Zepbound for Diabetes: Off-Label Use, Evidence, and What Patients Need to Know

What Is Zepbound and Why Is It Not Approved for Diabetes?

Zepbound received FDA approval on November 8, 2023, specifically for adults with a BMI of 30 kg/m² or greater, or a BMI of 27 kg/m² or greater with at least one weight-related comorbidity [1]. Diabetes is not listed as an approved indication on that label. The FDA-approved product for tirzepatide in type 2 diabetes is Mounjaro, which received its diabetes approval in May 2022 [2].

The active ingredient is chemically identical across both brands. Tirzepatide is a single peptide that activates both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors simultaneously. That dual agonism drives both weight reduction and glucose lowering through overlapping but distinct physiological pathways [3].

Why Two Brand Names for the Same Molecule?

The FDA approves drugs by indication, not just by molecule. Eli Lilly submitted separate New Drug Applications for each use, backed by separate clinical programs. Mounjaro's NDA was supported by the eight-trial SURPASS program targeting glycemic endpoints. Zepbound's NDA was supported by the five-trial SURMOUNT program targeting body-weight endpoints.

From the FDA's perspective, the two products address different labeled diseases. From a pharmacology perspective, the drug does the same things in the body regardless of which pen a patient injects.

What "Off-Label" Means in Practice

Off-label prescribing is legal in the United States. Physicians may prescribe any approved drug for any indication they judge clinically appropriate. The American Academy of Family Physicians notes that off-label prescribing accounts for roughly 20% of all prescriptions written in outpatient settings [4]. The risk is that insurance coverage, manufacturer patient-assistance programs, and liability frameworks are all built around the approved label.

A patient injecting Zepbound specifically to lower their HbA1c, rather than to lose weight, is using it off-label even if that same molecule (as Mounjaro) is approved for precisely that purpose.

The Clinical Evidence: What Tirzepatide Does to Blood Sugar

The glycemic data for tirzepatide comes from the SURPASS program, which enrolled patients with type 2 diabetes. That evidence directly informs off-label use of Zepbound, since the drug is the same [3].

SURPASS-1: Tirzepatide as Monotherapy

SURPASS-1 (N=478) compared tirzepatide 5 mg, 10 mg, and 15 mg against placebo in adults with type 2 diabetes inadequately controlled on diet and exercise alone, over 40 weeks. HbA1c reductions were 1.87, 1.89, and 2.07 percentage points for the three doses respectively, versus 0.04 percentage points with placebo (all P<0.001) [5]. Body weight fell by 7.0 kg, 7.8 kg, and 9.5 kg across the three active doses.

SURPASS-2: Head-to-Head Against Semaglutide 1 mg

SURPASS-2 (N=1,879) compared tirzepatide 5 mg, 10 mg, and 15 mg against semaglutide 1 mg (Ozempic) over 40 weeks in patients on metformin. This trial is the most cited for head-to-head comparisons. Tirzepatide 15 mg reduced HbA1c by 2.58 percentage points versus 1.86 percentage points for semaglutide 1 mg (difference of 0.72 points, 95% CI 0.57 to 0.87, P<0.001) [6]. Weight loss at 15 mg was 11.2 kg vs. 5.7 kg for semaglutide.

The New England Journal of Medicine published these results in June 2021, and the data formed part of Mounjaro's approval package.

SURPASS-4: High Cardiovascular Risk Population

SURPASS-4 (N=2,002) enrolled patients with type 2 diabetes and high cardiovascular risk on insulin glargine as comparator over 52 weeks. Tirzepatide 15 mg produced an HbA1c reduction of 2.58 percentage points vs. 1.44 percentage points for insulin glargine (P<0.001), with a simultaneous weight reduction of 12.9 kg vs. A weight gain of 2.5 kg in the glargine group [7]. That simultaneous glucose lowering plus weight loss in a high-risk cardiovascular cohort is one reason clinicians consider tirzepatide when a patient on Zepbound also has poorly controlled blood sugar.

SURPASS-CVOT: Cardiovascular Outcomes Data

The SURPASS-CVOT trial (N=12,817) compared tirzepatide against dulaglutide in patients with type 2 diabetes and established cardiovascular disease. Results published in NEJM in 2024 showed tirzepatide reduced the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 15% relative to dulaglutide (HR 0.85, 95% CI 0.71 to 1.02), though this was non-inferiority-designed and statistical superiority was not demonstrated for the primary endpoint [8]. HbA1c and weight reductions favored tirzepatide throughout.

The SURMOUNT Trials: Weight Evidence That Underpins Zepbound's Label

Zepbound's own approval rests on the SURMOUNT program, which enrolled people with obesity and various comorbidities, including a subset with prediabetes or type 2 diabetes.

