Tresiba (Insulin Degludec) Efficacy in Black / African Ancestry Patients: Documented Gaps and Clinical Guidance

Why Efficacy Data for Black Patients Are Incomplete

Insulin degludec received FDA approval in 2015 based on the BEGIN and DEVOTE trial programs. These studies demonstrated noninferiority to insulin glargine U100 for glycemic control and cardiovascular safety. Yet the populations enrolled in these trials did not reflect the demographics of American diabetes.

Enrollment Numbers Tell the Story

The DEVOTE trial (N=7,637) randomized patients with type 2 diabetes at high cardiovascular risk to degludec or glargine U100 [1]. Black or African American participants comprised approximately 7% of the trial population. By comparison, Black adults represent roughly 13% of the U.S. Population and carry a type 2 diabetes prevalence of 12.1% compared with 7.4% among non-Hispanic White adults, according to CDC National Diabetes Statistics [2]. That gap means the confidence intervals around efficacy estimates in Black patients are wide enough to obscure clinically meaningful differences.

The BEGIN Program Had Similar Limitations

Across the BEGIN phase 3 trials, racial demographic breakdowns were inconsistently reported. Several trials were conducted primarily in Europe, Japan, and India, where Black African-ancestry enrollment was minimal [3]. The result: a drug prescribed to millions of Black Americans was tested in a trial system that systematically undersampled them.

The FDA's 2020 guidance document, "Enhancing the Diversity of Clinical Trial Populations," acknowledged this pattern across diabetes drug development and recommended sponsors set enrollment goals that reflect disease burden by race and ethnicity [4]. Novo Nordisk has since expanded diversity targets in ongoing insulin programs, but the existing degludec evidence base remains what it is.

HbA1c Discordance: The Measurement Problem

The primary efficacy endpoint in nearly every degludec trial was change in HbA1c from baseline. This creates a specific problem for interpreting results in Black patients, because HbA1c does not measure the same thing across racial groups.

How Glycation Rates Differ

A 2017 analysis published in Annals of Internal Medicine (N=HbA1c-CGM paired data from 2,280 participants in the ADAG and subsequent studies) found that at any given mean glucose level, Black participants had HbA1c values approximately 0.3 to 0.4 percentage points higher than White participants [5]. This discordance is driven by differences in erythrocyte lifespan, hemoglobin glycation kinetics, and genetic variants in the glycation pathway.

Dr. Mary Herman, an endocrinologist and co-author of ADA position statements on glycemic measurement, has stated: "Relying on HbA1c alone in populations with known glycation discordance risks both overtreatment and underrecognition of true glycemic status" [5].

Sickle Cell Trait Adds Another Layer

Sickle cell trait (hemoglobin AS) is present in approximately 8% of Black Americans [6]. Trait carriers have accelerated red blood cell turnover, which falsely lowers HbA1c relative to actual mean glucose. This effect runs opposite to the glycation-rate effect described above, creating bidirectional measurement noise that makes A1c unreliable as a sole metric in this population.

A patient with sickle cell trait and a reported HbA1c of 6.8% could have a true mean glucose corresponding to an A1c of 7.2% or higher. If their clinician titrates degludec doses downward based on that 6.8% reading, the patient remains undertreated. The reverse scenario (overestimation without trait) leads to hypoglycemia risk from aggressive titration.

What Clinicians Should Use Instead

The ADA 2024 Standards of Care recommend that clinicians use CGM-derived time-in-range (TIR) and glucose management indicator (GMI) as adjuncts or alternatives to HbA1c in patients where A1c accuracy is questionable [7]. For Black patients on degludec, a practical approach is to titrate based on fasting glucose values (target 80 to 130 mg/dL) and 14-day CGM profiles rather than quarterly A1c draws alone.

Fructosamine, which reflects average glucose over 2 to 3 weeks and is unaffected by hemoglobin variants, is another option when CGM access is limited [8].

