[Severe gastroparesia associated with the use of GLP-1 receptor agonists for weight loss]. / Gastroparesia severa asociada al uso de agonistas del receptor GLP-1 para bajar de peso.

Initially developed as medications for diabetes mellitus, GLP-1 agonists have gained much popularity in the treatment of obesity and weight loss. The present case describes a 69-year-old woman with a history of peptic ulcer and use of NSAIDs, who presented with abdominal pain and oral intolerance refractory to conventional management, for which an upper digestive endoscopy was performed, diagnosing severe gastroparesis. Asking more about the story, revealed surreptitious use of semaglutide. She continued with supportive therapy and the symptoms resolved spontaneously. The present case report aims to warn of the potential risks of the use of GLP-1 analogues in the context of endoscopy with sedation.

Significant elevation of serum CA19-9 and CA242 levels induced by dulaglutide.

The use of dulaglutide, a common medication for managing type 2 diabetes, rarely causes elevated pancreatic tumour markers. Here, we report the case of a woman in her mid-60s with diabetes for over 10 years. The patient presented with markedly elevated serum CA19-9 and CA242 levels revealed during a routine health examination despite being asymptomatic. She had been receiving dulaglutide injections for 16 months. Imaging and interventional assessments did not reveal any hepatobiliary, gastrointestinal or pancreatic neoplasm. After excluding alternate diagnoses, the patient was determined to exhibit an adverse reaction to dulaglutide use. Management involved the discontinuation of dulaglutide, which resulted in normalisation of serum CA19-9 and CA242 levels within 6 weeks. This case underscores the importance of discontinuing dulaglutide and monitoring changes in the biomarker levels in asymptomatic patients receiving dulaglutide, rather than immediately resorting to imaging and endoscopic examinations.

Could GLP-1 Receptor Agonists Like Semaglutide Treat Addiction, Alzheimer Disease, and Other Conditions?

This Medical News story examines other potential uses of GLP-1 receptor agonists, the popular type 2 diabetes and weight-loss drugs.

Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes.

BACKGROUND: Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes. METHODS: We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group. CONCLUSIONS: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).

A pharmacokinetic study comparing the biosimilar HEC14028 and Dulaglutide (Trulicity®) in healthy Chinese subjects.

This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar HEC14028 compared to reference Trulicity® (dulaglutide) in healthy male Chinese subjects. This study was a single-center, randomized, open, single-dose, parallel-controlled comparative Phase I clinical trial, including a screening period of up to 14 days, a 17-day observation period after administration, and a 7-day safety follow-up period. A total of 68 healthy male subjects were randomly assigned (1:1) to the test group (HEC14028) and the reference group (dulaglutide) (single 0.75 mg abdominal subcutaneous dose). The primary objective was to evaluate the pharmacokinetic characteristics of HEC14028 and compare the pharmacokinetic similarities between HEC14028 and dulaglutide. The primary PK endpoints were maximum plasma concentration (Cmax) and area under the blood concentration-time curve from zero time to the estimated infinite time (AUC0-∞). The study results showed that HEC14028 and dulaglutide were pharmacokinetically equivalent: 90% confidence interval (CI) of Cmax and AUC0-∞ geometric mean ratios were 102.9%-122.0% and 97.1%-116.9%, respectively, which were both within the range of 80.00%-125.00%. No grade 3 or above treatment emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to withdrawal from the trial, or TEAEs leading to death were reported in this study. Both HEC14028 and dulaglutide showed good and similar safety profiles, and no incremental immunogenicity was observed in subjects receiving HEC14028 and dulaglutide.

Assessment of Thyroid Carcinogenic Risk and Safety Profile of GLP1-RA Semaglutide (Ozempic) Therapy for Diabetes Mellitus and Obesity: A Systematic Literature Review.