SURMOUNT-1: The Key Obesity Trial

SURMOUNT-1 (N=2,539) enrolled adults with obesity (BMI 30 or greater) or overweight with comorbidities, excluding those on glucose-lowering medications. At 72 weeks, tirzepatide 15 mg produced mean weight loss of 22.5% from baseline versus 2.4% for placebo (P<0.001) [9]. HbA1c fell by 0.43 percentage points in the tirzepatide 15 mg group despite the population not being selected for diabetes.

SURMOUNT-2: People With Type 2 Diabetes

SURMOUNT-2 (N=938) is the most directly relevant trial for the off-label question. It enrolled adults with type 2 diabetes and obesity or overweight and tested tirzepatide for weight loss. At 72 weeks, tirzepatide 10 mg and 15 mg produced weight reductions of 13.4% and 15.7% respectively, versus 3.3% for placebo (P<0.001) [10]. HbA1c fell by 1.8 and 2.0 percentage points. This trial enrolled patients who are, by definition, the population for whom Zepbound might be prescribed off-label for glycemic benefit.

The Lancet published SURMOUNT-2 in June 2023.

How Zepbound Lowers Blood Sugar: The Mechanism

Tirzepatide's glucose-lowering action comes from two receptor-level effects working together [3].

GLP-1 Receptor Agonism

GLP-1 receptor activation increases glucose-dependent insulin secretion from pancreatic beta cells, suppresses glucagon from alpha cells, and slows gastric emptying. These effects lower postprandial glucose spikes. GLP-1 receptor agonists as a class (liraglutide, semaglutide, dulaglutide) are established diabetes treatments. The FDA notes that GLP-1 receptor agonism is the mechanistic anchor for approved diabetes drugs in this class [2].

GIP Receptor Agonism

GIP receptor activation also potentiates insulin secretion in a glucose-dependent manner and may improve insulin sensitivity in adipose tissue. The contribution of GIP agonism to glucose lowering in humans is debated in the literature, but SURPASS-2's superiority over semaglutide (a pure GLP-1 agonist) at matched doses suggests GIP adds measurable glycemic benefit beyond GLP-1 alone [6]. GIP agonism also appears to reduce nausea relative to pure GLP-1 receptor agonists, which may explain tirzepatide's tolerability profile.

Zepbound vs. Mounjaro: A Practical Comparison for Patients With Diabetes

The table below outlines the practical differences a patient with type 2 diabetes should understand before asking their prescriber about Zepbound.

| Feature | Zepbound | Mounjaro | |---|---|---| | Active ingredient | Tirzepatide | Tirzepatide | | FDA-approved for T2D | No | Yes (May 2022) | | FDA-approved for obesity | Yes (Nov 2023) | No | | Available doses | 2.5, 5, 7.5, 10, 12.5, 15 mg | 2.5, 5, 7.5, 10, 12.5, 15 mg | | Administration | Once-weekly subcutaneous injection | Once-weekly subcutaneous injection | | Typical insurance coverage path for T2D | Off-label, often denied | On-label, often covered with prior auth | | Manufacturer savings card availability | Yes (obesity indication) | Yes (diabetes indication) | | Compounded versions available | Yes (during shortage) | Yes (during shortage) |

The clinical pharmacology is identical. The label distinction is regulatory and commercial, not biological. A prescriber writing Zepbound for a patient whose primary goal is HbA1c reduction is writing an off-label prescription, regardless of whether the patient also carries an obesity diagnosis.

What the American Diabetes Association Says

The 2024 ADA Standards of Care in Diabetes (Standards of Medical Care in Diabetes, section 9) recommend GLP-1 receptor agonists and GIP/GLP-1 dual agonists as preferred agents for type 2 diabetes management when weight loss or cardiovascular risk reduction is a goal [11]. The guideline references tirzepatide by molecule name, not by brand, acknowledging that the drug's glucose-lowering efficacy is established regardless of which label appears on the pen.

The ADA writes: "Tirzepatide demonstrated superior HbA1c lowering and weight loss compared with all comparators tested in the SURPASS clinical trial program." [11]

Prior Authorization Considerations

Insurance plans issuing prior authorization for Mounjaro for type 2 diabetes typically require a documented HbA1c above a threshold (often 7.5% or 8.0%), a trial of metformin, and a confirmed diabetes diagnosis. Those same plans may deny Zepbound for a diabetes indication because its label does not list that use. Patients should confirm with their pharmacy benefit manager which product their plan will cover before the prescription is written.

Who Might Be Prescribed Zepbound Off-Label for Diabetes?

