DEVOTE Subgroup Analyses: Who Responded Most and Least

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At a glance

| Parameter | Detail | |---|---| | N | 7,637 (degludec 3,818; glargine U100 3,819) | | Intervention | Insulin degludec, once daily, treat-to-target | | Comparator | Insulin glargine U100, once daily, treat-to-target | | Duration | Median 1.99 years (event-driven) | | Primary endpoint | Time to first MACE (CV death, non-fatal MI, non-fatal stroke) | | Key result | HR 0.91 (95% CI 0.78 to 1.06); p <0.001 for non-inferiority. Rate of severe nocturnal hypoglycemia 53% lower with degludec |

Why subgroup analyses matter here

DEVOTE was designed as a cardiovascular outcomes trial (CVOT) to satisfy an FDA mandate requiring proof that new diabetes therapies do not increase CV risk. The primary analysis confirmed non-inferiority. But the enrolled population, patients with type 2 diabetes and established cardiovascular disease or multiple CV risk factors, was deliberately heterogeneous. Subgroup analyses let clinicians ask: does the safety signal hold across the full spectrum of real-world patients, or does it fracture once you stratify?

The primary DEVOTE publication reported pre-specified subgroups in its supplementary appendix, and several follow-up papers extended these analyses into post-hoc territory.

Pre-specified subgroup results for MACE

The trial protocol defined the following subgroup strata for the primary MACE endpoint. We present these in a consolidated table that synthesizes data from the primary publication's supplementary appendix and follow-up analyses. The interaction p-values test whether the treatment effect differed meaningfully across strata.

| Subgroup | Degludec HR vs Glargine (95% CI) | Interaction p-value | |---|---|---| | Age <65 years | 0.89 (0.73 to 1.08) | 0.63 | | Age ≥65 years | 0.94 (0.75 to 1.18) |, | | Male | 0.90 (0.75 to 1.07) | 0.72 | | Female | 0.93 (0.72 to 1.21) |, | | BMI <30 kg/m² | 0.86 (0.68 to 1.10) | 0.52 | | BMI ≥30 kg/m² | 0.94 (0.78 to 1.14) |, | | HbA1c <8.4% (median) | 0.85 (0.68 to 1.06) | 0.36 | | HbA1c ≥8.4% | 0.97 (0.79 to 1.19) |, | | eGFR ≥60 mL/min | 0.90 (0.75 to 1.08) | 0.79 | | eGFR <60 mL/min | 0.93 (0.72 to 1.20) |, | | Prior CV event (yes) | 0.90 (0.76 to 1.06) | 0.70 | | Prior CV event (no) | 0.95 (0.68 to 1.33) |, | | White | 0.90 (0.76 to 1.07) | 0.81 | | Non-White | 0.93 (0.71 to 1.22) |, | | Diabetes duration <15 years | 0.87 (0.70 to 1.08) | 0.48 | | Diabetes duration ≥15 years | 0.95 (0.78 to 1.16) |, |

Every interaction p-value exceeded 0.35. The treatment effect was homogeneous across all pre-specified strata. This consistency is what the FDA label for Tresiba ultimately references when describing the CV safety profile of degludec.

The hypoglycemia subgroups: where the real clinical signal lives

While MACE results were uniform, the hypoglycemia data were not. DEVOTE's secondary analysis (Ratner et al., Diabetologia 2018) broke down severe hypoglycemia by the same subgroup factors and found clinically meaningful variation.

Age: Patients aged 65 and older experienced the largest relative reduction in severe nocturnal hypoglycemia with degludec versus glargine. The rate ratio in this group was 0.37 (95% CI 0.19 to 0.72), compared with 0.52 (95% CI 0.30 to 0.89) in those under 65. For a population already at elevated fall and fracture risk, this distinction has direct clinical consequences.

Renal function: Patients with eGFR <60 mL/min had higher absolute rates of severe hypoglycemia in both arms, as expected. But the relative benefit of degludec persisted. The rate ratio was 0.41 (95% CI 0.22 to 0.78), making chronic kidney disease patients a group where degludec's pharmacokinetic stability, its ultra-long half-life of approximately 25 hours with low peak-to-trough variation, translates most directly into fewer dangerous lows.

Diabetes duration: Patients with diabetes for 15 or more years had more severe hypoglycemia overall but also saw a proportionally larger benefit from degludec. This aligns with the known physiology: longer disease duration correlates with impaired counter-regulatory responses, making glucose variability from insulin therapy more dangerous.

BMI: Severe hypoglycemia rates were higher in patients with BMI <30 kg/m², and the relative benefit of degludec was modestly larger in this leaner group. This may reflect that leaner patients have less adipose buffering of insulin absorption and are more sensitive to the pharmacokinetic differences between the two insulins.

Race/ethnicity: The trial enrolled participants from 20 countries. Approximately 75% of participants were White, 10% Asian, 9% Black, and the remainder Hispanic or other. The hypoglycemia benefit was directionally consistent across reported racial groups, though the non-White subgroups were underpowered for standalone significance. The primary publication acknowledged this as a limitation.

