GLP-1 RAs Research Articles

GLP-1 Receptor Agonists and Related Mental Health Issues; Insights from a Range of Social Media Platforms Using a Mixed-Methods Approach.

The emergence of glucagon-like peptide-1 receptor agonists (GLP-1 RAs; semaglutide and others) now promises effective, non-invasive treatment of obesity for individuals with and without diabetes. Social media platforms' users started promoting semaglutide/Ozempic as a weight-loss treatment, and the associated increase in demand has contributed to an ongoing worldwide shortage of the drug associated with levels of non-prescribed semaglutide intake. Furthermore, recent reports emphasized some GLP-1 RA-associated risks of triggering depression and suicidal thoughts. Consistent with the above, we aimed to assess the possible impact of GLP-1 RAs on mental health as being perceived and discussed in popular open platforms with the help of a mixed-methods approach. Reddit posts yielded 12,136 comments, YouTube videos 14,515, and TikTok videos 17,059, respectively. Out of these posts/entries, most represented matches related to sleep-related issues, including insomnia (n = 620 matches); anxiety (n = 353); depression (n = 204); and mental health issues in general (n = 165). After the initiation of GLP-1 RAs, losing weight was associated with either a marked improvement or, in some cases, a deterioration, in mood; increase/decrease in anxiety/insomnia; and better control of a range of addictive behaviors. The challenges of accessing these medications were a hot topic as well. To the best of our knowledge, this is the first study documenting if and how GLP-1 RAs are perceived as affecting mood, mental health, and behaviors. Establishing a clear cause-and-effect link between metabolic diseases, depression and medications is difficult because of their possible reciprocal relationship, shared underlying mechanisms and individual differences. Further research is needed to better understand the safety profile of these molecules and their putative impact on behavioral and non-behavioral addictions.

Weight Loss Effect of GLP-1 RAs With Endoscopic Bariatric Therapy and Bariatric Surgeries.

Different treatment modalities are available for obesity management, including lifestyle changes, pharmacotherapy, endoscopic interventions, and surgeries. Limited evidence is available on the weight loss effect of combining glucagon-like peptide 1 receptor agonists (GLP-1 RAs) with endoscopic bariatric therapy (EBT) and bariatric surgeries (BS). In this systematic review, we compared the weight loss effect and metabolic changes of combining GLP-1 RAs with EBT and BS. Literature searches were performed in the Cochrane Database of Systematic Review, Cochrane Central Register of Controlled Trials, Embase, PubMed, Google Scholar, and PRISMA databases. Only randomized control trials and retrospective studies were included. A total of 11 studies was included. Nine studies compared BS with and without liraglutide and 2 compared EBT with and without liraglutide. Adding liraglutide to EBT or BS provided significant weight loss when compared with EBT or BS alone. When changes in weight were compared across the studies, EBT with liraglutide showed a weight loss effect comparable to the net weight loss (ie, nadir weight loss after BS-regained weight) achieved following BS alone. This review showcases a promising approach for managing obesity that combines GLP-1 RAs with EBT. This approach is expected to achieve shorter hospital stays, fewer side effects, and longer term weight loss benefits than BS alone. However, additional prospective studies with higher quality, more consistent outcome measures for weight loss and metabolic changes are needed to further evaluate the approach.

Glucagon-like Peptide-1 Receptor Agonist Treatment in Type 1 Diabetes

Type 1 diabetes (T1D) is characterized by a progressive decline of insulin production due to a marked destruction of pancreatic B cells. Intensive insulin therapy is the pillar of T1D management. More recently, continuous glucose monitoring devices, closed-loop systems (CLS) and smarter connected insulin pen systems have all significantly helped individuals to improve glycemic control. Despite these advances, however, more than three-quarters of the adult T1D population does not achieve recommended glycemic targets. In addition, aggressive insulin intensification potentiates weight gain and the risk of recurrent hypoglycemic events. Recent significant increase in rates of obesity has also led to a sharp increase in T1D patients who concurrently have adiposity-based chronic disease, increasing their insulin resistance and predisposition for cardiovascular events. While insulin will remain the basis of T1D management, there is an unmet need for individualized adjunctive therapeutic approaches focusing on the prevention of diabetic complications in addition to glycemic control. One such adjunctive therapy currently being explored in T1D are the glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a popular and robust approach in Type 2 diabetes (T2DM) to mimic the natural endogenous GLP-1 incretin. This brief review will focus on the rationale and existing evidence for the use of GLP-1 RAs in the management of T1D.