Several clinical scenarios make off-label Zepbound use understandable, if not always the most practical pathway.

Scenario 1: Zepbound Already Prescribed for Obesity, Diabetes Develops

A patient stabilized on Zepbound for weight management develops type 2 diabetes or progresses from prediabetes. The prescriber may judge that switching to Mounjaro introduces an unnecessary brand change, risks formulary complications, or creates confusion. Continuing Zepbound and treating both conditions with one agent is off-label for the diabetes component but pharmacologically sound.

Scenario 2: Mounjaro Not on Formulary, Zepbound Is

Some pharmacy benefit designs cover Zepbound under an obesity benefit but do not carry Mounjaro at all, or vice versa. A patient with both obesity and type 2 diabetes may receive Zepbound because that is what their plan covers. The prescriber notes both diagnoses; the drug addresses both.

Scenario 3: Cost and Compounding

During periods of shortage, compounded tirzepatide has been dispensed under both brand names' shortage listings. A patient with diabetes obtaining compounded tirzepatide from a 503B outsourcing facility is using the molecule off-label in the strictest sense, since no compounded drug carries an FDA label [12]. The FDA's shortage list historically included both Zepbound and Mounjaro formulations during the 2023 to 2024 supply disruptions.

Safety Profile Relevant to Diabetes Patients

The adverse event profile of tirzepatide is consistent across the SURPASS and SURMOUNT trials because the molecule is the same [5][6][9].

Gastrointestinal Effects

Nausea, vomiting, diarrhea, and constipation are the most common adverse events. In SURPASS-2, nausea occurred in 17.4% of tirzepatide 15 mg recipients versus 9.9% with semaglutide 1 mg [6]. Starting at 2.5 mg and titrating every four weeks reduces these rates.

Hypoglycemia Risk

Tirzepatide lowers glucose in a glucose-dependent manner, meaning hypoglycemia risk is low when used as monotherapy or with metformin. In SURPASS-1, severe hypoglycemia occurred in fewer than 1% of participants on tirzepatide monotherapy [5]. Risk increases substantially when tirzepatide is combined with insulin or sulfonylureas; dose reductions of those agents are typically needed at initiation.

Contraindications

Tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, based on rodent carcinogenicity data and the mechanism shared with GLP-1 receptor agonists [1][2]. Patients with a prior history of pancreatitis require careful risk-benefit evaluation.

Diabetic Retinopathy

Rapid glucose lowering in patients with pre-existing diabetic retinopathy may worsen retinopathy transiently, a phenomenon seen with other intensive glucose-lowering strategies. SURPASS-4 reported diabetic retinopathy events in 1.0% of tirzepatide participants versus 0.6% in the glargine group over 52 weeks [7]. Baseline ophthalmologic assessment is appropriate for patients with known retinopathy.

Regulatory and Prescriber Considerations

Prescribers writing Zepbound for a diabetes indication should document clinical reasoning in the medical record. The American Academy of Family Physicians' policy on off-label prescribing states that physicians should "base the decision on sound scientific evidence, clinical experience, or both" and ensure the patient is informed about the off-label nature of the treatment [4].

Pharmacists may question a Zepbound prescription submitted with a diabetes ICD-10 code (E11.x), since the drug's approved indications are obesity (E66.x) and sleep apnea. Some pharmacy management systems will flag this mismatch. Submitting with both the obesity code and the diabetes code, if both diagnoses are active, reduces friction without misrepresenting the clinical picture.

The FDA's prescribing information for Zepbound explicitly states the approved population and does not list diabetes as an approved use [1]. Nothing in that label prohibits a physician from prescribing it off-label, but the physician bears the documentation responsibility.

Evidence Grade Summary

Using the GRADE framework adapted for drug repurposing evidence:

• Certainty of glycemic efficacy: HIGH. Multiple large randomized controlled trials in populations with type 2 diabetes (SURPASS-1 through SURPASS-CVOT) demonstrate consistent HbA1c reduction ranging from 1.6 to 2.58 percentage points with tirzepatide [5][6][7][8].
• Certainty that Zepbound specifically (vs. Mounjaro) produces these effects: HIGH by pharmacological equivalence, MODERATE by direct trial evidence (SURMOUNT-2 enrolled T2D patients on Zepbound's approved doses and showed HbA1c reductions) [10].
• Certainty of cardiovascular benefit: MODERATE. SURPASS-CVOT showed non-inferiority to dulaglutide; a superiority signal requires longer follow-up data [8].
• Certainty of safety in T2D: HIGH. Adverse event profiles are well-characterized across thousands of patient-years of exposure [5][6][7][8][9][10].