Obesity increases the risk of type 2 diabetes and cardiovascular disease, the number one cause of death worldwide.
A 5–10% reduction in body weight alleviates obesity-related complications by improving anthropometric parameters, cardiometabolic parameters (blood glucose, blood pressure, plasma triglycerides), and quality of life, as well as reducing the risk of cardiovascular complications.
Achieving weight loss with a comprehensive lifestyle program that includes diet, exercise, and intensive behavioral therapy and then maintaining that weight is challenging.
Adding medications to lifestyle changes greatly increases the likelihood of achieving your desired weight loss goals.
Developed by Novo Nordisk, Wegovy (semaglutide) is a new drug for long-term weight management in adult patients whose body mass index (BMI) is:
- Equal to or greater than 30 kg/m2 (obesity);
- Is in the range of 27–30 kg/m2 (overweight) in the presence of at least one comorbid condition associated with overweight, such as arterial hypertension, type 2 diabetes mellitus, dyslipidemia, etc.
Approved by the U.S. Food and Drug Administration (FDA) in early June 2021, Wegovi should be used as an adjunct to a low-calorie diet and increased physical activity.
The regulatory verdict for Wegovi weight loss was based on the results of several 68-week phase III clinical trials (randomized, double-blind, placebo-controlled, multicentre, international) in adults in the STEP program:
- STEP 1 (NCT03548935): treatment of obesity or overweight (n=1961) with an extended study period of one more year;
- STEP 2 (NCT03552757): treatment of obesity or overweight (n=1210) in the diagnosis of type 2 diabetes (glycated hemoglobin [HbA1c] in the range of 7–10%);
- STEP 3 (NCT03611582): Treatment of obesity or overweight (n=611) with intensive behavioral lifestyle therapy;
- STEP 4 (NCT03548987): treatment of obesity or overweight (n=1964) among patients who, after a 20-week run-in period, achieved a target weekly dose of semaglutide of 2.4 mg.
In the STEP 1, STEP 2, and STEP 4 studies, patients were instructed to reduce their calorie intake (the deficit was approximately 500 kcal/day) and increase their physical activity (at least 150 minutes/week). In the STEP 3 study, participants had to start on an 8-week low-calorie diet (total energy intake 1000–1200 kcal/day) and then switch to a reduced-calorie diet (1200–1800 kcal/day) and increase physical activity (100 min/day). week with a gradual increase to 200 min/week).
Subjects were given weekly injectable semaglutide (with a gradual increase in dose to avoid side effects) or placebo.
In trials, Wegovi outperformed placebo in a statistically significant way, providing adequate weight loss and leading a decent proportion of patients to shed 5%, 10% and 15% of excess body weight.
Loss of extra pounds was observed in all subjects, regardless of age, gender, race, ethnicity, baseline BMI and weight, and the degree of impaired renal function.
Other beneficial effects of Vegovi include improved anthropometric parameters such as waist circumference and blood pressure, and improved cardiometabolic parameters including levels of HbA1c, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, and triglycerides.
Given that semaglutide, in the form of Ozempic, which is approved for the treatment of type 2 diabetes mellitus, is also allowed to reduce the risk of serious adverse cardiovascular events (MACE) in adult patients with type 2 diabetes mellitus and a history of cardiovascular disease, we can safely assume that Wegovi can also reduce the risks of MACE, such as non-fatal myocardial infarction, non-fatal stroke, death due to cardiovascular complications.
The most common adverse reactions to Wegovi versus placebo were nausea (44% vs 16%), diarrhea (30% vs 16%), vomiting (24% vs 6%), constipation (24% vs 11%) , abdominal pain (20% vs 10%), headache (14% vs 10%), fatigue (11% vs 5%), dyspepsia (9% vs 3%).
As you can see, the negative effects of the use of Wegovi stem mainly from the gastrointestinal tract. In most cases, they are mild to moderate in severity, reach their peak during the period of increasing the dose of semaglutide, are transient and almost disappear during stable therapy.
Instructions for use for Wegovi, as well as for all other analogues of glucagon-like peptide-1, are provided with a "black-framed" warning: semaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma, as well as in those who have been diagnosed with multiple endocrine neoplasia syndrome type II . In rodent tests, semaglutide has been associated with the development of C-cell thyroid tumors.
