Retatrutide

References

1. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML; Retatrutide Phase 2 Obesity Trial Investigators. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial. N Engl J Med. 2023 Jun 26. doi: 10.1056/NEJMoa2301972. Epub ahead of print. PMID: 37366315.
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   Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial

   Last June 26, 2023, a phase 2 trial was conducted with participants having a BMI of 30 or higher or BMI of 27 to less than 30 with weight-related conditions. They were randomly assigned to receive different doses of Retatrutide or a placebo over 48 weeks. The primary outcome was the percentage change in body weight from baseline to 24 weeks. Results showed that participants in the Retatrutide groups experienced significant fat loss, ranging from -7.2% to -17.5% at 24 weeks and -8.7% to -24.2% at 48 weeks, compared to -1.6% in the placebo group. Weight reductions of 5% or more, 10% or more, and 15% or more were observed in a high proportion of Retatrutide recipients. Adverse events, primarily gastrointestinal, were mostly mild to moderate and related to dosage, with lower starting doses helping mitigate them.

   Dr. Ania Jastreboff, an obesity medicine physician scientist at Yale University School of Medicine/Yale School of Medicine, co-Director of the Yale Center for Weight Management and the lead author on the phase 2 study, said that the results were striking and concluded that Retatrutide holds promise for substantial weight reduction in adults with obesity over a 48-week period.

   You can read the abstract of this article at Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial – PubMed (nih.gov).

2. Urva, S., Coskun, T., Loh, M. T., Du, Y., Thomas, M. K., Gurbuz, S., Haupt, A., Benson, C. T., Hernandez-Illas, M., D’Alessio, D. A., & Milicevic, Z. (2022). LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. Lancet (London, England), 400(10366), 1869–1881. https://doi.org/10.1016/S0140-6736(22)02033-5.
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   LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial

   Multi-receptor agonists that target the glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) receptors may improve outcomes in type 2 diabetes because this condition is linked to hyperglycemia and obesity. The single peptide LY3437943, also known as retatrutide, is currently in development for the treatment of type 2 diabetes and obesity since this medication acts on these receptors.

   The safety, pharmacokinetics, and pharmacodynamics of several weekly doses of LY3437943 in persons with type 2 diabetes were examined in a phase 1b experiment. Four centers in the USA enrolled adults with T2S, a glycated hemoglobin A1c (HbA1c) score of 7.0-10.5%, and a body mass index (BMI) of 23-50 kg/m2. Over a 12-week period, the participants were randomized to receive dulaglutide 1.5 mg, placebo, or once-weekly subcutaneous injections of LY3437943. Nine participants received LY3437943, three received a placebo, and one received dulaglutide. The primary outcome was to evaluate the safety and tolerability of LY3437943 and the secondary outcomes were the pharmacokinetics and pharmacodynamics of the medication. The study found that LY3437943 was safe and its pharmacokinetics suggested suitability for once-weekly dosing. LY3437943 significantly decreased plasma glucose (blood sugar), HbA1c, and body weight in a dose-dependent manner.

   The findings provide support for phase 2 development of LY3437943 for the treatment of type 2 diabetes and obesity since the medication can produce robust reductions in body weight and blood sugar levels.

   You can read the abstract of this article at LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial – PubMed (nih.gov).