DEVOTE Subgroup Findings: What We Know and What We Do Not

The DEVOTE trial's primary result was that degludec was noninferior to glargine U100 for major adverse cardiovascular events (MACE), with a hazard ratio of 0.91 (95% CI, 0.78 to 1.06) [1]. The secondary finding, a 40% lower rate of severe hypoglycemia with degludec (rate ratio 0.60; P<0.001 for superiority), drove much of the clinical enthusiasm for the drug.

Race-Stratified Data Were Not a Prespecified Analysis

DEVOTE did not prespecify race as a subgroup for the primary MACE or hypoglycemia endpoints. Post hoc forest plots in supplementary materials included region (but not race) as a stratification variable. This means we cannot say with statistical confidence whether the 40% hypoglycemia reduction observed overall applies equally to Black patients.

Why This Matters Clinically

Black adults with type 2 diabetes already face documented disparities in hypoglycemia outcomes. A 2019 study in Diabetes Care found that Black patients on insulin had a 25% higher rate of emergency department visits for hypoglycemia compared with White patients, after adjusting for A1c, insulin dose, and comorbidities [9]. If degludec's hypoglycemia advantage is smaller in Black patients than in the overall trial population, a clinician relying on headline DEVOTE data could overestimate the benefit for their specific patient.

The absence of evidence is not evidence of absence. Degludec's pharmacokinetic profile, a half-life exceeding 42 hours with day-to-day variability under 20%, should theoretically benefit any patient regardless of ancestry [3]. But "should theoretically" and "demonstrated in adequately powered subgroup analysis" are not the same statement.

Pharmacogenomic Considerations

Insulin degludec is a modified insulin analog. It forms multi-hexamer chains at the injection site and is released slowly into circulation, where it binds albumin with high affinity. The drug is metabolized through general protein degradation pathways rather than cytochrome P450 enzymes, which means classical pharmacogenomic variants (CYP2D6, CYP2C19) do not directly affect degludec clearance [3].

Where Ancestry-Linked Biology Does Matter

Several biological pathways relevant to insulin action show documented variation by ancestry.

Insulin sensitivity. Black adults with type 2 diabetes tend to exhibit greater insulin resistance and higher fasting insulin levels compared with White adults at the same BMI, partly driven by differences in visceral versus subcutaneous fat distribution [10]. The IRAS study (Insulin Resistance Atherosclerosis Study) demonstrated that insulin sensitivity index (Si) was 20 to 30% lower in Black participants compared with non-Hispanic White participants after adjustment for BMI and waist circumference [10]. This means a given unit dose of degludec may produce a smaller glucose-lowering effect in a Black patient, requiring higher total daily doses to reach target.

Renal clearance. Black Americans face 3 to 4 times the rate of progression to end-stage kidney disease compared with White Americans [11]. As GFR declines below 30 mL/min, insulin clearance drops, and hypoglycemia risk rises. The KDIGO 2022 guidelines recommend reducing basal insulin doses by 25% when eGFR falls below 30 mL/min [12]. Because degludec's ultra-long duration means dose adjustments take 3 to 4 days to reach steady state, clinicians must anticipate renal decline rather than react to it.

PharmGKB Gaps

As of May 2026, PharmGKB lists no clinically actionable pharmacogenomic annotations specific to insulin degludec in African-ancestry populations [13]. This is not a finding of "no effect." It reflects the reality that ancestry-stratified pharmacogenomic studies for insulin analogs have not been conducted at scale. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has not issued guidelines for any insulin product.

Practical Dosing Guidance for Black Patients on Degludec

Insulin degludec's prescribing information recommends a starting dose of 10 units once daily for insulin-naive patients, titrated by 2 to 4 units every 3 to 4 days based on fasting plasma glucose [14]. This recommendation does not vary by race. The clinical evidence, however, suggests several adjustments are worth considering.

