, patients with CC genotype showed a reduced risk of major cerebrovascular events in antihypertensive group (HR = 0.36, 95% CI 0.15-0.86, P = 0.021). For RASGRP1 rs56254815, compared with the AA genotype carriers, the systolic blood pressure of AG/GG carriers in the antihypertensive group decreased by 1.5mmhg on average (P = 0.04). In the placebo group, the blood pressure of AG/GG carriers was 1.7mmHg higher than that of AA carriers (P = 0.02). CONCLUSION: We found that patients with G allele of RASGRP1 (rs56254815) showed a better antihypertensive therapy efficacy in T2DM patients. The rs7403531 T allele could reduce the risk of major microvascular events and major eye diseases in T2DM patients receiving either hypoglycemic or antihypertensive therapy. Our findings suggest that RASGRP1 genetic polymorphism might predict the cardiovascular complications in T2DM patients.

[Prevalence of hypophosphatemia in children with diabetic ketoacidosis and treatment with subcutaneous regular insulin. Observational study]. / Prevalencia de Hipofosfatemia en niños con cetoacidosis diabética y tratamiento con insulina regular subcutánea. Estudio observacional.

Diabetic ketoacidosis (DKA) is one of the most serious complications of type 1 diabetes mellitus. Its treatment requires fluid and electrolyte replacement and insulin. Hypophosphatemia as a complication of treatment has been scarcely evaluated. OBJECTIVES: To estimate the incidence of hypophosphatemia in children with DKA, treated with subcutaneous regular insulin (IRS), and to explore factors associated with this complication. PATIENTS AND METHOD: Prospective, observational study. Patients diagnosed with DKA hospitalized in the general care ward were included. Data on phosphatemia, glycemia, acid-base status, and IRS amount (U/kg) received were recorded at baseline and after 24 h of treatment. Hypophosphatemia was defined as values below 2.5 mg/dl. The correlation between initial phosphate and at 24 h of treatment was evaluated; the incidence of hypophosphatemia at 24 h was expressed as a percentage of the total number of patients. RESULTS: 30 patients were included, 15 were female, mean age 11.4 ± 3.2 years. At 24 h of treatment with IRS, 36.7% (95%CI 22-55%) presented hypophosphatemia, mean value 1.9 ± 1.5 mg/dl. Initial bicarbonate < 10 mmol/L acted as a predictor of hypophosphatemia (OR 7.5; 95%CI 1.4-39.8%; p = 0.01). No patient required intravenous phosphate correction, and no associated clinical complications were observed. CONCLUSION: In the group studied, the incidence of hypophosphatemia reached 36.7% at 24 hours of treatment. Initial bicarbonate lower than 10 mmol/L was significantly associated with hypophosphatemia. No complications associated with hypophosphatemia were observed.

Is GFR decline induced by SGLT2 inhibitor of clinical importance?

BACKGROUND: Use of sodium-glucose-cotransporter-2 (SGLT2) inhibitors often causes an initial decline in glomerular filtration rate (GFR). This study addresses the question whether the initial decline of renal function with SGLT2 inhibitor treatment is related to vascular changes in the systemic circulation. METHODS: We measured GFR (mGFR) and estimated GFR (eGFR) in 65 patients with type 2 diabetes (T2D) at baseline and after 12 weeks of treatment randomized either to a combination of empagliflozin and linagliptin (SGLT2 inhibitor based treatment group) (n = 34) or metformin and insulin (non-SGLT2 inhibitor based treatment group) (n = 31). mGFR was measured using the gold standard clearance technique by constant infusion of inulin. In addition to blood pressure (BP), we measured pulse wave velocity (PWV) under standardized conditions reflecting vascular compliance of large arteries, as PWV is considered to be one of the most reliable vascular parameter of cardiovascular (CV) prognosis. RESULTS: Both mGFR and eGFR decreased significantly after initiating treatment, but no correlation was found between change in mGFR and change in eGFR in either treatment group (SGLT2 inhibitor based treatment group: r=-0.148, p = 0.404; non-SGLT2 inhibitor based treatment group: r = 0.138, p = 0.460). Noticeably, change in mGFR correlated with change in PWV (r = 0.476, p = 0.005) in the SGLT2 inhibitor based treatment group only and remained significant after adjustment for the change in systolic BP and the change in heart rate (r = 0.422, p = 0.018). No such correlation was observed between the change in eGFR and the change in PWV in either treatment group. CONCLUSIONS: Our main finding is that after initiating a SGLT2 inhibitor based therapy an exaggerated decline in mGFR was related with improved vascular compliance of large arteries reflecting the pharmacologic effects of SGLT2 inhibitor in the renal and systemic vascular bed. Second, in a single patient with T2D, eGFR may not be an appropriate parameter to assess the true change of renal function after receiving SGLT2 inhibitor based therapy. TRIAL REGISTRATION: clinicaltrials.gov (NCT02752113).

Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes.

BACKGROUND: Diabetes is associated with high risks of premature chronic kidney disease (CKD), cardiovascular diseases, cardiovascular death and impaired quality of life. People with diabetes are more likely to develop kidney impairment, and approximately one in three adults with diabetes have CKD. People with CKD and diabetes experience a substantially higher risk of cardiovascular outcomes. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors have shown potential effects in preventing kidney and cardiovascular outcomes in people with CKD and diabetes. However, new trials are emerging rapidly, and evidence synthesis is essential to summarising cumulative evidence. OBJECTIVES: This review aimed to assess the benefits and harms of SGLT2 inhibitors for people with CKD and diabetes. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 17 November 2023 using a search strategy designed by an Information Specialist. Studies in the Register are continually identified through regular searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled studies were eligible if they evaluated SGLT2 inhibitors versus placebo, standard care or other glucose-lowering agents in people with CKD and diabetes. CKD includes all stages (from 1 to 5), including dialysis patients. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the study risk of bias. Treatment estimates were summarised using random effects meta-analysis and expressed as a risk ratio (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The primary review outcomes were all-cause death, 3-point and 4-point major adverse cardiovascular events (MACE), fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, and kidney failure. MAIN RESULTS: Fifty-three studies randomising 65,241 people with CKD and diabetes were included. SGLT2 inhibitors with or without other background treatments were compared to placebo, standard care, sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, or insulin. In the majority of domains, the risks of bias in the included studies were low or unclear. No studies evaluated the treatment in children or in people treated with dialysis. No studies compared SGLT2 inhibitors with glucagon-like peptide-1 receptor agonists or tirzepatide. Compared to placebo, SGLT2 inhibitors decreased the risk of all-cause death (20 studies, 44,397 participants: RR 0.85, 95% CI 0.78 to 0.94; I2 = 0%; high certainty) and cardiovascular death (16 studies, 43,792 participants: RR 0.83, 95% CI 0.74 to 0.93; I2 = 29%; high certainty). Compared to placebo, SGLT2 inhibitors probably make little or no difference to the risk of fatal or nonfatal MI (2 studies, 13,726 participants: RR 0.95, 95% CI 0.80 to 1.14; I2 = 24%; moderate certainty), and fatal or nonfatal stroke (2 studies, 13,726 participants: RR 1.07, 95% CI 0.88 to 1.30; I2 = 0%; moderate certainty). Compared to placebo, SGLT2 inhibitors probably decrease 3-point MACE (7 studies, 38,320 participants: RR 0.89, 95% CI 0.81 to 0.98; I2 = 46%; moderate certainty), and 4-point MACE (4 studies, 23,539 participants: RR 0.82, 95% CI 0.70 to 0.96; I2 = 77%; moderate certainty), and decrease hospital admission due to heart failure (6 studies, 28,339 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 17%; high certainty). Compared to placebo, SGLT2 inhibitors may decrease creatinine clearance (1 study, 132 participants: MD -2.63 mL/min, 95% CI -5.19 to -0.07; low certainty) and probably decrease the doubling of serum creatinine (2 studies, 12,647 participants: RR 0.70, 95% CI 0.56 to 0.89; I2 = 53%; moderate certainty). SGLT2 inhibitors decrease the risk of kidney failure (6 studies, 11,232 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 0%; high certainty), and kidney composite outcomes (generally reported as kidney failure, kidney death with or without ≥ 40% decrease in estimated glomerular filtration rate (eGFR)) (7 studies, 36,380 participants: RR 0.68, 95% CI 0.59 to 0.78; I2 = 25%; high certainty) compared to placebo. Compared to placebo, SGLT2 inhibitors incur less hypoglycaemia (16 studies, 28,322 participants: RR 0.93, 95% CI 0.89 to 0.98; I2 = 0%; high certainty), and hypoglycaemia requiring third-party assistance (14 studies, 26,478 participants: RR 0.75, 95% CI 0.65 to 0.88; I2 = 0%; high certainty), and probably decrease the withdrawal from treatment due to adverse events (15 studies, 16,622 participants: RR 0.94, 95% CI 0.82 to 1.08; I2 = 16%; moderate certainty). The effects of SGLT2 inhibitors on eGFR, amputation and fracture were uncertain. No studies evaluated the effects of treatment on fatigue, life participation, or lactic acidosis. The effects of SGLT2 inhibitors compared to standard care alone, sulfonylurea, DPP-4 inhibitors, or insulin were uncertain. AUTHORS' CONCLUSIONS: SGLT2 inhibitors alone or added to standard care decrease all-cause death, cardiovascular death, and kidney failure and probably decrease major cardiovascular events while incurring less hypoglycaemia compared to placebo in people with CKD and diabetes.