The broadening application of glucagon-like peptide (GLP)-1 receptor agonists, specifically semaglutide (Ozempic) for the management of diabetes and obesity brings a critical need to evaluate its safety profile, considering estimates of up to 20 million prescriptions per year in the US until 2035. This systematic review aims to assess the incidence of thyroid cancer and detail the spectrum of adverse events associated with semaglutide, focusing on its implications for patient care. Through a systematic search of PubMed, Scopus, and Embase databases up to December 2023, ten randomized controlled trials (RCTs) involving 14,550 participants, with 7830 receiving semaglutide, were analyzed, with an additional number of 18 studies that were separately discussed because they reported data from the same RCTs. The review focused on thyroid cancer incidence, gastrointestinal symptoms, and other significant adverse events attributed to semaglutide. The incidence of thyroid cancer in semaglutide-treated patients was less than 1%, suggesting no significant risk. Adverse events were predominantly gastrointestinal, including nausea (2.05% to 19.95%) and diarrhea (1.4% to 13%). Nasopharyngitis and vomiting were also notable, with mean prevalences of 8.23% and 5.97%, respectively. Other adverse events included increased lipase levels (mean of 6.5%), headaches (mean prevalence of 7.92%), decreased appetite (reported consistently at 7%), influenza symptoms (mean prevalence of 5.23%), dyspepsia (mean prevalence of 5.18%), and constipation (mean prevalence of 6.91%). Serious adverse events varied from 7% to 25.2%, highlighting the need for vigilant patient monitoring. These findings underscore the gastrointestinal nature of semaglutide's adverse events, which, while prevalent, did not significantly deter from its clinical benefits in the treatment landscape. This systematic review provides a comprehensive assessment of semaglutide's safety profile, with a focus on gastrointestinal adverse events and a low incidence of thyroid cancer. Despite the prevalence of gastrointestinal symptoms, semaglutide remains an efficacious option for managing diabetes and obesity. The detailed characterization of adverse events underscores the importance of monitoring and managing these effects in clinical practice, excluding the hypothesis of carcinogenesis.

Acute pancreatitis due to different semaglutide regimens: An updated meta-analysis.

OBJECTIVES: Some concerns persist regarding the safety of semaglutide. The objective of this updated meta-analysis is to assess the risk of acute pancreatitis with the use of semaglutide, assessing the results according to the different administration regimens. METHODS: We performed an updated meta-analysis of randomised, placebo-controlled studies of semaglutide therapy that report acute pancreatitis. This meta-analysis was performed in line with PRISMA guidelines. A global and stratified analysis according to the therapeutic scheme used was performed using the fixed-effects model. RESULTS: Twenty-one eligible trials of semaglutide, including 34,721 patients, were identified and considered eligible for the analyses. Globally, semaglutide therapy was not associated with an increased risk of acute pancreatitis (OR 0.7; 95% CI 0.5-1.2, I2 0%). When we analysed the studies according to the different schemes used, the results were similar (group with oral semaglutide: OR 0.40; 95% CI 0.10-1.60, I2 0%; group with low subcutaneous doses of semaglutide: OR 0.80; 95% CI 0.40-1.90, I2 0%; group with high subcutaneous doses of semaglutide: OR 0.70; 95% CI 0.50-1.20, I2 0%; interaction p-value=0.689). CONCLUSION: This updated meta-analysis demonstrates that the use of semaglutide is not associated with an increased risk of acute pancreatitis compared to placebo. In the stratified analysis, the results were similar with the different semaglutide regimens analysed.

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.

The association between previous use of anti-obesity medication and semaglutide weight loss outcomes.

AIMS: To compare weight loss outcomes between patients starting semaglutide who had previously been on another anti-obesity medication (AOM) compared to those who were AOM-naïve. MATERIALS AND METHODS: We performed a retrospective study in patients with overweight or obesity taking semaglutide for weight loss for a duration of 3 to 12 months. Our primary endpoint was assessment of percentage of total body weight loss (TBWL) in patients who started semaglutide as their first AOM (AOM-naïve) compared to those who started semaglutide and had previously taken another AOM (non-AOM-naïve). The secondary outcome was a comparison of the proportions of patients achieving ≥5%, ≥10%, ≥15% and ≥20% TBWL between the groups. Our endpoints were analysed using independent t-tests and ANOVA/ANCOVA for continuous variables and Pearson's test for categorical variables. RESULTS: This study included 305 patients. Outcomes of semaglutide treatment were superior in AOM-naïve patients (n = 231) compared to non-AOM-naïve patients (n = 74) at 3 (6.3% vs. 3.8%), 6 (10.6% vs. 6.7%), 9 (14.0% vs. 9.1%) and 12 months (14.3% vs. 10.6%; p < 0.0001 at 3, 6 and 9 months, and p = 0.01 at 12 months). A greater proportion of patients in the AOM-naïve group achieved a TBWL ≥ 15% (48% vs 21%; p = 0.02) and ≥20% (27% vs 4% p < 0.01) at 12 months. CONCLUSION: The use of semaglutide in patients with previous intake of other AOMs was associated with inferior weight loss outcomes in comparison to patients who were AOM-naïve.

