Drug Update · Endocrinology

FDA Approves Semaglutide for CV Risk in Obesity: SELECT Cuts MACE 20%

July 10, 2026

Primary endpoint result

Primary CV end-point occurred in 6.5% vs 8.0% (HR 0.80; 95% CI 0.72-0.90; P<0.001) [1]

Trial name

SELECT

Patients randomized

17,604

FDA approval date

March 08, 2024

Approved dose

2.4 mg once weekly (WEGOVY injection) [2][12]

Clinical Perspective

Health care professionals treating adults with established cardiovascular disease and either obesity or overweight should be aware that Wegovy (semaglutide) injection is now FDA‑approved to reduce the risk of MACE in this population ^[3]. The approval is supported by the SELECT trial showing a primary end-point event in 6.5% of semaglutide-treated patients versus 8.0% with placebo (HR 0.80; 95% CI 0.72-0.90; P<0.001) ^[1]^[3]. How clinicians should balance the observed benefit with the trial discontinuation rates and the labeled risks, including the boxed warning for thyroid C-cell tumors and other listed adverse events, remains a key practical question for patient selection and monitoring?

Dr. Amit Desai, MBBS, MD (General Medicine), DM (Endocrinology) · Endocrinology

The FDA approved semaglutide (Wegovy) injection on March 08, 2024 to reduce the risk of major adverse cardiovascular events (MACE) in adults with established cardiovascular disease and either obesity or overweight ^[3]. The approval was based on the SELECT trial, which showed a primary cardiovascular end-point event in 6.5% of semaglutide-treated patients versus 8.0% with placebo (hazard ratio, 0.80; 95% CI, 0.72 to 0.90; P<0.001) ^[1]^[3].

Clinical Context

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist marketed as Wegovy (subcutaneous injection) and as tablets in other formulations; the product and labeling are maintained by Novo Nordisk ^[2]^[4]. The new indication targets adults with established cardiovascular disease and either obesity or overweight and is intended to be used in addition to a reduced-calorie diet and increased physical activity ^[3]^[2]. The FDA press release and prescribing information describe the approval specifically for reduction of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in this population ^[3]^[2]. The pivotal evidence for this indication comes from a multinational, placebo-controlled cardiovascular outcomes trial named SELECT ^[1]^[4].

Key Findings

The SELECT trial showed that semaglutide reduced the risk of a first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) by 20% versus placebo (hazard ratio, 0.80; 95% CI, 0.72 to 0.90; P<0.001). In SELECT, a primary end-point event occurred in 569 of 8,803 patients (6.5%) assigned to semaglutide and in 701 of 8,801 patients (8.0%) assigned to placebo ^[1].
SELECT enrolled a total of 17,604 patients (8,803 semaglutide; 8,801 placebo) with preexisting cardiovascular disease and overweight or obesity; mean duration of exposure to semaglutide or placebo was 34.2±13.7 months, and mean duration of follow-up was 39.8±9.4 months in the NEJM report ^[1]. The FDA and prescribing information summarize the trial as a multi‑national, multi‑center, placebo‑controlled double‑blind trial that randomized over 17,600 participants ^[3]^[4].
Secondary and other endpoints reported in the trial publication and label include numeric differences in components of MACE and in all-cause death; the prescribing information and trial report provide the full endpoint table and hierarchical testing results ^[1]^[4].

Safety & Tolerability

Boxed warning: risk of thyroid C-cell tumors; Wegovy is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) ^[2]^[3].
Acute pancreatitis has been reported and is listed in warnings and precautions ^[2]^[3].
Acute gallbladder disease, including cholelithiasis, has occurred in clinical trials and is listed in warnings and precautions ^[2].
Hypoglycemia risk with concomitant insulin or insulin secretagogues is described in the label ^[2].
Acute kidney injury due to volume depletion is listed as a warning and precaution ^[2].
Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported ^[2].
In SELECT, adverse events leading to permanent discontinuation of the trial product occurred in 1,461 patients (16.6%) in the semaglutide group and in 718 patients (8.2%) in the placebo group (P<0.001) ^[1].

Study Design

SELECT (Study 1 in the prescribing information) was a multi‑national, multi‑center, placebo‑controlled, double‑blind randomized cardiovascular outcomes trial in adults with established cardiovascular disease and either obesity or overweight; 17,604 patients were enrolled and randomized to semaglutide or placebo ^[1]^[4]. The primary endpoint was time to first occurrence of a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke in a time‑to‑first‑event analysis ^[1]^[4]. The NEJM report provided mean exposure (34.2±13.7 months) and mean follow-up (39.8±9.4 months) and the randomized group sizes of 8,803 and 8,801 patients ^[1]. The FDA approved the new indication for Wegovy injection on March 08, 2024 based on SELECT ^[3].

FAQ

Q1 What is semaglutide (Wegovy) approved for?

Wegovy (semaglutide) injection is approved to reduce the risk of major adverse cardiovascular events (cardiovascular death, non‑fatal myocardial infarction, or non‑fatal stroke) in adults with established cardiovascular disease and either obesity or overweight. Wegovy injection is also indicated for weight reduction and maintenance in adults and pediatric patients aged 12 years and older with obesity, and for adults with overweight with at least one weight‑related comorbid condition; it has an accelerated approval for noncirrhotic metabolic dysfunction‑associated steatohepatitis (MASH) with moderate to advanced fibrosis.

Q2 How does semaglutide work?

Semaglutide is a GLP‑1 analogue that selectively binds to and activates the GLP‑1 receptor. GLP‑1 receptor activation regulates appetite and caloric intake and semaglutide’s actions include effects on brain regions involved in appetite regulation; the exact mechanism for cardiovascular risk reduction has not been established in humans according to the prescribing information.

Q3 What is the recommended dose of semaglutide for cardiovascular risk reduction?

The prescribing information lists the usual recommended maintenance dosage of WEGOVY injection as 2.4 mg once weekly when used for weight reduction; the WEGOVY tablet recommended maintenance dosage for cardiovascular risk reduction and weight reduction is 25 mg orally once daily, and WEGOVY injection is administered once weekly as an adjunct to diet and increased physical activity with escalation per the label. Clinicians should consult current prescribing information for complete dosing guidance.

Q4 What are the most common side effects?

The label and trial report list multiple safety considerations. The product carries a boxed warning for risk of thyroid C‑cell tumors and is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or MEN 2; pancreatitis, acute gallbladder disease, hypoglycemia with insulin or insulin secretagogues, acute kidney injury due to volume depletion, severe gastrointestinal adverse reactions, hypersensitivity reactions including anaphylaxis and angioedema, and diabetic retinopathy complications are described in warnings and precautions. In SELECT, adverse events leading to permanent discontinuation occurred in 16.6% of semaglutide‑treated patients versus 8.2% of placebo‑treated patients.

Clinicians should consult current prescribing information for complete dosing guidance.

FDA Approves Semaglutide for CV Risk in Obesity: SELECT Cuts MACE 20%

FDA Approves Semaglutide for CV Risk in Obesity: SELECT Cuts MACE 20%

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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