Beverly Tchang, MD
December marks the advent of the approval of tirzepatide (Zepbound) for on-label treatment of obesity. In November 2023, the US Food and Drug Administration (FDA) approved it for the treatment of obesity in adults.
In May 2022, the FDA approved Mounjaro, which is tirzepatide, for type 2 diabetes. Since then, many physicians, including myself, have prescribed it off-label for obesity. As an endocrinologist treating both obesity and diabetes, I am sharing some lessons learned (many from my patients) on how best to prescribe tirzepatide.
Table 1. A Quick Guide to Tirzepatide (Zepbound)
Mechanism Dual glucagon-like peptide 1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist; increases the activity of these two gut peptides to increase fullness and decrease appetite
Indication Body mass index (BMI) ≥ 30 or BMI ≥ 27 with weight-related comorbidities (eg, heart disease, diabetes)
Administration Once-weekly subcutaneous injection according to the following titration schedule:
Weeks 1-4: 2.5 mg
Weeks 5-8: 5 mg
Weeks 9-12: 7.5 mg
Weeks 13-16: 10 mg
Weeks 17-20: 12.5 mg
Weeks 21-24: 15 mg
Contraindications Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2
Side effects Nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, injection site reactions, fatigue, hypersensitivity reactions, eructation, hair loss, gastroesophageal reflux disease
The Expertise
Because GLP-1 receptor agonists have been around since 2005, we’ve had over a decade of clinical experience with these medications. Table 2 provides more nuanced information on tirzepatide (as Zepbound, for obesity) based on our experiences with dulaglutide, liraglutide, semaglutide, and tirzepatide (as Mounjaro).
Table 2 . Further Details on Tirzepatide (Zepbound)
Mechanism In addition to suppressing appetite, tirzepatide may reduce cravings and other manifestations of “emotional eating.” The GIP component may also have positive effects on fat metabolism.
Indication BMI cutoffs ≥ 27 and ≥ 30 apply primarily to a White population. These thresholds should be adjusted downward for ethnicities in whom metabolic consequences occur at lower BMIs (eg, obesity in East Asian and South Asian populations is defined as BMI ≥ 25).
Some patients may seek medication before developing overweight or obesity, especially if they are experiencing rapid weight gain due to a medication. Although tirzepatide is not approved for the prevention of obesity, such preventive health discussions should be conducted between patients and their doctors to fully understand the risks and benefits.
Administration Although the typical patient will increase tirzepatide by 2.5 mg every 4 weeks, patients and clinicians may choose to hold a dose or pause uptitration to limit side effects.
According to the most recent clinical trial, if one or two consecutive doses are missed, the patient can resume tirzepatide at the last administered dose. If three or more consecutive doses are missed, the patient should restart dose escalation starting at 5 mg.
Contraindications Personal or family history of medullary thyroid carcinoma and multiple endocrine neoplasia type 2 are absolute contraindications.
Conditions like pancreatitis, gastroparesis, reflux, other thyroid cancers, and gallbladder disease may give a clinician pause but are not absolute contraindications. Prescribing tirzepatide in these scenarios requires a thorough risk vs benefit discussion.
Side Effects The most common side effects my patients experience are nausea, diarrhea, constipation, fatigue, and reflux. Many of these are manageable with some lifestyle strategies: smaller portion sizes, greater attentiveness to fullness signals, and emphasis on hydration (remember, GLP-1 suppresses our ability to sense thirst).
The Reality
In today’s increasingly complex healthcare system, the reality of providing high-quality obesity care is challenging. When discussing tirzepatide with patients, I use a 4 Cs schematic — comorbidities, cautions, costs, choices — to cover the most frequently asked questions.
Comorbidities
In trials, tirzepatide reduced A1c by about 2%. In one diabetes trial, tirzepatide reduced liver fat content significantly more than the comparator (insulin), and trials of tirzepatide in nonalcoholic steatohepatitis are ongoing. A prespecified meta-analysis of tirzepatide and cardiovascular disease estimated a 20% reduction in the risk for cardiovascular death, myocardial infarction, stroke, and hospitalized unstable angina. Tirzepatide as well as other GLP-1 agonists may be beneficial in alcohol use disorder. Prescribing tirzepatide to patients who have or are at risk of developing such comorbidities is an ideal way to target multiple metabolic diseases with one agent.
Cautions
The first principle of medicine is “do no harm.” Tirzepatide may be a poor option for individuals with a history of pancreatitis, gastroparesis, or severe gastroesophageal reflux disease. Because tirzepatide may interfere with the efficacy of estrogen-containing contraceptives during its uptitration phase, women should speak with their doctors about appropriate birth control options (eg, progestin-only, barrier methods). In clinical trials of tirzepatide, male participants were also advised to use reliable contraception. If patients are family-planning, tirzepatide should be discontinued 2 months (for women) and 4 months (for men) before conception, because its effects on fertility or pregnancy are currently unknown.
Costs
At a retail price of $1279 per month, Zepbound is only slightly more affordable than its main competitor, Wegovy (semaglutide 2.4 mg). Complex pharmacy negotiations may reduce this cost, but even with rebates, coupons, and commercial insurance, these costs still place tirzepatide out of reach for many patients. For patients who cannot access tirzepatide, clinicians should discuss more cost-feasible, evidence-based alternatives: for example, phentermine, phentermine-topiramate, naltrexone-bupropion, metformin, bupropion, or topiramate.
Choices
Patient preference drives much of today’s clinical decision-making. Some patients may be switching from semaglutide to tirzepatide, whether by choice or on the basis of physician recommendation. Although no head-to-head obesity trial exists, data from SURPASS-2 and SUSTAIN-FORTE can inform therapeutic equivalence:
- Semaglutide 1.0 mg to tirzepatide 2.5 mg will be a step-down; 5 mg will be a step-up
- Semaglutide 2.0 or 2.4 mg to tirzepatide 5 mg is probably equivalent
The decision to switch therapeutics may depend on weight loss goals, side effect tolerability, or insurance coverage. As with all medications, the use of tirzepatide should progress with shared decision-making, thorough discussions of risks vs benefits, and individualized regimens tailored to each patient’s needs.
The newly approved Zepbound is a valuable addition to our toolbox of obesity treatments. Patients and providers alike are excited for its potential as a highly effective antiobesity medication that can cause a degree of weight loss necessary to reverse comorbidities. The medical management of obesity with agents like tirzepatide holds great promise in addressing today’s obesity epidemic.
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