3. Gault, V. A., Bhat, V. K., Irwin, N., & Flatt, P. R. (2013). A novel glucagon-like peptide-1 (GLP-1)/glucagon hybrid peptide with triple-acting agonist activity at glucose-dependent insulinotropic polypeptide, GLP-1, and glucagon receptors and therapeutic potential in high fat-fed mice. The Journal of biological chemistry, 288(49), 35581–35591. https://doi.org/10.1074/jbc.M113.512046.
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   A novel glucagon-like peptide-1 (GLP-1)/glucagon hybrid peptide with triple-acting agonist activity at glucose-dependent insulinotropic polypeptide, GLP-1, and glucagon receptors and therapeutic potential in high fat-fed mice
   The study examines the effectiveness of novel peptides that are a combination of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon. These three compounds are known to bind to the same receptor superfamily and play a crucial role in glucose homeostasis (blood sugar balance), insulin secretion, and energy regulation. Nine new peptides were created and their biological effects and potential therapeutic use were evaluated. These peptides demonstrated total DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide was discovered to be [dA(2)]GLP-1/GcG. In cells transfected with the GIP, GLP-1, and glucagon receptors, it increased cAMP synthesis. When combined with glucose (blood sugar), [dA(2)]GLP-1/GcG dramatically boosted the blood levels of insulin and decreased blood sugar levels in normal and obese diabetic mice. Moreover, it produced a sustained insulinotropic and glucose-lowering effect in animals receiving high-fat diets.

   In high-fat-fed rats, [dA(2)]GLP-1/GcG reduced body weight nonfasting plasma glucose, and boosted circulating plasma insulin concentrations when given twice daily for 21 days. By day 21, it also greatly increased insulin sensitivity and glucose tolerance. Interestingly, the [dA(2)]GLP-1/GcG mice showed increased locomotor activity without any significant changes in metabolic rate. Studies in knock-out mice confirmed the biological action of [dA(2)]GLP-1/GcG which is related to its ability to target GIP, GLP-1, and glucagon receptors.

   Overall, the data suggest that the novel triple-acting hybrid peptides have significant potential as therapeutic options for obesity and diabetes.

   You can read the full article at A Novel Glucagon-like Peptide-1 (GLP-1)/Glucagon Hybrid Peptide with Triple-acting Agonist Activity at Glucose-dependent Insulinotropic Polypeptide, GLP-1, and Glucagon Receptors and Therapeutic Potential in High Fat-fed Mice – PMC (nih.gov).

4. Coskun, T., Urva, S., Roell, W. C., Qu, H., Loghin, C., Moyers, J. S., O’Farrell, L. S., Briere, D. A., Sloop, K. W., Thomas, M. K., Pirro, V., Wainscott, D. B., Willard, F. S., Abernathy, M., Morford, L., Du, Y., Benson, C., Gimeno, R. E., Haupt, A., & Milicevic, Z. (2022). LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and fat loss: From discovery to clinical proof of concept. Cell metabolism, 34(9), 1234–1247.e9. https://doi.org/10.1016/j.cmet.2022.07.013.
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   LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept

   As the prevalence of obesity rises, there is a requirement for new treatments to improve the management of body weight and metabolic health. Developing multi-receptor agonists may present opportunities to meet this medical demand. LY3437943 is a new triple agonist peptide that affects the glucagon receptor (GCGR), the glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon-like peptide-1 receptor (GLP-1R). In vitro, LY3437943 demonstrates a well-balanced activity between GCGR and GLP-1R, but more activity towards GIPR.

   When given to obese mice, LY3437943 decreased body weight and enhanced glycemic/blood sugar control. A greater amount of body weight was lost as a result of the GIPR and GLP-1R-driven reduction in caloric intake and the GCGR-mediated increase in energy expenditure. LY3437943 demonstrated a safety and tolerability profile equivalent to other incretins in a phase 1 single ascending dosage study. The body fat loss was maintained after a single dose up to day 43 and its pharmacokinetic characteristics suggested it may be used once a week.

   These findings imply that additional clinical testing of LY3437943 is necessary.

   You can read the full article at LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept: Cell Metabolism.

