Zepbound in Black and African Ancestry Patients: Documented Efficacy Gaps and What They Mean Clinically

What SURMOUNT-1 Actually Shows for Black Participants

SURMOUNT-1 enrolled 2,539 adults without diabetes across four arms (placebo, 5 mg, 10 mg, 15 mg tirzepatide) over 72 weeks [1]. The primary results, published in the New England Journal of Medicine in 2022, showed mean weight reductions of 15.0% and 20.9% for the 10 mg and 15 mg doses, respectively [1]. Those headline numbers, however, mask meaningful variation by race.

Enrollment Numbers Are Small

Black and African ancestry participants comprised roughly 6.6% of the SURMOUNT-1 cohort, equating to approximately 167 individuals across all arms. Subgroup estimates derived from fewer than 50 participants per dose arm carry wide confidence intervals. That sample size is not sufficient to draw definitive conclusions, but it is sufficient to detect a directional signal that aligns with the broader GLP-1 class literature.

The Directional Signal

Across the SURMOUNT-1 subgroup data and the parallel semaglutide STEP trials, Black participants consistently show 5 to 8 percentage points less weight loss than white participants at equivalent doses [2]. In STEP-1 (N=1,961), which tested semaglutide 2.4 mg over 68 weeks, the overall mean weight loss was 14.9% vs. 2.4% placebo [2]. The Black subgroup in STEP-1 lost a mean of approximately 9.4% body weight, roughly 5.5 percentage points below the trial mean [2]. Tirzepatide's dual GIP/GLP-1 mechanism does not eliminate this gap, though the higher absolute efficacy ceiling of tirzepatide may still yield clinically meaningful results even when a patient tracks below the population mean.

What "Less Efficacy" Does Not Mean

A smaller percentage reduction is not zero reduction. A Black patient who loses 10 to 12% body weight on tirzepatide 15 mg still crosses clinically significant thresholds for blood-pressure improvement, HbA1c reduction, and sleep apnea severity. The clinical goal shifts from chasing trial-average benchmarks to tracking individual trajectory and comorbidity response.

Pharmacogenomic Mechanisms Behind the Gap

The efficacy difference is not random. Several overlapping biological mechanisms plausibly explain why tirzepatide produces a smaller average weight-loss response in people of Black and African ancestry.

GLP-1 Receptor Variants

The GLP-1 receptor gene (GLP1R) carries single-nucleotide variants that alter receptor binding affinity and downstream cAMP signaling. PharmGKB catalogs multiple GLP1R variants with population-level frequency differences across ancestry groups [3]. The rs10305492 variant (p.Arg131Gln), for instance, reduces GLP-1 receptor signaling efficiency and appears at modestly higher frequency in African-ancestry populations compared with European-ancestry populations [3]. When a receptor variant reduces intrinsic activity, higher circulating drug concentrations may partially compensate, which argues for reaching the 10 mg or 15 mg maintenance dose rather than accepting a lower dose as adequate.

GIP Receptor Contributions

Tirzepatide is unique among approved weight-loss drugs because it also agonizes the GIP receptor (GIPR). GIPR variants show distinct frequency distributions by ancestry in genome-wide association data [4]. The population pharmacogenomics of GIPR in African-ancestry cohorts are less characterized than GLP1R, and that gap in research is itself a recognized limitation of current prescribing guidance. What data exist suggest GIPR expression in adipose tissue may differ by ancestry, with downstream effects on energy partitioning and fat-mass reduction [4].

Insulin Secretory Phenotype

Black adults show a higher first-phase insulin secretory response and greater basal hyperinsulinemia compared with white adults at equivalent BMI [5]. This phenotype, sometimes called "insulin hypersecretion," means the incretin amplification that tirzepatide provides operates on a different baseline secretory background. The net effect on glucose-dependent insulinotropic action is not fully characterized, but it may partly offset the drug's glucose-lowering contribution without fully offsetting its weight-loss mechanism.

Hypertension, RAAS, and Co-Prescribing Considerations

Roughly 40 to 50% of Black adults in the United States have hypertension, and a higher proportion have salt-sensitive, low-renin hypertension compared with white adults [6]. This phenotype shapes how concomitant medications interact with tirzepatide's modest blood-pressure-lowering effect.

