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The New England Journal of Medicine Sep 2023Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagon-like... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity.
METHODS
In this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point).
RESULTS
A total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from -8.6% to -12.6% across the orforglipron dose cohorts and was -2.0% in the placebo group. At week 36, the mean change ranged from -9.4% to -14.7% with orforglipron and was -2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class.
CONCLUSIONS
Daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists. (Funded by Eli Lilly; GZGI ClinicalTrials.gov number, NCT05051579.).
Topics: Adult; Humans; Administration, Oral; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Hypoglycemic Agents; Obesity; Weight Loss
PubMed: 37351564
DOI: 10.1056/NEJMoa2302392 -
Science (New York, N.Y.) Aug 2023Proton leakage from organelles is a common signal for noncanonical light chain 3B (LC3B) lipidation and inflammasome activation, processes induced upon stimulator of...
Proton leakage from organelles is a common signal for noncanonical light chain 3B (LC3B) lipidation and inflammasome activation, processes induced upon stimulator of interferon genes (STING) activation. On the basis of structural analysis, we hypothesized that human STING is a proton channel. Indeed, we found that STING activation induced a pH increase in the Golgi and that STING reconstituted in liposomes enabled transmembrane proton transport. Compound 53 (C53), a STING agonist that binds the putative channel interface, blocked STING-induced proton flux in the Golgi and in liposomes. STING-induced LC3B lipidation and inflammasome activation were also inhibited by C53, suggesting that STING's channel activity is critical for these two processes. Thus, STING's interferon-induction function can be decoupled from its roles in LC3B lipidation and inflammasome activation.
Topics: Humans; Golgi Apparatus; Hydrogen-Ion Concentration; Inflammasomes; Ion Channels; Liposomes; Membrane Proteins; Microtubule-Associated Proteins; Protein Domains; Protons; HEK293 Cells
PubMed: 37535724
DOI: 10.1126/science.adf8974 -
Diabetologia Oct 2023Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along... (Review)
Review
Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along with their derivatives they have shown therapeutic success in type 2 diabetes, with the potential for further improvements in glycaemic, cardiorenal and body weight-related outcomes. In type 2 diabetes, the incretin effect (greater insulin secretory response after oral glucose than with 'isoglycaemic' i.v. glucose, i.e. with an identical glycaemic stimulus) is markedly reduced or absent. This appears to be because of a reduced ability of GIP to stimulate insulin secretion, related either to an overall impairment of beta cell function or to specific defects in the GIP signalling pathway. It is likely that a reduced incretin effect impacts on postprandial glycaemic excursions and, thus, may play a role in the deterioration of glycaemic control. In contrast, the insulinotropic potency of GLP-1 appears to be much less impaired, such that exogenous GLP-1 can stimulate insulin secretion, suppress glucagon secretion and reduce plasma glucose concentrations in the fasting and postprandial states. This has led to the development of incretin-based glucose-lowering medications (selective GLP-1 receptor agonists or, more recently, co-agonists, e.g. that stimulate GIP and GLP-1 receptors). Tirzepatide (a GIP/GLP-1 receptor co-agonist), for example, reduces HbA and body weight in individuals with type 2 diabetes more effectively than selective GLP-1 receptor agonists (e.g. semaglutide). The mechanisms by which GIP receptor agonism may contribute to better glycaemic control and weight loss after long-term exposure to tirzepatide are a matter of active research and may change the pessimistic view that developed after the disappointing lack of insulinotropic activity in people with type 2 diabetes when exposed to GIP in short-term experiments. Future medications that stimulate incretin hormone and other receptors simultaneously may have the potential to further increase the ability to control plasma glucose concentrations and induce weight loss.