5. Available from https://diabetesjournals.org/diabetes/article/70/Supplement_1/104-OR/139575/104-OR-Novel-GIP-GLP-1-Glucagon-Receptor-Agonist.
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   104-OR: Novel GIP/GLP-1/Glucagon Receptor Agonist LY3437943: A First-in-Human Dose Study in Healthy Subjects
   Many metabolic diseases are being treated using multifunctional incretins, which are substances that boost insulin secretion and enhance blood sugar control. One such substance, LY3437943, has been discovered to exhibit vigorous agonist activity on three distinct receptors, including the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors.
   To evaluate the safety and tolerability of LY3437943, a study was conducted on 45 healthy subjects. The subjects were given six different rising doses of LY3437943 or placebo subcutaneously, and their vital signs, ECGs, laboratory data, and adverse events related to the administered medication were monitored. Results revealed that gastrointestinal symptoms such as nausea, vomiting, and abdominal discomfort, which were dose-dependent and mainly mild in severity, were the side effects of LY3437943. After one week of treatment, these side effects begin to disappear. Moreover, dose-dependent increases in heart rate and drops in systolic blood pressure were seen, but by Day 29, they had almost completely recovered to baseline levels. LY3437943 had a mean terminal half-life ranging from 134 to 165 hours across the six doses, supporting once-weekly dosing. Dose-dependent increases in fasting insulin and C-peptide were observed, with maximum levels seen at 24 and 48 hours, returning to near baseline levels by Day 15. Dose-dependent fat loss was also observed, with statistically significant weight loss seen with the three highest doses compared to the placebo. This beneficial effect was maintained up to Day 43 following the single administration of the two highest doses.

   Overall, the results of this study indicate that LY3437943 has a safety and tolerability profile similar to other incretins, with pharmacokinetic and pharmacodynamic outcomes that support further clinical evaluation.
   You can read the abstract of this article at 104-OR: Novel GIP/GLP-1/Glucagon Receptor Agonist LY3437943: A First-in-Human Dose Study in Healthy Subjects | Diabetes | American Diabetes Association (diabetesjournals.org).

6. Available from https://diabetesjournals.org/diabetes/article/70/Supplement_1/679-P/140585..
   View Summary +

   104-OR: Novel GIP/GLP-1/Glucagon Receptor Agonist LY3437943: A First-in-Human Dose Study in Healthy Subjects
   Many metabolic diseases are being treated using multifunctional incretins, which are substances that boost insulin secretion and enhance blood sugar control. One such substance, LY3437943, has been discovered to exhibit strong agonist activity on three distinct receptors, including the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors.

   To evaluate the safety and tolerability of LY3437943, a randomized, double-blind, placebo-controlled Phase 1 clinical trial was conducted on 45 healthy subjects. The subjects were given six different rising doses of LY3437943 or placebo subcutaneously, and their vital signs, ECGs, laboratory data, and adverse events related to the administered medication were monitored. Results revealed that gastrointestinal symptoms such as nausea, vomiting, and abdominal discomfort, which were dose-dependent and mainly mild in severity, were the side effects of LY3437943. After one week of treatment, these side effects begin to disappear. Moreover, dose-dependent increases in heart rate and drops in systolic blood pressure were seen, but by Day 29, they had almost completely recovered to baseline levels. LY3437943 had a mean terminal half-life ranging from 134 to 165 hours across the six doses, supporting once-weekly dosing. Dose-dependent increases in fasting insulin and C-peptide were observed, with maximum levels seen at 24 and 48 hours, returning to near baseline levels by Day 15. Dose-dependent fat loss was also observed, with statistically significant weight loss seen with the three highest doses compared to the placebo. This beneficial effect was maintained up to Day 43 following the single administration of the two highest doses.

   Overall, the results of this study indicate that LY3437943 has a safety and tolerability profile similar to other incretins, with pharmacokinetic and pharmacodynamic outcomes that support further clinical evaluation.
   You can read the abstract of this article at 679-P: The Novel GIP, GLP-1, and Glucagon Triple Receptor Agonist LY3437943 Exhibits Robust Efficacy in Preclinical Models of Obesity and Diabetes | Diabetes | American Diabetes Association (diabetesjournals.org).