SAT085 Oral Glucagon-like Peptide-1 Receptor Agonist As Adjuvant Treatment In HNF1A-MODY

Abstract Disclosure: D.T. Broome: Grant Recipient; Self; NIH U54DK118612-04. Research Investigator; Self; Fractyl Laboratories, Novo Nordisk. Maturity-onset diabetes of the young (MODY) is an inherited form of monogenic diabetes caused by a mutation in a single gene. HNF1A-MODY is the most common treatment-requiring form of MODY with a reported frequency of 1.2%1. Early genetic diagnosis leads to more precise treatment, and sulfonylureas have been recognized as first-line treatment in patients with HNF1A-MODY. Although sulfonylurea treatment is often effective early in the disease course, patients often experience sulfonylurea treatment failure. As a result, there has been recent investigation into additional treatment options that are effective. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have previously been published for use in patients with HNF1A-MODY2,3, and recognized as a potential effective treatment in patients with HNF1A-MODY. Although GLP-1 RAs have been reported for use as injectable agents, there is currently no evidence reporting their effectiveness as oral medications. In this report, we present a novel case of use of oral semaglutide as adjuvant treatment to sulfonylurea in a patient with HNF1A-MODY. A 48-year-old female with a history of diabetes since age 22, later confirmed as HNF1A-MODY at age 45 (Heterozygous HNF1A mutation, c.608G>A (p.Arg203His), NM_000545.5), was glimepiride for 3 years and without micro- or macrovascular complications. She developed a 15-lb weight gain, and her HbA1c increased to 7% (HbA1c gradually increasing from 5.4% to 7.0% over 3 years) despite her taking glimepiride 4 mg twice daily prescribed by her primary care physician. Thereafter, her primary care physician prescribed oral semaglutide 3 mg once daily for 4 weeks, which was titrated to 7 mg once daily. After initiation of oral semaglutide, her glimepiride was reduced to 2 mg once daily, her HbA1c improved to 5.4%, and she lost 30 lbs over a 6-month timeframe. This is the first report demonstrating the benefits of oral GLP-1 RA treatment in a patient with HNF1A-MODY, and this clinical case provides further support of use GLP-1 RA use as adjuvant treatment to sulfonylurea in patients with HNF1A-MODY.

FRI639 Effect Of Early Initiation Of GLP-1 RAs On Weight Reduction Among People With Type 2 Diabetes