Topics: Humans; Incretins; Diabetes Mellitus, Type 2; Blood Glucose; Glucagon-Like Peptide-1 Receptor; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Body Weight; Weight Loss; Insulin
PubMed: 37430117
DOI: 10.1007/s00125-023-05956-x -
International Journal of Molecular... Dec 2023The treatment of type 2 diabetes (T2D) necessitates a multifaceted approach that combines behavioral and pharmacological interventions to mitigate complications and... (Review)
Review
The treatment of type 2 diabetes (T2D) necessitates a multifaceted approach that combines behavioral and pharmacological interventions to mitigate complications and sustain a high quality of life. Treatment encompasses the management of glucose levels, weight, cardiovascular risk factors, comorbidities, and associated complications through medication and lifestyle adjustments. Metformin, a standard in diabetes management, continues to serve as the primary, first-line oral treatment across all age groups due to its efficacy, versatility in combination therapy, and cost-effectiveness. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) offer notable benefits for HbA1c and weight reduction, with significant cardiovascular benefits. Sodium-glucose cotransporter inhibitors (SGLT-2i) lower glucose levels independently of insulin while conferring notable benefits for cardiovascular, renal, and heart-failure outcomes. Combined therapies emphasizing early and sustained glycemic control are promising options for diabetes management. As insulin therapy remains pivotal, metformin and non-insulin agents such as GLP-1 RA and SGLT-2i offer compelling options. Notably, exciting novel treatments like the dual GLP-1/ glucose-dependent insulinotropic polypeptide (GIP) agonist show promise for substantially reducing glycated hemoglobin and body weight. This comprehensive review highlights the evolving landscape of pharmacotherapy in diabetes, the drugs currently available for treating diabetes, their effectiveness and efficacy, the impact on target organs, and side effects. This work also provides insights that can support the customization of treatment strategies.
Topics: Humans; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Quality of Life; Blood Glucose; Metformin; Insulin; Insulin, Regular, Human; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor
PubMed: 38138975
DOI: 10.3390/ijms242417147 -
Annals of Internal Medicine May 2024The American College of Physicians (ACP) developed this clinical guideline to update recommendations on newer pharmacologic treatments of type 2 diabetes. This clinical...
DESCRIPTION
The American College of Physicians (ACP) developed this clinical guideline to update recommendations on newer pharmacologic treatments of type 2 diabetes. This clinical guideline is based on the best available evidence for effectiveness, comparative benefits and harms, consideration of patients' values and preferences, and costs.
METHODS
This clinical guideline is based on a systematic review of the effectiveness and harms of newer pharmacologic treatments of type 2 diabetes, including glucagon-like peptide-1 (GLP-1) agonists, a GLP-1 agonist and glucose-dependent insulinotropic polypeptide agonist, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and long-acting insulins, used either as monotherapy or in combination with other medications. The Clinical Guidelines Committee prioritized the following outcomes, which were evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach: all-cause mortality, major adverse cardiovascular events, myocardial infarction, stroke, hospitalization for congestive heart failure, progression of chronic kidney disease, serious adverse events, and severe hypoglycemia. Weight loss, as measured by percentage of participants who achieved at least 10% total body weight loss, was a prioritized outcome, but data were insufficient for network meta-analysis and were not rated with GRADE.
AUDIENCE AND PATIENT POPULATION
The audience for this clinical guideline is physicians and other clinicians. The population is nonpregnant adults with type 2 diabetes.
RECOMMENDATION 1
RECOMMENDATION 2
Topics: Humans; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Adult; Drug Therapy, Combination; Insulin
PubMed: 38639546
DOI: 10.7326/M23-2788 -
JAMA Surgery Jun 2024Glucagon-like peptide-1 receptor agonist (GLP-1 RA) use is rapidly increasing in the US, driven by its expanded approval for weight management in addition to...
IMPORTANCE
Glucagon-like peptide-1 receptor agonist (GLP-1 RA) use is rapidly increasing in the US, driven by its expanded approval for weight management in addition to hyperglycemia management in patients with type 2 diabetes. The perioperative safety of these medications, particularly with aspiration risk under anesthesia, is uncertain.
OBJECTIVE
To assess the association between GLP-1 RA use and prevalence of increased residual gastric content (RGC), a major risk factor for aspiration under anesthesia, using gastric ultrasonography.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional study prospectively enrolled patients from a large, tertiary, university-affiliated hospital from June 6 through July 12, 2023. Participants followed preprocedural fasting guidelines before an elective procedure under anesthesia. Patients with altered gastric anatomy (eg, from previous gastric surgery), pregnancy, recent trauma (<1 month), or an inability to lie in the right lateral decubitus position for gastric ultrasonography were excluded.