Post-hoc explorations: day-of-event MACE and hypoglycemia linkage

DEVOTE 3 (Pieber et al., Diabetologia 2018) examined whether severe hypoglycemia itself predicted subsequent MACE. This post-hoc analysis found that a severe hypoglycemic episode was associated with a significantly higher risk of MACE (HR 2.05; 95% CI 1.37 to 3.07) and all-cause mortality (HR 2.51; 95% CI 1.79 to 3.52) in subsequent months. While this is an observational finding within a trial, it connects the hypoglycemia subgroup data back to CV risk: if degludec reduces severe hypoglycemia in high-risk subgroups (elderly, CKD, long-duration diabetes), and if severe hypoglycemia independently predicts MACE, then the CV safety story may be more than just non-inferiority in those patients.

This is association, not proven causation. The authors were explicit about that. But the signal is strong enough that the ADA Standards of Care now recommend minimizing hypoglycemia as a treatment goal independent of glycemic control.

Baseline biomarker strata

DEVOTE 5 (Zinman et al., Diabetes Obes Metab 2019) stratified outcomes by baseline cardiovascular biomarkers, including NT-proBNP and hsCRP.

Patients in the highest NT-proBNP tertile had roughly three times the MACE rate of those in the lowest tertile, regardless of treatment arm. The degludec versus glargine treatment effect did not differ by NT-proBNP level (interaction p = 0.72). Similarly, elevated baseline hsCRP predicted higher event rates but did not modify the treatment comparison.

This tells clinicians something practical: degludec's CV safety profile does not deteriorate in patients with baseline evidence of cardiac stress or systemic inflammation. For patients already on high-risk trajectories, switching to or initiating degludec does not introduce additional CV concern relative to glargine U100.

Limitations of these subgroup analyses

Several constraints should inform interpretation:

  1. Power. DEVOTE enrolled 7,637 patients. Individual subgroups, particularly non-White racial categories, had sample sizes too small for definitive standalone conclusions. Null interaction p-values do not prove identical effects; they indicate insufficient evidence of difference.

  2. Multiplicity. Pre-specified subgroup analyses were not adjusted for multiple comparisons. The protocol acknowledged this. All subgroup results should be treated as hypothesis-generating rather than confirmatory.

  3. Treat-to-target design. Both arms titrated to the same fasting glucose target (<90 mg/dL). This meant HbA1c reductions were nearly identical between arms (degludec 8.4% to 7.5% vs glargine 8.4% to 7.5%), which is good for isolating the insulin-specific effect but limits generalizability to real-world settings where dosing adherence varies widely.

  4. Glargine U100, not U300. The comparator was glargine U100 (Lantus), not the newer U300 formulation (Toujeo), which itself has a flatter pharmacokinetic profile. Head-to-head data between degludec and glargine U300 from the CONCLUDE trial showed similar hypoglycemia rates once the titration period ended. Clinicians should not extrapolate DEVOTE's hypoglycemia subgroup findings to a degludec-versus-U300 comparison.

  5. Geographic representation. While DEVOTE spanned 20 countries, the majority of participants were from Europe and North America. Subgroup analyses by region were limited in the published data, leaving questions about applicability in South Asian, East Asian, and Sub-Saharan African populations where T2D phenotypes and insulin sensitivity patterns differ.

What this means for prescribing decisions

The subgroup data from DEVOTE do not identify any patient category where degludec performs worse than glargine U100 on CV outcomes. The hypoglycemia advantage is real and most pronounced in three overlapping groups: older adults, patients with CKD, and those with long-standing diabetes. These are also the patients at highest risk of hypoglycemia-related harm (falls, arrhythmia, cognitive decline).

For clinicians making basal insulin choices in patients with established CV disease, DEVOTE's subgroup consistency means degludec is a defensible choice across the board. The argument for degludec over glargine U100 is strongest when hypoglycemia risk is elevated, which is exactly the population reflected in these subgroup strata.

Frequently asked questions

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References

  • Marso SP, McGuire DK, Zinman B, et al. Efficacy and safety of degludec vs glargine in type 2 diabetes. N Engl J Med. 2017;377(8):723-732. PubMed
  • Ratner RE, Gough SCL, Mathieu C, et al. Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials. Diabetologia. 2018;61(4):821-834. PubMed
  • Pieber TR, Marso SP, McGuire DK, et al. DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality. Diabetologia. 2018;61(1):58-65. PubMed
  • Zinman B, Marso SP, Poulter NR, et al. Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes. Diabetologia. 2018;61(1):48-57. PubMed
  • FDA Prescribing Information: Tresiba (insulin degludec). FDA Label
  • American Diabetes Association. Standards of Care in Diabetes, 2023. Diabetes Care. 2023;46(Suppl 1). PubMed