Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1

Hammoud, Rola; Drucker, Daniel J.

doi:10.1038/s41574-022-00783-3

Cited by 88 publications

(46 citation statements)

References 187 publications

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“…Given the rise in popularity of incretin agonists for the management of obesity, a more comprehensive review of the physiological (and pathophysiological) effects of incretins is warranted. Although the impact of both GLP‐1 and GIP is the main focus reviewed especially in relation to their mechanisms of action as antiobesity medications, it is important to note that both have broad effects through several systems in the body 40 …”

Section: Effects Of Endogenous and Exogenous Incretins On Key Tissues...mentioning

confidence: 99%

Review article: Pharmacologic management of obesity ‐ updates on approved medications, indications and risks

Lupianez‐Merly,

Dilmaghani,

Vosoughi

et al. 2024

Aliment Pharmacol Ther

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SummaryBackgroundObesity has reached epidemic proportions, with >40% of the US population affected. Although traditionally managed by lifestyle modification, and less frequently by bariatric therapies, there are significant pharmacological advancements.AimsTo conduct a narrative review of the neurohormonal and physiological understanding of weight gain and obesity, and the development, clinical testing, indications, expected clinical outcomes, and associated risks of current FDA‐approved and upcoming anti‐obesity medications (AOMs).MethodsWe conducted a comprehensive review in PubMed for articles on pathophysiology and complications of obesity, including terms ‘neurohormonal’, ‘obesity’, ‘incretin’, and ‘weight loss’. Next, we searched for clinical trial data of all FDA‐approved AOMs, including both the generic and trade names of orlistat, phentermine/topiramate, bupropion/naltrexone, liraglutide, and semaglutide. Additional searches were conducted for tirzepatide and retatrutide ‐ medications expecting regulatory approval. Searches included combinations of terms related to mechanism of action, indications, side effects, risks, and future directions.ResultsWe reviewed the pathophysiology of obesity, including specific role of incretins and glucagon. Clinical data supporting the use of various FDA‐approved medications for weight loss are presented, including placebo‐controlled or, when available, head‐to‐head trials. Beneficial metabolic effects, including impact on liver disease, adverse effects and risks of medications are discussed, including altered gastrointestinal motility and risk for periprocedural aspiration.ConclusionAOMs have established efficacy and effectiveness for weight loss even beyond 52 weeks. Further pharmacological options, such as dual and triple incretins, are probable forthcoming additions to clinical practice for combating obesity and its metabolic consequences such as metabolic dysfunction‐associated steatotic liver disease.

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Section: Effects Of Endogenous and Exogenous Incretins On Key Tissues...mentioning

confidence: 99%

Review article: Pharmacologic management of obesity ‐ updates on approved medications, indications and risks

Lupianez‐Merly,

Dilmaghani,

Vosoughi

et al. 2024

Aliment Pharmacol Ther

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“…While their primary effects are on the pancreas-gut axis, aiming to modulate insulin production, they also exert extra-pancreatic actions. A direct modulation of cellular energy substrates metabolism has been proposed, with effects on several peripheral organs including the heart [43,44 ▪▪ ].…”

Section: Mechanisms Underlying Cardioprotection Of Glucagon-like Pept...mentioning

confidence: 99%

Beyond Weight Loss: the Emerging Role of Incretin-Based Treatments in Cardiometabolic HFpEF

Capone,

Nambiar,

Schiattarella

2024

Current Opinion in Cardiology

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Purpose of review Incretin-based drugs are potent weight-lowering agents, emerging as potential breakthrough therapy for the treatment of obesity-related phenotype of heart failure with preserved ejection fraction (HFpEF). In this review article, we will discuss the contribution of weight loss as part of the benefits of incretin-based medications in obese patients with HFpEF. Furthermore, we will describe the potential effects of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists on the heart, particularly in relation to HFpEF pathophysiology. Recent findings In the STEP-HFpEF trial, the GLP-1 receptor agonist semaglutide significantly improved quality of life outcomes in obese HFpEF patients. Whether the beneficial effects of semaglutide in obese patients with HFpEF are merely a consequence of body weight reduction is unclear. Considering the availability of other weight loss strategies (e.g., caloric restriction, exercise training, bariatric surgery) to be used in obese HFpEF patients, answering this question is crucial to provide tailored therapeutic options in these subjects. Summary Incretin-based drugs may represent a milestone in the treatment of obesity in HFpEF. Elucidating the contribution of weight loss in the overall benefit observed with these drugs is critical in the management of obese HFpEF patients, considering that other weight-lowering strategies are available and might represent potential alternative options for these patients.

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“…Tirzepatide is a single molecule that combines glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonism resulting in synergistic effects on appetite, food intake, and metabolic function . Tirzepatide is approved in many countries, including the US, EU, and Japan, as a once-weekly subcutaneous injectable for type 2 diabetes and for the treatment of obesity in the US and UK .…”

Section: Introductionmentioning

confidence: 99%

“…5,[7][8][9][10][11][12] Tirzepatide is a single molecule that combines glucosedependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonism 13 resulting in synergistic effects on appetite, food intake, and metabolic function. [14][15][16] Tirzepatide is approved in many countries, including the US, EU, and Japan, as a once-weekly subcutaneous injectable for type 2 diabetes and for the treatment of obesity in the US and UK. [16][17][18] In a placebo-controlled trial of participants with obesity or overweight without diabetes, tirzepatide led to mean reductions in body weight up to 20.9% after 72 weeks of treatment.…”

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confidence: 99%

Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity

Aronne,

Sattar,

Horn

et al. 2024

JAMA

162

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ImportanceThe effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown.ObjectiveTo assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction.Design, Setting, and ParticipantsThis phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes.InterventionsParticipants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks.Main Outcomes and MeasuresThe primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period.ResultsParticipants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was −5.5% with tirzepatide vs 14.0% with placebo (difference, −19.4% [95% CI, −21.2% to −17.7%]; P &lt; .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P &lt; .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo.Conclusions and RelevanceIn participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction.Trial RegistrationClinicalTrials.gov Identifier: NCT04660643

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Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1

Cited by 88 publications

References 187 publications

Review article: Pharmacologic management of obesity ‐ updates on approved medications, indications and risks

Review article: Pharmacologic management of obesity ‐ updates on approved medications, indications and risks

Beyond Weight Loss: the Emerging Role of Incretin-Based Treatments in Cardiometabolic HFpEF

Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity

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