EXPOSURE
Use of a once-weekly GLP-1 RA.
MAIN OUTCOMES AND MEASURES
The primary outcome was the presence of increased RGC, defined by the presence of solids, thick liquids, or more than 1.5 mL/kg of clear liquids on gastric ultrasonography. Analysis was adjusted for confounders using augmented inverse probability of treatment weighting, a propensity score-based technique. Secondarily, the association between the duration of drug interruption and the prevalence of increased RGC was explored.
RESULTS
Among the 124 participants (median age, 56 years [IQR, 46-65 years]; 75 [60%] female), the prevalence of increased RGC was 56% (35 of 62) in patients with GLP-1 RA use (exposure group) compared with 19% (12 of 62) in patients who were not taking a GLP-1 RA drug (control group). After adjustment for confounding, GLP-1 RA use was associated with a 30.5% (95% CI, 9.9%-51.2%) higher prevalence of increased RGC (adjusted prevalence ratio, 2.48; 95% CI, 1.23-4.97). There was no association between the duration of GLP-1 RA interruption and the prevalence of increased RGC (adjusted odds ratio, 0.86; 95% CI, 0.65-1.14).
CONCLUSIONS AND RELEVANCE
Use of a GLP-1 RA was independently associated with increased RGC on preprocedural gastric ultrasonography. The findings suggest that the preprocedural fasting duration suggested by current guidelines may be inadequate in this group of patients at increased risk of aspiration under anesthesia.
Topics: Humans; Female; Male; Middle Aged; Cross-Sectional Studies; Glucagon-Like Peptide-1 Receptor; Prospective Studies; Ultrasonography; Aged; Gastrointestinal Contents; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Risk Factors; Anesthesia
PubMed: 38446466
DOI: 10.1001/jamasurg.2024.0111 -
The Lancet. Diabetes & Endocrinology Mar 2024Obesity is a widespread and chronic condition that requires long-term management; research into additional targets to improve treatment outcomes remains a priority. This... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Obesity is a widespread and chronic condition that requires long-term management; research into additional targets to improve treatment outcomes remains a priority. This study aimed to investigate the safety, tolerability, and efficacy of glucagon receptor-GLP-1 receptor dual agonist survodutide (BI 456906) in obesity management.
METHODS
In this randomised, double-blind, placebo-controlled, dose-finding phase 2 trial conducted in 43 centres in 12 countries, we enrolled participants (aged 18-75 years, BMI ≥27 kg/m, without diabetes) and randomly assigned them by interactive response technology (1:1:1:1:1; stratified by sex) to subcutaneous survodutide (0·6, 2·4, 3·6, or 4·8 mg) or placebo once-weekly for 46 weeks (20 weeks dose escalation; 26 weeks dose maintenance). The primary endpoint was the percentage change in bodyweight from baseline to week 46. Primary analysis included the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of trial medication and who had analysable data for at least one efficacy endpoint) and was based on the dose assigned at randomisation (planned treatment), including all data censored for COVID-19-related discontinuations; the sensitivity analysis was based on the actual dose received during maintenance phase (actual treatment) and included on-treatment data. Safety analysis included all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov (NCT04667377) and EudraCT (2020-002479-37).
FINDINGS
Between March 30, 2021, and Nov 11, 2021, we enrolled 387 participants; 386 (100%) participants were treated (0·6 mg, n=77; 2·4 mg, n=78; 3·6 mg, n=77; 4·8 mg, n=77; placebo n=77) and 233 (60·4%) of 386 completed the 46-week treatment period (187 [61%] of 309 receiving survodutide; 46 [60%] of 77 receiving placebo). When analysed according to planned treatment, mean (95% CI) changes in bodyweight from baseline to week 46 were -6·2% (-8·3 to -4·1; 0·6 mg); -12·5% (-14·5 to -10·5; 2·4 mg); -13·2% (-15·3 to -11·2; 3·6 mg); -14·9% (-16·9 to -13·0; 4·8 mg); -2·8% (-4·9 to -0·7; placebo). Adverse events occurred in 281 (91%) of 309 survodutide recipients and 58 (75%) of 77 placebo recipients; these were primarily gastrointestinal in 232 (75%) of 309 survodutide recipients and 32 (42%) of 77 placebo recipients.