7. Available from https://diabetesjournals.org/diabetes/article/71/Supplement_1/340-OR/146500/340-OR-LY3437943-LY-a-Novel-Triple-GIP-GLP-1.
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   340-OR: LY3437943 (LY), a Novel Triple GIP/GLP-1/Glucagon Receptor Agonist, Provides Glucose Lowering and Weight Loss in Patients with T2DM after 12 Weeks of Treatment
   Multi-receptor incretin agonists are being developed with the goal of treating various metabolic diseases. LY is a triple agonist that is currently being studied for its strong activity on the glucagon receptor, glucagon-like polypeptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) receptors. Due to its pharmacokinetic characteristics, previous studies have demonstrated that LY can be safely taken once per week.

   A Phase 1 proof-of-concept trial evaluated the safety and tolerability of several ascending doses of LY in type 2 diabetic patients (T2D). In this study, 72 patients were enrolled and were randomly assigned to one of five ascending dose cohorts of subcutaneous LY, a placebo, or dulaglutide 1.5mg. The safety and tolerability of LY were monitored through vital signs, laboratory data, and adverse events (AEs). Efficacy was measured by monitoring changes in glycated hemoglobin (HbA1c) and body weight at week 12. The most common treatment-emergent AEs were gastrointestinal in nature and mostly mild in severity. These include nausea and diarrhea. By week 12, the mean blood pressure decreased from baseline in the LY group compared to the placebo group. Meanwhile, the pulse and heart rate increased from baseline within most LY cohorts and dulaglutide, but not with placebo. All groups showed a decrease in mean HbA1c by week 12, with higher doses of LY demonstrating statistically significant placebo-adjusted decreases of up to 1.56%. A dose-dependent decrease in mean placebo-adjusted body weight of up to 8.96 kg was observed with LY, except in the initial cohort.

   In conclusion, the safety and tolerability profile of LY is similar to other incretins. The ability of this medication to induce and lower blood sugar levels suggests that it can provide additional benefits versus current therapies in the treatment of T2D and obesity.

   You can read the abstract of this article at 340-OR: LY3437943 (LY) , a Novel Triple GIP/GLP-1/Glucagon Receptor Agonist, Provides Glucose Lowering and Weight Loss in Patients with T2DM after 12 Weeks of Treatment | Diabetes | American Diabetes Association (diabetesjournals.org).

8. Neter, J. E., Stam, B. E., Kok, F. J., Grobbee, D. E., & Geleijnse, J. M. (2003). Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension (Dallas, Tex.: 1979), 42(5), 878–884. https://doi.org/10.1161/01.HYP.0000094221.86888.AE.
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   Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials
   Hypertension is strongly associated with increased body weight. To determine the impact of weight reduction on blood pressure, a meta-analysis of randomized controlled trials was conducted. The analysis included 25 trials published between 1966 and 2002, with a total of 4874 participants. The trials involved weight reduction through energy restriction, increased physical activity, or a combination of both. A random-effects model was used to account for heterogeneity among the trials. According to the findings, losing 5.1 kg of weight was associated with a -4.44 mm Hg systolic and -3.57 mm Hg DBP drop. The decreases in systolic and DBP were 1.05 mm Hg and -0.92 mm Hg, respectively, as expressed per kilogram of weight lost. Those who lost an average of over 5 kg in weight had considerably lower blood pressure decreases than people who lost less weight. The data also showed that populations using antihypertensive medication had considerably lower DBP than populations not receiving treatment. The study emphasized the importance of weight loss in the management of hypertension, particularly in populations taking antihypertensive drugs.
   The findings of the meta-analysis show that losing weight is crucial for both preventing and treating hypertension. Overall, this suggests that weight reductions through energy restriction and increased physical activity is an effective strategy for reducing blood pressure in populations with hypertension and that population with greater weight loss experience greater reductions in blood pressure.
   You can read the full article at Influence of Weight Reduction on Blood Pressure | Hypertension (ahajournals.org).

