Semaglutide

Ozempic · Wegovy · Rybelsus · S-tier (Dr. Alex Tatem) · Strong evidence

The drug that started the GLP-1 era. It produces less weight loss than tirzepatide or retatrutide, but it has the deepest safety record and proven heart and kidney benefits.

Dr. Tatem’s take

He calls GLP-1 drugs the “S tier standards”. On Diary of a CEO he said they are “hands down” the best peptides for anyone with insulin-resistance issues.

In Dr. Tatem’s tier list

• In both Pt. 1 and Pt. 3 he credits semaglutide with starting the modern peptide revolution — earlier GLP-1 drugs like liraglutide existed, but semaglutide was the one to “knock it out of the park.”
• His caveat: its weight loss comes mainly from caloric restriction (slower gut, smaller appetite), not a higher metabolism — which is what tirzepatide and retatrutide improve on.
• He uses the GLP-1s as “the S tier standards” other diet compounds get compared against.

History & background

GLP-1 drugs trace back to exendin-4, found in Gila monster venom in the early 1990s (approved as exenatide in 2005). Novo Nordisk’s liraglutide followed in 2010; semaglutide, engineered for once-weekly dosing, was approved as Ozempic in December 2017 and as Wegovy for weight loss in June 2021.

The SELECT trial (2023) showed a 20% reduction in heart attacks, strokes and cardiovascular deaths, changing its role from a weight-loss drug to a cardiovascular one. An oral Wegovy pill was approved in December 2025.

Benefits

• About 15% average weight loss at 68 weeks (STEP 1).
• 20% fewer major heart events in people with cardiovascular disease (SELECT, n=17,604).
• Protects kidney function in diabetic kidney disease (FLOW).
• Approved for fatty-liver disease with fibrosis (MASH).

Risks

• Boxed warning for thyroid C-cell tumors (don’t use with MTC/MEN2 history).
• Pancreatitis, gallbladder disease, worsening diabetic retinopathy.
• Rare association with sudden optic-nerve injury (NAION).
• GI side effects. 7% quit because of adverse events in STEP 1.

Dosing protocols (informational, labeled by evidence)

• Clinical trial / label: FDA label – Wegovy — 0.25 mg/wk × 4 wk → 0.5 → 1 → 1.7 → 2.4 mg (each step 4 wk), SubQ, Weekly, Chronic
• Clinical trial / label: Wegovy HD high dose — 7.2 mg/wk after titrating past 2.4 mg, SubQ, Weekly, Chronic
• Clinical trial / label: FDA label – Ozempic (T2D) — 0.25 mg × 4 wk → 0.5 → 1 → 2 mg, SubQ, Weekly, Chronic
• Community (bro science): 'Microdosing' — Well below label start, commonly ~0.1–0.25 mg/wk, SubQ, Weekly, Ongoing

Status: FDA-approved: Ozempic (type 2 diabetes, CV and kidney risk), Wegovy injection (weight, CV risk, MASH liver disease) and Wegovy pill (25 mg daily, Dec 2025).

Grade and commentary: Dr. Alex Tatem. Watch: Truth About Popular Peptides Tier List (What Works, What’s Overhyped) | Pt. 3, Peptide Expert: What Do Peptides Actually Do? (EXPLAINED) - Dr Alex Tatem. Subscribe: @DrAlexTatem.