Risk of Stroke in Real-World US Individuals with Type 2 Diabetes Receiving Semaglutide or a Dipeptidyl Peptidase 4 Inhibitor.

INTRODUCTION: People with type 2 diabetes (T2D) have a higher risk of stroke and worse outcomes than those without T2D. Pooled data from randomized controlled trials indicate that the glucagon-like peptide 1 receptor agonist semaglutide is associated with stroke risk reduction in people with T2D at high cardiovascular risk. We compared real-world stroke risk in people with T2D or T2D plus atherosclerotic cardiovascular disease (ASCVD) initiating either semaglutide or a dipeptidyl peptidase 4 inhibitor (DPP4i). METHODS: Adults (≥ 18 years old) in a US claims database with a claim indicating initiation of either semaglutide or a DPP4i (index date) during the index period (1 January 2018-30 September 2020), a diagnosis code for T2D on or before the index date and at least 12 months' continuous enrolment in the database pre-index were included and propensity score matched 1:1 on baseline demographic and clinical characteristics. The primary outcome was time to first stroke event during follow-up. Healthcare resource utilization was also compared between groups. RESULTS: The analysis included 17,920 matched pairs with T2D and 4234 matched pairs with T2D and ASCVD. The groups were well matched on baseline characteristics. People initiating semaglutide had a lower risk of stroke over short-term follow-up than those initiating a DPP4i (T2D: hazard ratio 0.63 [95% confidence interval 0.41-0.95], p = 0.029; T2D plus ASCVD: 0.45 [0.24-0.86], p = 0.015). Semaglutide was also associated with a lower rate of inpatient, outpatient and emergency room visits compared with a DPP4i. CONCLUSION: This proof-of-concept analysis indicates that semaglutide has the potential to reduce the risk of stroke in people with T2D when prescribed in clinical practice.

Use of Dulaglutide, Semaglutide, and Tirzepatide in Diabetes and Weight Management.

PURPOSE: Glucagon-like peptide 1 receptor agonists (GLP1-RA) are effective therapies in lowering glycosylated hemoglobin (HbA1c), providing cardioprotective benefits, and lowering weight. The use of GLP1-RA solely for weight-loss has become commonplace in many practices, which in turn has made it difficult in some areas for those with type 2 diabetes (T2DM) to obtain these much-needed medications. METHODS: Using recent published literature, along with clinical experience, it has become apparent that many GLP1-RAs have become difficult to obtain for patients with diabetes. FINDINGS: Many clinicians started to prescribe the brand Ozempic® (semaglutide*) and dulaglutide for weight loss despite neither of them being Food and Drug Administration (FDA) approved for this indication. Ozempic, having outperformed dulaglutide in in both HbA1c reduction and weight loss, along with FDA approval of semaglutide for weight loss, has quickly become widely used off-label for weight loss. This off-label use may have increased, despite the approval of semaglutide,† because many insurances will not cover semaglutide solely for weight management. Most recently, Eli Lilly was able to develop tirzepatide,‡ which was FDA approved in May of 2022, and they are seeking fast-track FDA approval for weight loss and are projected to gain this approval within 2023. IMPLICATIONS: Insurance coverage for weight management remains sparse, and obtaining these therapies for diabetes has now become more burdensome, with insurance companies requiring a prior authorization proving FDA-approved diagnosis of T2DM. Hopefully, should more GLP1-Ras receive approval for weight loss, along with an increase in insurance coverage, the burden on patients with diabetes will be lessened as they are able to quickly obtain this highly effective therapy.