Abstract Disclosure: C. Chinthammit: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. R. Mody: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. D. Liu: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. B.D. Benneyworth: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. C. Vallarino: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. Early initiation of glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy is associated with improved glycemic outcomes among people with type 2 diabetes (T2D). However, there is limited real-world evidence suggesting a similar impact on weight reduction. This study examined the relationship between timing of initiation of a GLP-1 RA and magnitude of weight reduction. This retrospective cohort study used data from the Optum® de-identified Market Clarity database from April 1, 2014, to March 31, 2020. Adults with T2D who initiated GLP-1 RA treatment during the index period, April 1, 2016 - March 31, 2019, were included. Date of first prescription was defined as index date. Patients were required to have continuous enrollment ≥2 years pre-index and 1-year post-index; have ≥1 weight and BMI values during the 6-month baseline and 1-year post-index periods; baseline BMI ≥25 kg/m2, and ≥1 pre-index oral antihyperglycemic drug (OAD) claim. Timing of GLP-1 RA initiation was proxied by the number of classes of OADs (1 OAD, 2 OADs, 3+ OADs) prescribed in the pre-index period, with fewer OADs indicating initiation of GLP-1 RA earlier in disease progression. Outcomes included weight change from baseline to 6 and 12 months of follow-up and proportion of patients achieving ≥5% weight reduction after GLP-1 RA initiation. In order to control for confounding, multivariable analyses (MVA) used weights based on propensity scores to examine the relationship between timing of GLP-1 RA initiation and post-index weight outcomes. Of the 4,194 patients evaluated, 1,317 (31.4%), 1,480 (35.3%), and 1,397 (33.3%) were classified into the 1 OAD, 2 OAD, and 3+ OAD cohorts, respectively. Baseline characteristics were fairly uniform across the three cohorts, but the 1 OAD cohort had more females (59.5%) than 2 OAD (51.1%) and 3+ OAD (44.7%), and a higher mean baseline BMI (1 OAD: 38.7 kg/m2; 2 OAD: 37.4 kg/m2; 3+ OAD: 36.4 kg/m2; p<0.0001). The 1 OAD cohort experienced a larger magnitude of weight reduction from baseline to 6 months (-3.0 kg) and 12 months (-3.1 kg) of follow-up vs 2 OAD (-2.4 kg and -2.7 kg) and 3+ OAD (-2.3 kg and -2.4 kg). The 1 OAD cohort had the largest proportion of patients who achieved ≥5% weight reduction at 6 months (24.9%) and 12 months of follow-up (25.5%) vs 2 OAD (19.7% and 22.1%) and 3+ OAD (21.4% and 20.6%). MVA showed that earlier GLP-1 RA initiation (1 OAD) was associated with greater weight reduction at 6 months (p=0.008) and 12 months (p=0.012) of follow-up compared to later initiation (3+ OAD). No significant differences in weight change were observed between the 2 OAD and 3+ OAD cohorts. This study showed that earlier initiators (1 OAD) of a GLP-1 RA experienced a larger magnitude of weight reduction than later initiators (3+ OADs). The research underscores the importance of further exploring the potential impact of early T2D treatment on weight reduction. Presentation: Friday, June 16, 2023

2023 Clinical Practice Guidelines for Diabetes: Recommendations for Pharmacological Treatment of Type 2 Diabetes

The 2023 clinical practice guidelines for diabetes in Korea are reviewed and updated biennially by the Committee of Clinical Practice Guidelines of the Korean Diabetes Association based on the latest scientific research and clinical trials. The 2023 guidelines include several updates to recommendations for pharmacological treatment of type 2 diabetes. The new guidelines make it clear that the treatment plan should include antidiabetic agents proven to reduce cardiorenal risk in adults with type 2 diabetes and established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease. When considering injection-based combination therapy, GLP-1 receptor agonists (GLP-1 RAs) are recommended prior to basal insulin. If the target blood glucose level cannot be reached with GLP-1 RAs or basal insulin treatment alone, combination treatment with GLP-1 RAs and basal insulin is recommended. This review summarizes the recommendations for pharmacological treatment for type 2 diabetes in the 2023 Korean Diabetes Association treatment guidelines, focusing on major revisions.

Approach to Fatty Liver Disease in Patients with Type 2 Diabetes

Type 2 diabetes is a major risk factor for development and progression of non-alcoholic fatty liver disease (NAFLD). Fatty liver is prevalent in people with type 2 diabetes, and overweight or obesity in these patients aggravates insulin resistance and steatohepatitis, which appear to be drivers for the disease progression. The goal of screening is not to identify steatosis itself, but rather to identify patients at risk for adverse hepatic outcomes such as cirrhosis, hepatocellular carcinoma, and death from liver disease. The most important risk factors for disease progression are liver fibrosis and its severity. There is a consensus that the FIB-4 (fibrosis-4 index) is the most cost-effective strategy for initial screening of hepatic fibrosis in a clinical setting. At present, there are no approved drugs for the treatment of NAFLD. Clinically significant improvements in NAFLD are achieved with weight loss. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium glucose cotransporter 2 (SGLT2) inhibitors are effective for inducing weight loss in patients with type 2 diabetes, and some GLP-1 RAs and SGLT2 inhibitors have been shown to be effective for treating steatohepatitis. Therefore, GLP-1 RAs and SGLT2 inhibitors should be considered when choosing antidiabetic agents in patients with type 2 diabetes and NAFLD, especially in those who are overweight or obese.