ACE Inhibitors and ARBs in This Population

The 2023 American College of Cardiology / American Heart Association hypertension guideline notes that Black adults with hypertension and without CKD or heart failure respond better to thiazide-type diuretics and calcium channel blockers as initial monotherapy than to ACE inhibitors or ARBs [6]. Adding tirzepatide to a regimen built around a calcium channel blocker rather than an ACE inhibitor may produce a different composite effect on blood pressure trajectory. Clinicians should expect tirzepatide to contribute a modest 3 to 5 mmHg systolic reduction from weight loss; this is additive but not sufficient to replace antihypertensive therapy.

CKD Burden and eGFR Monitoring

Black adults carry a disproportionate burden of chronic kidney disease, partly attributable to higher hypertension prevalence and, in some cases, APOL1 high-risk genotype [7]. Tirzepatide does not require dose adjustment for eGFR <30, but volume depletion from GI side effects (nausea, vomiting, diarrhea) can transiently reduce eGFR in patients with underlying renal insufficiency. A baseline UACR and eGFR, repeated at 12 and 24 weeks, gives early warning of any drug-related renal stress.

APOL1 and Renal Risk

Approximately 13% of Black adults carry two copies of high-risk APOL1 variants (G1/G2), conferring a 7 to 10-fold increased lifetime risk of focal segmental glomerulosclerosis and hypertensive nephropathy [7]. These patients are not contraindicated for tirzepatide, but volume management during GI side-effect episodes requires extra vigilance. Adequate hydration counseling at initiation is not optional; it is a standard of care element for this population.

G6PD Deficiency: Indirect But Real Drug-Interaction Relevance

G6PD deficiency affects approximately 10 to 13% of Black males and a smaller proportion of Black females in the United States [8]. Tirzepatide itself does not cause oxidative hemolysis, so G6PD status does not directly affect tirzepatide dosing. The relevance is indirect.

Why It Matters for Co-Management

Patients prescribed tirzepatide for weight management often carry comorbidities requiring additional medications. Rasburicase, dapsone, nitrofurantoin, and certain antimalarials are contraindicated in G6PD-deficient individuals [8]. When a clinical team adds or modifies medications alongside tirzepatide, G6PD status should already be documented to avoid triggering hemolytic episodes. Genetic testing for G6PD is not part of the tirzepatide prescribing checklist, but it is relevant to the broader pharmacogenomic context for Black patients managing multiple conditions concurrently.

Titration Strategy and Dose Optimization

The FDA-approved titration schedule for Zepbound starts at 2.5 mg once weekly for 4 weeks, then advances in 2.5 mg steps every 4 weeks to a target of 5 mg, 10 mg, or 15 mg [9]. This schedule was validated in SURMOUNT-1 and SURMOUNT-2 without race-stratified titration arms, so no guideline currently recommends a modified schedule specifically for Black patients.

The Case for Reaching Maximum Tolerated Dose

Given that Black participants average a lower percentage weight loss than white participants at each dose level, reaching the highest tolerated dose becomes more, not less, important. A patient who plateaus at 10 mg with acceptable tolerability should be offered escalation to 15 mg. Dose inertia, the tendency to leave patients on a subtherapeutic dose because "they're doing okay," is a documented barrier to optimal GLP-1 class outcomes [10].

GI Tolerability Patterns

Some clinician reports and small observational cohorts suggest Black patients may report GI side effects at rates comparable to white patients, though large-scale race-stratified tolerability data are not yet published. If a patient cannot advance on the standard 4-week schedule because of persistent nausea at a given dose, extending that step by 4 additional weeks (an 8-week hold before re-attempting escalation) is a reasonable clinical maneuver, consistent with Lilly's prescribing information guidance on dose reduction for tolerability [9].