Real-world glycated haemoglobin changes among type 2 diabetes mellitus patients treated with a maintenance dose of 7 mg or 14 mg of oral semaglutide.

AIM: To describe the change in glycated haemoglobin (HbA1c) among patients with type 2 diabetes following treatment with a 7 or 14 mg maintenance dose of oral semaglutide. MATERIALS AND METHODS: This retrospective, claims-based study included adult patients with type 2 diabetes with a pre-index HbA1c of ≥7%, initiating treatment with oral semaglutide between 1 November 2019 and 30 June 2020; the patients had continuous health plan enrolment for ≥12 months before (pre-index) and ≥6 months following (post-index) the date of the first oral semaglutide claim (index). Patients were required to have a maintenance dose of 7 or 14 mg. Pre-index demographic and clinical characteristics were captured, as were doses at initiation and prescriber specialty. The change in HbA1c between the latest post-index and pre-index HbA1c measurements was calculated among all patients and among those with ≥90 days of continuous treatment (persistent patients). RESULTS: This study included 520 patients, most of whom had a complex medical history, experienced a range of comorbidities and received an average of 11.5 different classes of medications during the pre-index period. The mean HbA1c reduction during the 6-month post-initiation period was 1.2% (p < .001) for all patients and 1.4% (p < .001) for persistent patients. CONCLUSIONS: In this real-world study, patients with a pre-index HbA1c ≥7% who initiated treatment with oral semaglutide with a 7 or 14 mg maintenance dose had significantly lower HbA1c levels following treatment.

Effect of semaglutide on major cardiovascular events.

Overview of: Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med 2023;389:2221-32.

Glycaemic control efficacy of switching from dipeptidyl peptidase-4 inhibitors to oral semaglutide in subjects with type 2 diabetes: A multicentre, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 2 study).

AIM: To assess whether oral semaglutide provides better glycaemic control, compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) continuation, in people with type 2 diabetes. MATERIALS AND METHODS: In this multicentre, open-label, prospective, randomized, parallel-group comparison study, participants receiving DPP-4is were either switched to oral semaglutide (3-14 mg/day) or continued on DPP-4is. The primary endpoint was the change in glycated haemoglobin (HbA1c) over 24 weeks. Secondary endpoints included changes in metabolic parameters and biomarkers, along with the occurrence of adverse events. Factors associated with HbA1c improvement were also explored. RESULTS: In total, 174 eligible participants were enrolled; 17 dropped out of the study. Consequently, 82 participants in the DPP-4i group and 75 participants in the semaglutide group completed the study and were included in the analysis. Improvement in HbA1c at week 24 was significantly greater when switching to semaglutide compared with DPP-4i continuation [-0.65 (95% confidence interval: -0.79, -0.51) vs. +0.05 (95% confidence interval: -0.07, 0.16) (p < .001)]. Body weight, lipid profiles and liver enzymes were significantly improved in the semaglutide group than in the DPP-4i continuation group. Multiple linear regression analysis revealed that baseline HbA1c and homeostasis model assessment 2-R were independently associated with HbA1c improvement after switching to semaglutide. Seven participants in the semaglutide group discontinued medication because of gastrointestinal symptoms. CONCLUSIONS: Although the potential for gastrointestinal symptoms should be carefully considered, switching from DPP-4is to oral semaglutide may be beneficial for glycaemic control and metabolic abnormalities in people with higher HbA1c and insulin resistance.

Evaluation and comparison of efficacy and safety of tirzepatide and semaglutide in patients with type 2 diabetes mellitus: A Bayesian network meta-analysis.