Comparative efficacy of glucose-lowering drugs on liver steatosis as assessed by means of magnetic resonance imaging in patients with type 2 diabetes mellitus: systematic review and network meta-analysis

PurposeTo assess the comparative efficacy of glucose-lowering drugs on liver steatosis as assessed by means of magnetic resonance imaging (MRI) in patients with T2D.MethodsWe searched several databases and grey literature sources. Eligible trials had at least 12 weeks of intervention, included patients with T2D, and assessed the efficacy of glucose-lowering drugs as monotherapies. The primary outcome of interest was absolute reduction in liver fat content (LFC), assessed by means of MRI. Secondary efficacy outcomes were reduction in visceral and subcutaneous adipose tissue. We performed random effects frequentist network meta-analyses to estimate mean differences (MDs) with 95% confidence intervals (CIs). We ranked treatments based on P-scores.ResultsWe included 29 trials with 1906 patients. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors (P-score 0.84) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) (0.71) were the most efficacious in terms of liver fat content reduction. Among individual agents, empagliflozin was the most efficacious (0.86) and superior to pioglitazone (MD -5.7, 95% CI -11.2 to -0.3) (very low confidence). GLP-1 RAs had also the most favorable effects on visceral and subcutaneous adipose tissue.ConclusionsGLP-1 RAs and SGLT-2 inhibitors seem to be the most efficacious glucose-lowering drugs for liver steatosis in patients with T2D. Assessment of their efficacy on NAFLD in patients irrespective of presence of T2D is encouraged.

Shorter-acting glucagon-like peptide-1 receptor agonists are associated with increased development of gastro-oesophageal reflux disease and its complications in patients with type 2 diabetes mellitus: a population-level retrospective matched cohort study

BackgroundShorter half-life glucagon-like peptide-1 receptor agonists (GLP-1 RAs) delay gastric emptying (DGE) more than GLP-1 RAs with longer half-lives. DGE is a known risk factor for gastro-oesophageal reflux disease (GERD)...

Glycaemic Control and Weight Reduction: A Narrative Review of New Therapies for Type 2 Diabetes.

Early and intensive treatment of type 2 diabetes (T2D) has been associated with lower risk of diabetes-related complications. Control of overweight and obesity, which are strongly associated with T2D and many of its complications, is also key in the management of the disease. New therapies allow for individualised glycaemic control targets with greater safety. Thus, in patients with a higher cardiovascular and renal risk profile, current guidelines encourage early treatment with metformin together with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 inhibitors with proven cardiovascular benefit. GLP-1 RAs combine highly efficacious glucose-lowering activity with a reduced risk of hypoglycaemia. Recently, tirzepatide, a first-in-class drug that activates both glucose-dependent insulinotropic polypeptide and GLP-1 receptors, has demonstrated very high efficacy in glycated haemoglobin (HbA1c) and weight reduction in clinical trials. Tirzepatide has the potential to help people with T2D reach recommended glycaemic and weight targets (HbA1c < 7% and > 5% weight reduction) and to allow some patients to reach HbA1c measurements close to normal physiological levels and substantial weight reduction. In 2022, tirzepatide was approved by the US Food and Drug Administration and the European Medicines Agency for treatment of people with T2D and is currently in development for chronic weight management.

Antidiabetic Molecule Efficacy in Patients with Type 2 Diabetes Mellitus-A Real-Life Clinical Practice Study.