INTERPRETATION
All tested survodutide doses were tolerated, and dose-dependently reduced bodyweight.
FUNDING
Boehringer Ingelheim.
Topics: Adolescent; Adult; Aged; Humans; Middle Aged; Young Adult; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Obesity; Peptides; Treatment Outcome
PubMed: 38330987
DOI: 10.1016/S2213-8587(23)00356-X -
Diabetes, Obesity & Metabolism Sep 2023
Topics: Humans; Glucagon; Glucagon-Like Peptide 1; Receptors, Glucagon; Gastric Emptying; Insulin; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Diabetes Mellitus, Type 2; Blood Glucose
PubMed: 37311727
DOI: 10.1111/dom.15167 -
Nature Medicine Jan 2024Concerns over reports of suicidal ideation associated with semaglutide treatment, a glucagon-like peptide 1 receptor (GLP1R) agonist medication for type 2 diabetes...
Concerns over reports of suicidal ideation associated with semaglutide treatment, a glucagon-like peptide 1 receptor (GLP1R) agonist medication for type 2 diabetes (T2DM) and obesity, has led to investigations by European regulatory agencies. In this retrospective cohort study of electronic health records from the TriNetX Analytics Network, we aimed to assess the associations of semaglutide with suicidal ideation compared to non-GLP1R agonist anti-obesity or anti-diabetes medications. The hazard ratios (HRs) and 95% confidence intervals (CIs) of incident and recurrent suicidal ideation were calculated for the 6-month follow-up by comparing propensity score-matched patient groups. The study population included 240,618 patients with overweight or obesity who were prescribed semaglutide or non-GLP1R agonist anti-obesity medications, with the findings replicated in 1,589,855 patients with T2DM. In patients with overweight or obesity (mean age 50.1 years, 72.6% female), semaglutide compared with non-GLP1R agonist anti-obesity medications was associated with lower risk for incident (HR = 0.27, 95% CI = 0.200.32-0.600.36) and recurrent (HR = 0.44, 95% CI = 0.32-0.60) suicidal ideation, consistent across sex, age and ethnicity stratification. Similar findings were replicated in patients with T2DM (mean age 57.5 years, 49.2% female). Our findings do not support higher risks of suicidal ideation with semaglutide compared with non-GLP1R agonist anti-obesity or anti-diabetes medications.
Topics: Humans; Female; Middle Aged; Male; Diabetes Mellitus, Type 2; Suicidal Ideation; Retrospective Studies; Overweight; Obesity; Anti-Obesity Agents; Hypoglycemic Agents; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides
PubMed: 38182782
DOI: 10.1038/s41591-023-02672-2 -
Cardiology in ReviewDespite the worldwide epidemic of obesity, there remain few approved pharmacological treatment options to bridge the gap between lifestyle therapy and bariatric surgery....
Despite the worldwide epidemic of obesity, there remain few approved pharmacological treatment options to bridge the gap between lifestyle therapy and bariatric surgery. Cagrilintide is an amylin-analog, now being developed in combination with the GLP-1 agonist semaglutide to achieve sustained weight loss in persons with overweight and obesity. Amylin, released with insulin from beta cells in the pancreas, induces its satiating effect via both the homoeostatic and hedonic regions of the brain. Semaglutide, a GLP-1 receptor agonist, reduces appetite via GLP-1 receptors in the hypothalamus and increases the production of insulin, and reduces glucagon secretion, delaying gastric emptying. These separate, but related mechanisms of action of an amylin-analog and a GLP-1 receptor agonist appear to have an additive effect on appetite reduction. Given the heterogeneity and complex pathogenesis of obesity, combination therapy with multiple pathophysiological targets is a logical approach to increasing weight loss response with pharmacotherapy. Cagrilintide alone, as well as cagrilintide in combination with semaglutide have shown promising weight loss in clinical trials that supports the further development of this therapy for sustained weight management.
Topics: Humans; Islet Amyloid Polypeptide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide 1; Obesity; Insulin; Weight Loss; Diabetes Mellitus, Type 2; Hypoglycemic Agents
PubMed: 36883831
DOI: 10.1097/CRD.0000000000000513