BACKGROUND: As new antidiabetic drugs, tirzepatide (Tir) and semaglutide (Sem) are progressively applied in clinical practice. However, their efficacy and safety profiles have not been comprehensively assessed. Therefore, a Bayesian network meta-analysis was used to evaluate and compare the efficacy and safety of Tir and Sem in treating type 2 diabetes mellitus (T2DM). METHODS: PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov were systematically searched from inception to April 3rd, 2023. Randomized clinical trials (RCTs) comparing the efficacy and safety of Tir and Sem with placebo or the other antidiabetic drugs in treating T2DM were included. The efficacy outcomes included changes in glycated hemoglobin (HbA1c), body weight (BW), body mass index (BMI), and the proportion of participants with HbA1c< 7 %. The safety outcome was the proportion of participants experiencing gastrointestinal adverse events (GIAEs). RESULTS: A total of 38 studies involving 34,166 participants were included. Compared to 1 mg of subcutaneous Sem (Sem SC), 5 mg, 10 mg and 15 mg of Tir demonstrated superior efficacy in reducing HbA1c (mean difference (MD), [95 % CI], -0.22 [-0.40, -0.03] %, -0.42 [-0.60, -0.24] % and -0.53 [-0.71, -0.35] %, respectively) and BW (MD [95 % CI], -1.48 [-2.53, -0.43] kg, -4.00 [-5.05, -2.95] kg and -5.71 [-6.73, -4.68] kg, respectively). Conversely, 7 mg and 14 mg of oral Sem (Sem PO) displayed inferior efficacy in reducing HbA1c (MD [95 % CI], 0.47 [0.26, 0.68] % and 0.35 [0.16, 0.54] %, respectively) and BW (MD [95 % CI], 2.36 [1.24, 3.48] kg and 1.11 [0.10, 2.13] kg). However, 20 mg and 40 mg of Sem PO were non-inferior in reducing HbA1c (MD [95 % CI], 0.13 [-0.29, 0.55] % and 0.01 [-0.38, 0.40] %, respectively) and BW (MD [95 % CI], -0.41 [-2.71, 1.90] kg and -1.32 [-3.58, 0.92] kg). In terms of safety, compared to 1 mg of Sem SC, 5 mg, 10 mg and 15 mg of Tir did not significantly increase the incidence of GIAEs (odd ratio (OR) [95 % CI], 0.70 [0.42, 1.10], 0.87 [0.52, 1.36] and 0.99 [0.60, 1.54], respectively), while 7 mg of Sem PO showed a lower incidence of GIAEs (OR [95 % CI], 0.48 [0.25, 0.83]). Compared to insulin, 0.5 mg of Sem SC, 1 mg of Sem SC, 5 mg of Tir, 10 mg of Tir and 15 mg of Tir displayed better efficacy in lowering HbA1c (MD [95 % CI], -0.40 [-0.63, -0.18] %, -0.69 [-0.90, -0.48] %, -0.91 [-1.10, -0.72] %, -1.11 [-1.30, -0.92] % and -1.22 [-1.41, -1.03] %, respectively) and BW (MD [95 % CI], -5.34[-6.60, -4.09] kg, -6.70 [-7.90,-5.51] kg, -8.18 [-9.27, -7.10] kg, -10.70 [-11.79, -9.61] kg and -12.41 [-13.49,-11.33] kg, respectively). According to the surface under the cumulative ranking curve (SUCRA) value, among all the included interventions, 15 mg of Tir exhibited the most potent effect in reducing HbA1c (99.81 %) and BW (99.98 %), followed by 10 mg of Tir (96.83 % and 95.72 %), 5 mg of Tir (92.88 % and 86.04 %), 1 mg of Sem SC (85.85 % and 74.97 %), 40 mg of Sem PO (83.66 % and 84.31 %), 20 mg of Sem PO (76.98 % and 77.12 %), 300 mg of Can (49.93 % and 60.89 %), insulin (36.38 % and 0.22 %) and 100 mg of Sit (12.28 % and 18.51 %) respectively. Meanwhile, 5 mg, 10 mg, and 15 mg of Tir (48.32 %, 30.96 %, and 21.07 %, respectively), 0.5 mg and 1 mg of Sem SC (33.54 % and 24.77 %, respectively) significantly increased the incidence of GIAEs. CONCLUSION: Both Tir and Sem demonstrated favorable antidiabetic effects and were particularly suitable for T2DM patients who were obese or overweight. Despite a high incidence of GIAEs, their safety profile was deemed acceptable. Tir was the best option among all the included interventions.