In this paper, we aim to evaluate the efficacy of antidiabetic cardioprotective molecules such as Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) and Glucagon-like Peptide 1 Receptor Agonists (GLP-1 RAs) when used with other glucose-lowering drugs, lipid-lowering, and blood pressure (BP)-lowering drugs in a real-life setting. A retrospective, observational study on 477 patients admitted consecutively in 2019 to the outpatient clinic of a tertiary care unit for Diabetes Mellitus was conducted. Body mass index (BMI), blood pressure (BP) (both systolic and diastolic), and metabolic parameters, as well as A1c hemoglobin, fasting glycaemia and lipid profile, including total cholesterol (C), HDL-C, LDL-C and triglycerides), were evaluated at baseline and two follow-up visits were scheduled (6 months and 12 months) in order to assess the antidiabetic medication efficacy. Both SGLT-2i and GLP-1 RAs were efficient in terms of weight control reflected by BMI; metabolic control suggested by fasting glycaemia and A1c; and the diastolic component of BP control when comparing the data from the 6 and 12-month visits to the baseline, and when comparing the 12-month visit to the 6-month visit. Moreover, when comparing SGLT-2i and GLP-1 RAs with metformin, there are efficacy data for SGLT-2i at baseline in terms of BMI, fasting glycaemia, and HbA1c. In this retrospective study, both classes of cardioprotective molecules, when used in conjunction with other glucose-lowering, antihypertensive, and lipid-lowering medications, appeared to be efficient in a real-life setting for the management of T2DM.

Cardiovascular efficacy and safety of antidiabetic agents: A network meta-analysis of randomized controlled trials.

An important characteristic of glucose-lowering therapies (GLTs) is their ability to prevent cardiovascular complications. We aimed to investigate the cardiorenal efficacy and general safety of GLTs. Multicentre, randomized, clinical trials that included over 100 participants comparing antidiabetic agents with a placebo or a different antidiabetic agent and reporting major adverse cardiovascular events (MACEs), or primarily reporting heart failure, were searched in the PubMed, Embase and Cochrane databases. Data were extracted independently for random-effects network meta-analyses to calculate the hazard ratio estimates. Forty-three trials that compared nine types of GLTs were included in the present analysis. The risk of three-point MACE was reduced in the presence of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and thiazolidinedione therapy compared with the placebo, dipeptidyl peptidase-4 inhibitors, or insulin therapy. GLP-1 RAs were favourable for cardiovascular and renal outcomes. SGLT-2is reduced renal outcomes by ~40%, which was superior to other GLTs. Thiazolidinedione therapy increased the risks of hospitalization for heart failure and had no benefits on mortality. Adverse events leading to drug discontinuation were higher with GLP-1 RAs and thiazolidinediones than placebo. GLP-1 RAs, SGLT-2is and thiazolidinediones reduced three-point MACE compared with other GLTs. Each drug class had unique advantages and disadvantages.

The Impact of Web-Based Continuing Medical Education Using Patient Simulation on Real-World Treatment Selection in Type 2 Diabetes: Retrospective Case-Control Analysis.

Despite guidelines recommending the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in certain patients with type 2 diabetes (T2D), they are not being prescribed for many of these patients. Web-based continuing medical education (CME) patient simulations have been used to identify clinicians' practice gaps and improve clinical decision-making as measured within a simulation, but the impact of this format on real-world treatment has not been researched. This study aimed to evaluate the effect of a simulation-based CME intervention on real-world use of GLP-1 RAs by endocrinologists and primary care physicians. Two evaluation phases of the CME simulation were conducted: phase I, the CME simulation phase, was a paired, pre-post study of 435 physician learners in the United States; and phase II, the real-world phase, was a retrospective, matched case-control study of 157 of the 435 physicians who had claims data available for the study period. Phase I CME results showed a 29 percentage point increase in correct decisions from pre- to postfeedback (178/435, 40.9% to 304/435, 69.9%; P<.001) in selecting treatment that addresses both glycemic control and cardiovascular event protection. Phase II results showed that 39 of 157 (24.8%) physicians in the intervention group increased use of GLP-1 RAs, compared to 20 of 157 (12.7%) in the comparison group. Being in the intervention group predicted GLP-1 RA use after education (odds ratio 4.49; 95% CI 1.45-13.97; P=.001). A web-based CME simulation focused on secondary prevention of cardiovascular events in a patient with T2D was associated with increased use of evidence-based treatment selection in the real world.

The effects of GLP-1 receptor agonists on visceral fat and liver ectopic fat in an adult population with or without diabetes and nonalcoholic fatty liver disease: A systematic review and meta-analysis.

