Retatrutide

A. Aids in Weight Reduction

Trial results show promising insights into the potential of retatrutide for addressing obesity and various weight-related conditions:

1. In a phase 2 trial published in the New England Journal of Medicine on June 26, 2023, 338 obese adults with a body mass index of 30 were enrolled. [1] The primary endpoint was the percentage change in body weight from baseline to 24 weeks. The secondary endpoint encompassed the percentage change in body weight from baseline to 48 weeks, as well as achieving weight reduction of 5% or more, 10% or more, or 15% or more. After 48 weeks, the groups who received a weekly injection of retatrutide showed varying percentages of change in mean weight reduction: -8.7% for the 1-mg group, -17.1% for the combined 4-mg group, -22.8% for the combined 8-mg group, and -24.2% for the 12-mg group (highest dose), in contrast to -2.1% observed in the placebo group. Improvements in LDL-cholesterol, triglycerides, fasting glucose, insulin levels, total cholesterol, HbA1c, as well as systolic and diastolic blood pressure were also observed.
2. In adults (aged 20-70 years) with type 2 diabetes for at least 3 months, the administration of retatrutide at 3/6/9/12 mg resulted in robust reductions in body weight with an acceptable safety profile. After nine months, the participants also lost an average of 17% of their body weight. Combining glucagon receptor agonism with GIP and GLP-1 receptor agonism may be one of the reasons retatrutide showed its potent weight loss effects. [2]
3. In high-fat-fed mice, twice daily administration of retatrutide for 21 days decreased body weight and nonfasting blood sugar levels and increased circulating insulin concentrations in the blood. [3]
4. In mice with obesity, the administration of retatrutide (LY3437943) decreased body weight, improved blood sugar control, and increased energy expenditure. [4]
5. In forty-five healthy human subjects, the three highest doses of subcutaneous (under the skin) administration of retatrutide produced a statistically significant weight loss that was maintained up to day 43. [5]
6. In diet-induced obese mice, retatrutide reduced appetite and body weight by 45% via reduced fat mass, making it superior to other GIPR and GLP-1R agonists. [6]

7. In patients with type 2 diabetes (T2D) and obesity, subcutaneous administration of retatrutide for 12 weeks resulted in reductions in body weight of up to 8.96 kg with a safety and tolerability profile similar to other incretins (weight loss peptides). [7]

B. Improves Blood Sugar Levels

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Retatrutide improves blood sugar levels through its effects on the hormones insulin and glucagon. Insulin lowers blood sugar levels while glucagon increases blood sugar levels to achieve homeostasis or balance. As a GLP-1 agonist and GR agonist, retatrutide enhances insulin release from the pancreas while reducing glucagon release. This in turn helps achieve healthy blood sugar levels.

Evidence from retatrutide trials suggests that the medication can produce beneficial effects on the blood sugar levels of people with diabetes and uncontrolled blood sugar:

1. In adults (aged 20-70 years) with T2D for at least 3 months, the administration of retatrutide at 3/6/9/12 mg resulted in robust reductions in blood sugar levels with an acceptable safety profile compared with placebo treatment. [2]
2. In high-fat-fed mice, twice daily administration of retatrutide for 21 days decreased nonfasting blood sugar levels by increasing circulating insulin concentrations in the blood. [3]

3. In obese mice, the administration of retatrutide improved blood sugar control and increased energy expenditure which persisted up to day 43. [4]

4. In forty-five healthy human subjects, the three highest doses of subcutaneous administration of retatrutide resulted in increased mean fasting insulin and C-peptide, with maximum levels observed at 24 and 48 hours, which in turn lowered blood sugar levels. [5]
5. In diet-induced obese mice, retatrutide lowered blood sugar and insulin levels, indicating improved insulin sensitivity (the body’s response to the effects of insulin). [6]
6. In patients with T2D, subcutaneous administration of retatrutide for 12 weeks decreased glycated hemoglobin, also known as HbA1c and is a measure of blood sugar, with a higher safety and tolerability profile. [7]

C. Improves Blood Pressure

As a weight loss drug, retatrutide can help improve blood pressure by treating obesity. By decreasing energy intake and increasing energy expenditure, retatrutide can promote fat loss. Evidence suggests that weight loss is associated with blood pressure reduction. [8-10] This indicates that retatrutide may be beneficial in people with hypertension.

Studies support the blood pressure-lowering effects of retatrutide:

1. A Phase 1 retatrutide clinical trial, which is the first human study assessing the safety and tolerability of single-ascending doses of retatrutide (LY3437943), included forty-five healthy subjects who were randomized to receive subcutaneous LY3437943 (6 rising dose levels) or placebo. [5] During the treatment period, important data such as vital signs, electrocardiogram (ECG), laboratory data, and adverse events were monitored. Fasting insulin, C-peptide, weight, and appetite were also measured. Results showed that the subjects who received retatrutide had significant weight loss, increased insulin levels, and decreased systolic blood pressure (returned to near baseline by Day 29).
2. A Phase 1 proof-of-concept study assessed the safety and tolerability of several ascending doses of retatrutide in patients with T2D. [7] In this study, seventy-two diabetic patients were randomized to receive retatrutide or placebo. During the treatment, the researchers assessed vital signs, laboratory data, and adverse events. After 12 weeks, the group that received retatrutide had decreases in blood pressure with a higher safety and tolerability profile compared to the placebo group.