GLP-1 Antagonists and Obesity

In a recently published randomized controlled trial, five once-weekly semaglutides significantly reduced body weight and waist circumference in adults with obesity. The results of this study reinforce the role of GLP-1 agonists in treating obesity and its associated comorbidities, such as type 2 diabetes. For more information, just click the Semaglutide San Diego to proceed.

The primary pharmacodynamic endpoint was the area under the plasma semaglutide concentration-time curve over the steady-state dosing interval (AUC0-168h,sema, SS). Secondary pharmacodynamic endpoints included Cmax,sema, SS, and time to Tmax,sema, SS.

The drug has been shown to significantly improve glycemic control in adults with type 2 diabetes when used as an adjunct therapy to diet and exercise. The medication is also effective in weight loss and has been linked to fewer gastrointestinal adverse events than placebo. However, its efficacy in treating obesity and other weight-related comorbidities has not been well established.

This article reviews results from several recent RCTs that evaluated the effectiveness and tolerability of semaglutide. It also describes the results of a meta-analysis that considers the combination of semaglutide plus an SGLT-2 inhibitor or metformin versus placebo, which is based on data from the SUSTAIN 8, 9, 10, and CHINA trials. The meta-analysis incorporated a comprehensive literature search, and all relevant studies were included in the analysis.

Results from the PIONEER 7 extension phase were also included in the meta-analysis. This trial randomized participants to either continue sitagliptin or switch to oral semaglutide with flexible-dose adjustment for long-term treatment of obesity and associated comorbidities. Results from the study showed that oral semaglutide was superior to sitagliptin in achieving clinically meaningful reductions in body weight, waist circumference, and systolic blood pressure (supportive secondary endpoints; Extended Data Fig. 6) (Table 2 and Fig. 2).

Results from the PIONEER 7 extension trial and other recent studies indicate that once-weekly subcutaneous semaglutide 2.4 mg administered as an add-on to behavioral interventions is superior to placebo for reducing body weight and cardiometabolic risk factors in adults with obesity or overweight and at least one additional weight-related comorbidity, regardless of whether the patient has diabetes. In addition, the drug was associated with improvements in systolic blood pressure, diastolic blood pressure, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol (all supportive secondary endpoints; Table 2 and Extended Data Fig. 6) and was associated with a reduced risk of coronary heart disease and cardiovascular mortality (Table 2 and Extended Data Fig. 6).

The safety profile of semaglutide was assessed in a series of clinical trials. The first, STEP 5 (Studies of a once-weekly GLP-1 receptor agonist in Patients with Type 2 Diabetes), was a CVOT trial that enrolled 300 participants with type-2 diabetes who were randomly assigned to receive either placebo or semaglutide 2.4 mg subcutaneously administered every week at the beginning of the study and for 68 weeks in addition to lifestyle intervention. Semaglutide led to greater reductions from baseline in systolic blood pressure and waist circumference than placebo (both were confirmatory secondary endpoints; Table 2, Fig. 2) and improvements in glycated hemoglobin, fasting plasma glucose, hepatic enzymes, total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and triglycerides (all were supportive secondary endpoints; Table 2).

The overall rate of adverse events (AEs) was similar between the semaglutide and exenatide ER groups. The most common AEs were gastrointestinal events, and the majority of these occurred during dose escalation and did not lead to treatment discontinuation. The most serious AEs reported were pancreatitis, and one person in the semaglutide group died (from hepatocellular carcinoma).

The most commonly reported other adverse reactions associated with semaglutide were nausea, vomiting, diarrhea, constipation, and fatigue. The most frequent laboratory abnormalities were increased creatinine, ALT, and AST.

Unlike some other GLP-1 RAs, oral semaglutide does not appear to increase the risk of pancreatitis in patients with type 2 diabetes. However, it may increase nausea and diarrhea, which can cause patients to discontinue treatment. Moreover, the drug is not recommended in patients with a history of medullary thyroid cancer or multiple endocrine neoplasia of type 2.