To uncover the effect of GLP-1 receptor agonists (GLP-1 RAs) on the visceral- and hepatic fat content of adults. PubMed, EMBASE, Cochrane Library, and Web of Science were searched from inception until November 2022. Randomized controlled trials (RCTs) of GLP-1Ras was extracted, including reports of effects on visceral adipose tissue and hepatic fat content in individuals with type 2 diabetes, non-type 2 diabetes, NAFLD (non-alcoholic fatty liver disease), and non-NAFLD. Meta-analyses used random-effects models. 1736 individuals in the 30 qualified RCTs were included, comprising 1363 people with type 2 diabetes and 318 with NFLD. GLP-1 RAs reduced visceral adipose tissue (standard mean difference [SMD] = -0.59, 95% CI [-0.83, -0.36], P<0.00001) and hepatic fat content (weighted mean difference [WMD] = -3.09, 95% CI [-4.16, -2.02], P<0.00001) compared to other control treatment. Subgroup analysis showed that GLP-1Ras dramatically decreased visceral fat in patients with type 2 diabetes (SMD = -0.49, 95% CI [-0.69, -0.29] P<0.00001), NAFLD (SMD = -0.99, 95% CI [-1.64, -0.34] P = 0.003), non-type 2 diabetes (SMD = -1.38, 95% CI [-2.44, -0.32] P = 0.01), and non-NAFLD (SMD = -0.53, 95% CI [-0.78, -0.28] P<0.0001). GLP-1Ras reduced the liver fat level of type 2 diabetes (WMD = -3.15, 95% CI [-4.14, -2.15] P<0.00001), NAFLD (WMD = -3.83, 95% CI [-6.30, -1.37] P = 0.002), and type 2 diabetes with NAFLD (WMD = -4.27, 95% CI [-6.80, -1.74] P = 0.0009), while showed no impact on the hepatic fat content in non-Type 2 diabetes (WMD = -12.48, 95% CI [-45.19, 20.24] P = 0.45). LP-1 RAs significantly reduce visceral- and liver fat content in adults.

The Impact of GLP-1 RAs and DPP-4is on Hospitalisation and Mortality in the COVID-19 Era: A Two-Year Observational Study.

Novel antidiabetic drugs have the ability to produce anti-inflammatory effects regardless of their glucose-lowering action. For this reason, these molecules (including GLP-1 RAs and DPP-4is) were hypothesized to be effective against COVID-19, which is characterized by cytokines hyperactivity and multiorgan inflammation. The aim of our work is to explore the potential protective role of GLP-1 RAs and DPP-4is in COVID-19 (with the disease intended to be a model of an acute stressor) and non-COVID-19 patients over a two-year observation period. Retrospective and one-versus-one analyses were conducted to assess the impact of antidiabetic drugs on the need for hospitalization (in both COVID-19- and non-COVID-19-related cases), in-hospital mortality, and two-year mortality. Logistic regression analyses were conducted to identify the variables associated with these outcomes. Additionally, log-rank tests were used to plot survival curves for each group of subjects, based on their antidiabetic treatment. The performed analyses revealed that despite similar hospitalization rates, subjects undergoing home therapy with GLP-1 RAs exhibited significantly lower mortality rates, even over a two-year period. These individuals demonstrated improved survival estimates both within hospital and non-hospital settings, even during a longer observation period.

The role of weight control in the management of type 2 diabetes mellitus: Perspectives on semaglutide

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used to address multiple aspects of type 2 diabetes mellitus (T2DM) management, including glycaemic control, weight loss, and cardiovascular risk reduction. Semaglutide, a well-established GLP-1 RA approved for T2DM treatment and weight management, demonstrates marked efficacy in achieving these clinically important goals. The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) consensus report emphasizes the importance of a holistic approach to T2DM treatment, with weight control as a key component for improving patient outcomes. Notably, semaglutide is mentioned in the consensus report as having 'very high' efficacy for both glucose lowering and weight loss in T2DM treatment. Nevertheless, as has been observed with other weight-lowering drugs, weight loss observed with semaglutide appears less profound in individuals with T2DM than in those with obesity without T2DM, a phenomenon requiring further investigation. The semaglutide safety and tolerability profiles are well established, and it is approved in some countries to reduce cardiovascular risk in certain populations with T2DM. Thus, semaglutide offers a well-established therapeutic option that aligns well with guideline recommendations for T2DM management, emphasizing the high importance of weight control and amelioration of other cardiometabolic risk factors.