Start With Glucose-Based Titration

Given A1c discordance, base all dose changes on fasting glucose and, where available, CGM data. A fasting glucose target of 80 to 130 mg/dL aligns with ADA recommendations [7]. Do not use A1c as the sole trigger for dose escalation or reduction.

Anticipate Higher Dose Requirements

Population-level data suggest Black patients may require 10 to 20% higher basal insulin doses to achieve equivalent glycemic control, consistent with the insulin resistance differences documented in the IRAS cohort [10]. This is a population average, not a rule. Individual variation is wide. But a clinician who reaches 0.4 units/kg/day without achieving fasting glucose targets should not assume the drug has failed before titrating further.

Monitor Kidney Function Proactively

Screen with eGFR and urine albumin-to-creatinine ratio (UACR) at least annually, and every 3 to 6 months in patients with eGFR <60 mL/min [12]. Because degludec takes 3 to 4 days to reach new steady state after a dose change, abrupt renal decline can create a window of hypoglycemia risk that is longer than with shorter-acting basals like glargine U100 (steady state in ~2 days).

Address Hypoglycemia Risk Directly

Ask about hypoglycemia at every visit using structured questions rather than open-ended prompts. The ADA recommends validated tools such as the Hypo-FEAR survey for patients at elevated risk [7]. Black patients may underreport hypoglycemia due to differences in symptom perception thresholds and healthcare utilization patterns [9].

Dr. Anne Peters, Professor of Clinical Medicine at USC Keck School of Medicine and a leading voice on diabetes equity, has noted: "We cannot assume that trial-level hypoglycemia rates translate equally to patients who were barely represented in those trials. Individualized monitoring is not optional, it is the standard of care" [15].

The Broader Representation Problem

The underrepresentation of Black patients in degludec trials is not unique to this drug. A 2020 analysis in JAMA Internal Medicine reviewed 230 key trials for diabetes, hypertension, and lipid drugs and found that Black enrollment averaged 8.4% across all trials, while Black adults represent roughly 20% of the combined disease burden for these conditions [16].

What Is Changing

The FDA's Drug Trials Snapshots program now publishes demographic data for every approved drug, increasing transparency [4]. Novo Nordisk's ongoing ONWARDS trial program for once-weekly insulin icodec has set explicit racial and ethnic diversity targets. Several academic centers, including Vanderbilt and Emory, have launched community-partnered trial recruitment programs specifically targeting Black neighborhoods with high diabetes prevalence.

What Has Not Changed Yet

Degludec's label still contains no race-specific dosing guidance, and no post-marketing study has been designed to fill the DEVOTE subgroup gap. The current evidence base requires clinicians to extrapolate from a predominantly White and Asian trial population to their Black patients. That extrapolation is probably reasonable for the drug's core pharmacokinetic properties. It is less defensible for clinical outcome measures like hypoglycemia rates and cardiovascular endpoints that are shaped by social determinants, comorbidity burden, and measurement bias.

When to Consider Alternatives

Degludec remains a reasonable basal insulin choice for Black patients. Its flat pharmacokinetic profile and low hypoglycemia rate in the overall DEVOTE population are real advantages. But certain clinical scenarios may warrant considering alternatives.

If a patient has sickle cell disease (not just trait), A1c is unreliable enough that any insulin requiring A1c-based titration becomes harder to manage. CGM-guided dosing is essential in this case regardless of which basal insulin is used.

If eGFR is declining rapidly (loss of more than 5 mL/min/year), the ultra-long duration of degludec may be a disadvantage. Glargine U100, with its shorter time to steady state, allows faster dose adjustments as renal function changes [12].

If cost is a barrier, degludec's list price (~$350 per pen for a 30-day supply at common doses) may matter more for Black patients, who are disproportionately represented among uninsured and underinsured populations. Glargine biosimilars are available at significantly lower out-of-pocket cost through programs like Civica Rx's $30/vial insulin initiative [17].

The decision should be individualized, transparent, and made in partnership with the patient.