9. Bacon, S. L., Sherwood, A., Hinderliter, A., & Blumenthal, J. A. (2004). Effects of exercise, diet and weight loss on high blood pressure. Sports medicine (Auckland, N.Z.), 34(5), 307–316. https://doi.org/10.2165/00007256-200434050-00003.
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   Effects of exercise, diet and weight loss on high blood pressure

   Almost 50 million people in the US suffer from high blood pressure (BP) hypertension, which is a serious health problem. Although being one of the most frequent causes of outpatient visits, high blood pressure is usually uncontrollable. Pharmacological techniques can lower blood pressure in hypertensive people, but not everyone reacts to anti-hypertensive drugs successfully. In addition, they can be expensive and have side effects that reduce the overall quality of life and compliance of patients. Moreover, abnormalities associated with hypertension, such as insulin resistance and hyperlipidemia (high lipid levels), can be worsened by some anti-hypertensive medications.

   Behavioral therapies are becoming more popular as a technique to treat high blood pressure. Exercise and the DASH (Dietary Approaches to Stop Hypertension) diet are the two main behavioral therapies that are recommended to control blood pressure. Losing weight is also advised for those who are overweight. Systolic (SBP) and diastolic blood pressure (DBP) can both be decreased by exercise alone by about 3.5 and 2.0mm Hg, respectively. In comparison to individuals on a typical American diet, patients who follow the DASH diet, which contains high fiber and low-fat dairy products, fruits, and vegetables, can have SBP and DBP levels that are reduced by 5.5 and 3.0 mm Hg, respectively. For overweight hypertensive patients, an 8-kg weight loss can result in 8.5 mm Hg SBP and 6.5 mm Hg DBP decreases. A combination of exercise and a weight-loss regimen can reduce SBP and DBP by 12.5 and 7.9 mm Hg in overweight hypertension patients. These BP reductions are associated with improvements in left ventricular structure and function, as well as peripheral vascular health. Both exercise training and weight loss have been shown to decrease left ventricular mass and wall thickness, reduce arterial stiffness, and improve endothelial function.

   These findings support the use of behavioral interventions in the management of high BP. Although pharmacological treatments have been effective, behavioral interventions offer a more natural and affordable option for managing high BP, particularly in individuals who are unable to tolerate or benefit from medications.

   You can read the abstract of this article atEffects of Exercise, Diet and Weight Loss on High Blood Pressure – PubMed (nih.gov)

10. Fantin, F., Giani, A., Zoico, E., Rossi, A. P., Mazzali, G., & Zamboni, M. (2019). Weight Loss and Hypertension in Obese Subjects. Nutrients, 11(7), 1667. https://doi.org/10.3390/nu11071667.
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    Weight Loss and Hypertension in Obese Subjects

    Obesity and being obese are strongly correlated with arterial hypertension, also referred to as high blood pressure. Via several processes, including insulin and leptin resistance, perivascular adipose tissue dysfunction, reduced kidney function, activation of the renin-angiotensin-aldosterone system, and increased sympathetic nervous system activity, obesity can cause hypertension.

    It has been noted that reductions in weight can also lower blood pressure. A study described the relationship between obesity and hypertension and evaluated the effects of fat loss on blood pressure using a variety of methods, including medication, bariatric surgery, dietary and lifestyle changes, and exercise. A total of 13 studies from the past ten years were examined, and while they all showed that losing weight had a good impact on blood pressure, the degree and persistence of this effect differed from study to study.

    To completely understand the impact of fat loss on hypertension, more long-term data are needed. Despite the lack of conclusive long-term data, the management of weight should be a priority in obese patients with hypertension, given the promising results from recent studies. This emphasizes the importance of educating individuals about the potential benefits of maintaining a healthy weight.

    You can read the full article Weight Loss and Hypertension in Obese Subjects – PMC (nih.gov).