Cost-effectiveness analysis of once-daily oral semaglutide versus placebo and subcutaneous glucagon-like peptide-1 receptor agonists added to insulin in patients with type 2 diabetes in China.

Introduction: Oral semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that improves glycated hemoglobin levels and body weight in patients with type 2 diabetes (T2DM). We aim to evaluate the cost-effectiveness of once-daily oral semaglutide in comparison to placebo and injectable GLP-1 RAs in Chinese patients with T2DM inadequately controlled on basal insulin. Methods: The United Kingdom Prospective Diabetes Study Outcomes Model (UKPDS OM2.1) was used to estimate the cost-effectiveness by calculating the incremental cost-effectiveness ratio (ICER). Baseline characteristics of the simulation cohort were obtained from the PIONEER 8 trial. Utility and safety inputs were derived from a network meta-analysis of 12 trials. Direct medical costs were retrieved from published literature and discounted at an annual rate of 5%. We used a willingness-to-pay (WTP) threshold of $36,528.3 per quality-adjusted life-year (QALY) gained. Scenario analysis, and one-way and probabilistic sensitivity analysis were performed. Results: The effectiveness of oral semaglutide was 10.39 QALYs with a total cost of $30,223.10, while placebo provided 10.13 QALYs at a lower total cost of $20,039.19. Oral semaglutide was not cost-effective at an ICER of $39,853.22 and $88,776.61 per QALY compared to placebo and exenatide at the WTP. However, at an annual price of $1,871.9, it was cost-effective compared with dulaglutide, liraglutide, and lixisenatide. The model was most sensitive to the discount rate and annual cost of oral semaglutide. The price of oral semaglutide needed to be reduced to $1,711.03 per year to be cost-effective compared to placebo and other injectable GLP-1 RAs except for exenatide and semaglutide injection. Conclusion: We found that once-daily oral semaglutide, at a comparable price of semaglutide injection, proves to be a cost-effective add-on therapy to insulin for Chinese patients with T2DM, especially when compared to subcutaneous GLP-1 RAs other than injectable semaglutide and exenatide. However, to achieve cost-effectiveness in comparison to placebo, further cost reduction of oral semaglutide is necessary. The estimated annual cost of $1,711.03 for oral semaglutide demonstrates a more cost-effective option than placebo, highlighting its potential value in the management of T2DM.

Predictors of Responsiveness to GLP-1 Receptor Agonists in Insulin-Treated Patients with Type 2 Diabetes.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are potent antihyperglycemic agents with beneficial effects on weight, cardiovascular, and renal outcomes. Physicians lack guidance as to which patients with insulin-requiring type 2 diabetes will respond best to GLP-1 RAs with respect to glycemic control, insulin dose reduction, and weight loss. This study evaluated the efficacy of GLP-1 RAs in patients with type 2 diabetes on insulin and patient factors that may predict a beneficial clinical response. Adults with type 2 diabetes treated with insulin who had a GLP-1 RA added to their regimen were evaluated retrospectively. Baseline parameters and outcomes at 3, 6, and 12 months were collected. Among the 81 patients included, there was a mean reduction in hemoglobin A1C of 0.94% (SD, 0.26; p = 0.0007), 0.40% (SD, 0.21; p = 0.0636), and 0.58% (SD, 0.23, p = 0.0154) at 3, 6, and 12 months, respectively, following the addition of a GLP-1 RA. There was also a reduction in body weight noted at each time point. Baseline characteristics including BMI, duration of diabetes, and insulin requirement did not significantly affect A1C reduction when GLP-1 RA was added. At 3 months, patients with a random C-peptide that was normal (≥0.8 ng/ml) were significantly more likely to have discontinued insulin than those with random C-peptide that was low (<0.8 ng/ml) (11 of 23 vs. 0 of 7 patients, p = 0.029). The addition of a GLP-1 RA reduced HbA1C, weight, and insulin requirements in this cohort of patients with type 2 diabetes on insulin. BMI, baseline insulin dose, and diabetes duration did not predict response. A C-peptide level ≥ 0.8 ng/ml predicted a beneficial response after 3 months of therapy.