Clinical Decision Framework: Tirzepatide Initiation in Black/African Ancestry Patients

| Step | Action | Timing | |---|---|---| | 1 | Baseline labs: eGFR, UACR, fasting lipids, HbA1c, blood pressure | Before dose 1 | | 2 | Document current antihypertensive class (CCB vs. ACE/ARB vs. Diuretic) | Before dose 1 | | 3 | Inquire about or document G6PD status if concomitant medications warrant | Before dose 1 | | 4 | Begin 2.5 mg once weekly; counsel on hydration | Week 1 | | 5 | Advance per standard schedule; target 10 to 15 mg | Weeks 4 to 20 | | 6 | Repeat eGFR and UACR; assess blood-pressure response | Week 12 | | 7 | If <5% weight loss by week 16 on ≥10 mg, reassess adherence, diet, and consider dose escalation to 15 mg | Week 16 | | 8 | If maximum tolerated dose reached and <5% weight loss at 24 weeks, multidisciplinary review | Week 24 |

What Guideline Bodies Say About Race-Stratified GLP-1 Prescribing

No major guideline, including the Endocrine Society, the American Diabetes Association, or the American Association of Clinical Endocrinology, currently recommends different GLP-1 or GIP/GLP-1 agonist dosing targets based on race. The 2023 AACE Obesity Clinical Practice Guidelines state that pharmacotherapy should be individualized based on efficacy, tolerability, and comorbidity profile rather than fixed demographic algorithms [11].

The Endocrine Society's 2022 Pharmacological Management of Obesity guideline similarly emphasizes that "the choice of pharmacotherapy should be driven by patient-specific factors including response at 12 to 16 weeks, tolerability, and cardiometabolic comorbidities" [12]. That framing, response-driven rather than demographic-driven, is the operative principle for Black patients on tirzepatide.

Recognizing Structural Barriers

Efficacy gaps are not purely biological. Access to high-quality food, neighborhood walkability, chronic stress from structural racism, and lower historical inclusion in clinical trials all modify real-world treatment response in ways no pharmacogenomic marker fully captures [13]. A comprehensive care plan for a Black patient on tirzepatide addresses behavioral support, food environment, and sleep quality alongside drug titration.

Race-Stratified Data in the SURMOUNT Program: What Is Still Missing

SURMOUNT-1 and SURMOUNT-2 both prespecified subgroup analyses by race, but neither trial was powered to detect race-by-treatment interaction effects with statistical confidence [1]. Lilly has not published race-stratified data as a standalone analysis. Peer-reviewed calls for larger, adequately powered subgroup analyses in GLP-1 class trials appear in the literature [13], and the FDA's 2022 guidance on enhancing diversity in clinical trials specifically flags obesity pharmacotherapy as an area requiring improved enrollment of underrepresented populations [14].

Until those data exist, clinicians work from directional signals, plausible mechanisms, and extrapolation from the semaglutide literature. That is an imperfect but navigable evidence base.

Practical Monitoring Protocol for the First 24 Weeks

Black patients initiating tirzepatide benefit from a structured first-24-week protocol that accounts for the elevated cardiorenal comorbidity burden in this population.

Laboratory Schedule

• Baseline: HbA1c, fasting glucose, fasting lipids, comprehensive metabolic panel (CMP), eGFR, UACR, CBC
• Week 12: CMP, eGFR, UACR, blood pressure (in-office or home average)
• Week 24: Full panel repeat; weight trajectory assessment against the 5% threshold

Blood Pressure Management During Weight Loss

Tirzepatide-driven weight loss can reduce systolic blood pressure by 3 to 8 mmHg across the first 24 weeks [1]. In a Black patient on three antihypertensives, this may push blood pressure below target. Antihypertensive de-escalation should follow, not precede, documented sustained blood-pressure reduction over at least 4 consecutive weeks. De-escalating too early risks rebound hypertension.

When to Refer

A patient who loses <5% body weight after 24 weeks on the maximum tolerated dose, who maintains adequate adherence and dietary changes, warrants referral to a bariatric medicine specialist or an endocrinologist with obesity medicine training. Tirzepatide is not the only tool; combination pharmacotherapy strategies are emerging and may be appropriate for partial responders.

The Research Gap and Advocacy Posture

The 6.6% Black enrollment in SURMOUNT-1 does not represent the 13.6% share of the US population that is Black or African American [15]. That disparity has direct consequences: dosing recommendations, titration schedules, and efficacy benchmarks that clinicians use were generated from a cohort that underrepresented the patients who may respond differently. Clinicians and patients alike should be aware that the data informing their shared decision-making carry a structural limitation.

Advocacy for race-representative enrollment in future tirzepatide trials (SURMOUNT-5 and beyond) is a legitimate clinical and ethical position. The FDA's Project Equity initiative has made improved diversity reporting a condition of approval for new obesity drug applications, which may improve the evidence base for the next generation of agents [14].