Semaglutide combined with empagliflozin vs. monotherapy for non-alcoholic fatty liver disease in type 2 diabetes: Study protocol for a randomized clinical trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM). Lifestyle intervention remains a preferred treatment modality for NAFLD. The glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been developed as new glucose-lowering drugs, which can improve fatty liver via an insulin-independent glucose-lowering effect. However, studies exploring the efficacy of GLP-1 receptor agonists combined with SGLT-2 inhibitors in patients with NAFLD and T2DM are scanty. Thus, the present randomised controlled trial aims at comparing the efficacy and safety of semaglutide plus empagliflozin with each treatment alone in patients with NAFLD and T2DM. METHODS: This 52-week double-blinded, randomised, parallel-group, active-controlled trial evaluates the effects of semaglutide, empagliflozin and semaglutide + empagliflozin in 105 eligible overweight/obese subjects with NAFLD and T2DM. The primary outcome will be a change from baseline to week 52 in the controlled attenuation parameter, free fatty acid and glucagon. Secondary endpoints include changes in liver stiffness measurement, liver enzymes, blood glucose, lipid levels, renal function, electrolyte balances, minerals and bone metabolism, cytokines, high-sensitivity C-reactive protein, ferritin, anthropometric indicators, nonalcoholic fatty liver fibrosis score, fibrosis 4 score and homeostatic model assessment for insulin resistance. In addition, intention-to-treat, interim analysis and safety analysis will be performed. DISCUSSION: This double-blinded, randomised, clinical trial involves a multi-disciplinary approach and aims to explore the synergistic effects of the combination of semaglutide and empagliflozin. The results can provide important insights into mechanisms of GLP-1 receptor agonists and/or SGLT-2 inhibitors in patients with NAFLD and T2DM. TRIAL REGISTRATION: This study has been registered with Chinese Clinical Trial Registry (ChiCTR2300070674).

Clinical perspectives on the frequency of hypoglycemia in treat-to-target randomized controlled trials comparing basal insulin analogs in type 2 diabetes: a narrative review.

The objective of this review was to comprehensively present and summarize trends in reported rates of hypoglycemia with one or two times per day basal insulin analogs in individuals with type 2 diabetes to help address and contextualize the emerging theoretical concern of increased hypoglycemic risk with once-weekly basal insulins.Hypoglycemia data were extracted from treat-to-target randomized clinical trials conducted during 2000-2022. Published articles were identified on PubMed or within the US Food and Drug Administration submission documents. Overall, 57 articles were identified: 44 assessed hypoglycemic outcomes in participants receiving basal-only therapy (33 in insulin-naive participants; 11 in insulin-experienced participants), 4 in a mixed population (insulin-naive and insulin-experienced participants) and 9 in participants receiving basal-bolus therapy. For the analysis, emphasis was placed on level 2 (blood glucose <3.0 mmol/L (<54 mg/dL)) and level 3 (or severe) hypoglycemia.Overall, event rates for level 2 or level 3 hypoglycemia across most studies ranged from 0.06 to 7.10 events/person-year of exposure (PYE) for participants receiving a basal-only insulin regimen; the rate for basal-bolus regimens ranged from 2.4 to 13.6 events/PYE. Rates were generally lower with second-generation basal insulins (insulin degludec or insulin glargine U300) than with neutral protamine Hagedorn insulin or first-generation basal insulins (insulin detemir or insulin glargine U100). Subgroup categorization by sulfonylurea usage, end-of-treatment insulin dose or glycated hemoglobin reduction did not show consistent trends on overall hypoglycemia rates. Hypoglycemia rates reported so far for once-weekly basal insulins are consistent with or lower than those reported for daily-administered basal insulin analogs.