Exploring the underlying mechanisms of obesity and diabetes and the potential of Traditional Chinese Medicine: an overview of the literature.

Obesity and diabetes are closely related metabolic disorders that have become major public health concerns worldwide. Over the past few decades, numerous studies have explored the underlying mechanisms of these disorders and identified various risk factors, including genetics, lifestyle, and dietary habits. Traditional Chinese Medicine (TCM) has been increasingly recognized for its potential to manage obesity and diabetes. Weight loss is difficult to sustain, and several diabetic therapies, such as sulfonylureas, thiazolidinediones, and insulin, might make it harder to lose weight. While lifestyle changes should be the primary approach for people interested in lowering weight, drugs are also worth investigating. Since some of the newer glucose-lowering medications that cause weight loss, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), are additionally utilized or are under consideration for use as anti-obesity drugs, the frontier between glucose-lowering medication and weight loss drugs appears to be shifting. This review provides an overview of the literature on the underlying mechanisms of obesity and diabetes and the prospect of TCM in their management. We discuss the various TCM interventions, including acupuncture, herbal medicine, and dietary therapy, and their effects on metabolic health. We also highlight the potential of TCM in regulating gut microbiota, reducing inflammation, and improving insulin sensitivity. The findings suggest that TCM may provide a promising approach to preventing and managing obesity and diabetes. However, further well-designed studies are needed to confirm the efficacy and safety of TCM interventions and to elucidate their underlying mechanisms of action.

The Impact of Glucagon-Like Peptide-1 Receptor Agonist on the Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus: A Meta-Analysis and Systematic Review.

Since 2005, the cardioprotective effects of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have garnered attention. The cardioprotective effect could be an added benefit to the use of GLP-1 RA. This systematic review and meta-analysis aimed at summarizing observational studies that recruited type 2 diabetes individuals with fewer cardiovascular (CV) events before enrolling in the research. Systematically, the databases were searched for observational studies reporting compound CV events and deaths in type 2 diabetics without having the risk of cardiovascular diseases (CVDs) compared to other glucose-lowering agents. A meta-analysis was carried out using random effects model to estimate the overall hazard ratio (HR) with a 95% confidence interval (CI). Five studies were found eligible for the systematic review including a total of 64,452 patients receiving either liraglutide (three studies) or exenatide (two studies). The pooled HR for major adverse cardiac event (MACE) and extended MACE was 0.72 (95% CI: 0.65 - 0.93, I2 = 68%) and 0.93 (95% CI: 0.89 - 0.98, I2 = 29%), respectively. The pooled HR for hospitalization due to heart failure (HHF) and occurrence of HF was 0.84 (95% CI: 0.77 - 0.91, I2 = 79%) and 0.83 (95% CI: 0.75 - 0.94, I2 = 95%), respectively. For stroke, GLP-1 RA was associated with a significant risk reduction of 0.86 (95% CI: 0.75 - 0.98, I2 = 81%). There was no significant myocardial infarction (MI) risk reduction with GLP-1 RA. As for all-cause mortality, the pooled HR for the occurrence of all-cause mortality was 0.82 (95% CI: 0.76 - 0.88, I2 = 0%). The pooled HR for the occurrence of CV death was 0.75 (95% CI: 0.65 - 0.85, I2 = 38%). GLP-1 RA therapy was associated with a significantly low risk of MACE, extended MACE, all-cause mortality, and CV mortality. Except for MACE, the heterogenicity among the studies was low. We conclude that GLP-1 RA is associated with a low risk of CV events composites and mortality. The findings support the cardioprotective effect of GLP-1 RA.