If we evaluate the effectiveness of semaglutide on an average, that is, without reference to the presence or absence of diabetes, adherence or not to a lifestyle change program, the degree of adherence to treatment, it turns out that after one year of stable therapy (plus 4 months of the period of gradual dose selection) with Wegovi 15.2% of excess body weight can be eliminated. And this is the best indicator relative to other existing pharmacological interventions.
It is appropriate to provide general data on the effectiveness of all other drugs to combat overweight and obesity. It should be understood that the information is for reference only and does not aim to make any comparisons of drugs among themselves, since it would be methodologically incorrect to do so due to differences between both the design of the clinical trials themselves and the initial characteristics and characteristics of the populations of their participants.
Thus, for example, the pooled data included results from studies in which obese patients may have concomitantly suffered from type 2 diabetes mellitus and therefore followed background hypoglycemic therapy. Again, the ultimate efficacy of any weight loss drug varies greatly from patient to patient and is not affected by degree of obesity, age, or pre-treatment eating habits.
And one more thing: the results presented did not include the results of the "ideal" patients who strictly adhered to the prescribed course of treatment. In other words, the effectiveness of the pharmacological correction of overweight given below can shift for the better (by a few percent) if you strictly follow the prescribed therapy regimen (do not skip the next dose and complete the entire course of treatment) and its features (for example, connect a dietary diet or physical activity).
Wanting to build more evidence for semaglutide in managing obesity in adult patients, Novo Nordisk is conducting a series of additional clinical trials comparing 2.4 mg semaglutide with placebo (unless otherwise noted):
- STEP 5 (NCT03693430) [Completed]: Treatment of obesity or overweight (n=304) over two years (104 weeks);
- STEP 6 (NCT03811574) [Completed]: Treatment of obesity or overweight (n=400) for 68 weeks in Japanese and Korean patients with 1.7 or 2.4 mg semaglutide, Japanese participants allowed diagnosis of diabetes mellitus 2 -th type;
- STEP 7 (NCT04251156) [ongoing]: Treatment of obesity or overweight (n=375) for 44 weeks, eligible participants diagnosed with type 2 diabetes;
- STEP 8 (NCT04074161) [Completed]: Treatment of obesity or overweight (n=1964) for 68 weeks, comparison group receiving Victoza (liraglutide) at a daily dose of 3.0 mg;
-NCT04102189 [Completed]: Treatment of obesity or overweight in adolescents (n=1964) for 68 weeks.
Such an impressive performance of a cocktail of semaglutide and cagrilintide, fast and powerful, suggests the future slogan: "Two drugs - minus one kilogram per week."
Importantly, the combination therapy was well tolerated, with the most common gastrointestinal adverse reactions, such as nausea and vomiting, being mild to moderate in severity. At the same time, their frequency was comparable to that observed with the monoapplication of any GLP-1R agonist, such as semaglutide. In other words, no major safety concerns for cagrilintide have been identified so far.
Cagrilintide (AM833, NN9838) is an amylin receptor (AMYR) agonist that regulates energy homeostasis and activates a satiety signal resulting in decreased food intake and increased energy expenditure in the face of fat loss. Kagrilintide is thought to act on the homeostatic and hedonic areas of the brain to induce satiety, and moreover, influences the choice of specific food, which leads to changes in eating behavior. Because kagrilintide and semaglutide act in different brain regions, their coadministration results in an additive effect on appetite regulation.
In the 26-week phase II clinical trial NCT03856047 (randomized, double-blind, placebo-controlled, active arm, multicentre, international) in adult patients (n=706) with obesity or overweight and without type 2 diabetes, there were there was a statistically significant advantage of weekly mono-application of cagrilintide over placebo and Victoza.
Weight loss provided by cagrilintide was 6.0-10.8% (dose-dependent: 0.3; 0.6; 1.2; 2.4 or 4.5 mg) and did not plateau by the end of the study. In the placebo and liraglutide groups: 3.0% and 9.0%. In the maximum 4.5-mg dose of cagrilintide, weight loss of at least 5%, 10%, or 15% occurred in 88.7%, 53.5%, and 18.7% of patients. Adverse reactions to kagrilintide, occurring with acceptable tolerability, were reported mainly from the gastrointestinal tract.
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