Tirzepatide

Tirzepatide is engineered as a single molecule that activates two distinct incretin receptors. Its 39-amino-acid sequence is based on the native GIP hormone, with modifications that give it high affinity for the GLP-1 receptor as well. A C20 fatty diacid moiety linked via a linker allows albumin binding, extending the half-life to approximately 5 days and enabling once-weekly dosing.

GLP-1 Receptor Activation: Like Semaglutide, tirzepatide activates GLP-1 receptors in the brain (reducing appetite and food intake), the pancreas (stimulating glucose-dependent insulin secretion), and the gut (slowing gastric emptying). These effects drive appetite suppression, improved blood sugar control, and the subjective feeling of prolonged fullness after meals.

GIP Receptor Activation: This is tirzepatide's distinguishing feature. GIP receptor activation in the brain may enhance the anorexigenic (appetite-suppressing) signal beyond what GLP-1 alone provides. In adipose tissue, GIP signaling appears to shift metabolism toward fat oxidation and improve adipocyte insulin sensitivity. In the pancreas, GIP augments the insulin-secretory response triggered by GLP-1, resulting in better glycemic control at equivalent doses.

Synergistic Effects: The dual activation creates metabolic effects greater than the sum of individual receptor activation. This is evident in the clinical data: tirzepatide outperforms both semaglutide (GLP-1 only) and GIP agonists (GIP only) in weight loss and HbA1c reduction. Animal studies suggest the combination may also have unique effects on energy expenditure, though this remains under investigation.

Biased Agonism: Research indicates tirzepatide exhibits biased agonism at the GLP-1 receptor, preferentially activating cAMP signaling over beta-arrestin recruitment. This may explain why some patients report less nausea with tirzepatide than with semaglutide, as beta-arrestin pathways are implicated in GI side effects.

Superior Weight Loss SURMOUNT-1 demonstrated 22.5% average body weight reduction at the 15 mg dose over 72 weeks, the highest of any approved medication. At the 10 mg dose, the average was still 21.4%. Over one-third of participants at the highest dose lost more than 25% of their starting weight. These results close the gap between pharmaceutical and surgical weight loss interventions.

Better Tolerability for Some Users Anecdotally and in cross-trial comparisons, tirzepatide appears to cause less nausea than semaglutide for many patients, particularly during the early titration phase. The biased agonism at the GLP-1 receptor may partially explain this. That said, GI side effects are still common and dose-dependent.

Blood Sugar Control In the SURPASS trials for type 2 diabetes, tirzepatide reduced HbA1c by up to 2.58 percentage points, with 80-90% of participants reaching the target of under 7%. Many patients achieved normal HbA1c levels (under 5.7%), which is rarely seen with any diabetes medication. Some participants were able to discontinue insulin entirely.

Body Composition Improvements Tirzepatide appears to improve body composition favorably. While all weight loss involves some lean mass reduction, data suggests tirzepatide may preserve a slightly higher proportion of lean mass compared to calorie restriction alone. The GIP receptor's role in adipose tissue metabolism could contribute to preferential fat loss.

Metabolic Improvements Beyond weight and glucose, tirzepatide reduces triglycerides, improves HDL cholesterol, lowers blood pressure, and reduces markers of systemic inflammation (CRP, IL-6). The SURMOUNT-2 trial in patients with both obesity and type 2 diabetes showed significant improvements across all metabolic parameters.

For those who want maximum weight loss or have not responded adequately to GLP-1 monotherapy, tirzepatide is currently the strongest approved option. Retatrutide, still in trials, adds glucagon receptor activity and may push results even further.

Common Side Effects - Nausea (reported in 25-33% of participants, generally milder than semaglutide for many) - Diarrhea - Decreased appetite (this is both a therapeutic effect and a side effect) - Vomiting - Constipation - Abdominal pain - Injection site reactions

Less Common Side Effects - Gallbladder events, including gallstones and cholecystitis (risk correlates with rate of weight loss) - Pancreatitis (rare but documented in post-marketing data) - Hair thinning (reported by some users, likely related to rapid weight loss and caloric deficit rather than a direct drug effect) - Hypoglycemia (mainly when combined with insulin or sulfonylureas) - Allergic reactions at injection site

Contraindications - Personal or family history of medullary thyroid carcinoma (MTC) or MEN 2 syndrome. Like all GLP-1 class drugs, tirzepatide carries a boxed warning about thyroid C-cell tumors in rodents. - History of pancreatitis (use with caution under medical supervision). - Pregnancy or planned pregnancy (discontinue at least 2 months before trying to conceive due to its long half-life). - Severe gastrointestinal disease (gastroparesis, inflammatory bowel disease). - Patients on insulin or sulfonylureas need dose reductions to prevent hypoglycemia.

Titration Is Non-Negotiable: Starting at the full 15 mg dose without titration would cause severe, prolonged GI distress in most people. The standard 4-week titration steps exist for good reason.