In the SUSTAIN 8 trial, participants were randomized to receive subcutaneous once-weekly semaglutide (3.4 mg, using a pre-filled pen injector) or placebo as add-on therapy to insulin plus metformin. The primary endpoint was the change from baseline in HbA1c; the change from baseline in body weight was the confirmatory secondary endpoint. Analysis of continuous endpoints was by regression modeling with randomized treatment as the fixed factor and baseline value of the outcome measure as the covariate; analysis of binary confirmatory endpoints was by logistic regression.

Oral semaglutide significantly reduced HbA1c and body weight compared to placebo as an add-on therapy to insulin plus metformin in patients with type 2 diabetes. The drug also significantly reduced glycemic variability and did not impair renal function or cardiovascular outcomes. However, it did not reduce the progression of diabetic retinopathy.

A recent meta-analysis incorporating 17 RCTs found that subcutaneous semaglutide improved glycemic control, weight loss, and systolic blood pressure (SBP) compared to placebo or other GLP-1 RAs. This improvement was driven by reduced body weight and blood glucose, although sBP was not significantly different between semaglutide and other GLP-1 agonists. In addition, the meta-analysis did not show an increased risk of hypoglycemia or gastrointestinal side effects. However, the authors noted that the results should be cautiously interpreted due to the limited number of SGLT-2 inhibitor trials.

The pharmacokinetics of semaglutide were assessed in healthy subjects and patients with T2D across multiple studies in the SUSTAIN and PIONEER programs. In these trials, oral doses of 0.5 mg and 1 mg were administered once weekly by mouth or subcutaneously to patients with T2D for up to 26 weeks (electronic supplementary table S8).

The primary pharmacokinetic endpoint was the area under the plasma concentration-time curve from time zero to infinity following a 0.5 mg dose of oral semaglutide (AUC0-last). Other supportive secondary pharmacokinetic endpoints included the maximum observed plasma concentration of semaglutide after one dose (Cmax), the time to Cmax (tmax), the terminal elimination half-life of semaglutide (t 1/2), and the clearance of semaglutide in the feces and urine (CL/F).

Semaglutide was well-absorbed after oral administration, with a mean estimated volume of distribution of 12.5 L and 8 L after subcutaneous and oral administration, respectively. It is more than 99% bound to plasma proteins, including albumin, and the main routes of elimination are proteolytic cleavage at the peptide backbone and sequential beta-oxidation of the fatty acid side chain. Semaglutide is excreted primarily in the feces.

It may delay gastric emptying and affect absorption of orally administered medications, especially those with a narrow therapeutic index, such as theophylline. It is therefore recommended that patients taking oral semaglutide should not take theophylline unless clinically appropriate and monitored closely for the presence of adverse reactions.

Semaglutide may increase the risk of low blood sugar (hypoglycemia) if used with certain medicines. It is important to discuss this with your doctor. If you experience symptoms of hypoglycemia, contact your doctor immediately. They will advise you on what to do, and you might need to change your dose of other glucose-lowering medications.

Obesity is a serious health problem worldwide, and its prevalence is rapidly increasing. It is characterized by fat accumulation and is defined by a body mass index (BMI) above 30. This condition is associated with many complications, including heart disease. Several strategies have been used to treat it. These include diet, exercise, and weight loss medications. The most popular and effective one is metformin, but other drugs have also been used. Semaglutide is the newest drug in this class. It is a GLP-1 receptor agonist that reduces glucose production by the liver and stomach. It is also an appetite suppressant. This compound has been shown to improve blood glucose control and reduce weight in patients with type 2 diabetes.

It is important to know how semaglutide works before starting this medication. It is a GLP-1 receptor antagonist approved for use in adults to lower blood sugar in people with type 2 diabetes. It can be administered by mouth or by injection under the skin. It has fewer side effects than other GLP-1 inhibitors. However, it does increase the risk of cholelithiasis and pancreatitis. It should not be used in people with peptic ulcers or those who are at high risk of developing them.

A study on 703 participants with type 2 diabetes and moderate kidney impairment compared weekly-once s.c. 1.0 mg of semaglutide with placebo. It proved that this medicine is more effective than empagliflozin in lowering HbA1c and body weight. However, there were more cases of cholelithiasis in semaglutide group. It is also not recommended for people with hepatic impairment.