CARMELINA - Linagliptin in type 2 diabetes
Bottom line: In patients with type 2 diabetes with additional risk for CV or renal adverse events, linagliptin did not reduce the risk of CV events, nephropathy or retinopathy vs placebo over 2.2 years. Linagliptin may increase the risk of acute pancreatitis (NNH 500).
This is consistent with all other trials of DPP-4 inhibitors showing no clinical benefit from this class of medications.
Patients (n=6991)
Included
Adults with T2DM with HbA1c 6.5-10.0%
+ antihyperglycemic meds stable for at least 2 months
+ either high CV or renal risk
High CV risk: Existing CAD/stroke/PAD, or micro/macroalbuminuria (urinary albumin:creatinine ratio [UACR] >30 mg/g)
High renal risk: eGFR 15-45, or eGFR 45-75 + UACR >200 mg/g
Key exclusion criteria
ACS/PCI/CABG in last 2 months or PCI/CABG planned
Stroke/TIA in last 3 months
Typical baseline characteristics
66 y/o, male (62%), white (80%)
Diabetes mean duration 15 y, HbA1c 8.0%
Ischemic heart disease (27%), HF (27%)
eGFR mean 55 mL/min/1.73 m^2: 30-45 (28%), <30 (15%)
Meds:
Antihyperglycemics: Insulin (58%), metformin (54%), sulfonylurea (32%)
ASA (62%), statin (72%), ACEI/ARB (81%)
Intervention & control
I: Linagliptin 5 mg PO daily
C: Matching placebo
Co-interventions: Glycemic control using most available antihyperglycemics (no DPP-4i, SGLT2i or GLP-1 receptor agonists)
Results @ median 2.2 years
Efficacy
No reduction in the original primary outcome (“4-point MACE” a composite of CV death, MI, stroke, or hospitalization for unstable angina): Linagliptin 13.3%, placebo 13.2%
Hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.88-1.13
CV death: 7.3% vs 7.6%
Non-fatal MI: 4.5% vs 3.9%
Non-fatal stroke: 1.9% vs 2.1%
UA hospitalization: 1.2% vs 1.4%
Consistent lack of benefit in all subgroups (if anything, HR 1.20 in pts with baseline HbA1c >8%)
No effect on death from any cause: 10.5% vs 10.7% (HR 0.98, 95% CI 0.84-1.13)
No reduction in kidney outcomes (composite of death due to kidney disease, end-stage renal disease, or sustained -50% eGFR): 6.6% vs 6.5% (HR 0.98, 0.82-1.18)
No reduction in retinopathy: 1.0% vs 1.4% (HR 0.73, 95% CI 0.47-1.12)
Safety
Serious adverse events: 37.0% vs 38.5%
D/C due to adverse event: 10.3% vs 11.5%
Possible increase in acute pancreatitis: 0.3% vs 0.1% (NNH 500)
No increase in HF hospitalizations: 6.0% vs 6.5% (HR 0.90, 0.74-1.08)
Surrogate outcomes vs placebo
HbA1c: At month 3: -0.5%; over entire trial: -0.36%
No difference in weight, SBP, DBP, LDL-C, HDL-C
Internal validity
Low risk of allocation, performance, detection bias:
Computer-generated random sequence;
Block-randomized by interactive phone/web system;
Participants, clinicians & investigators blinded;
Central adjudication of CV & renal events by committee unaware of treatment allocation.
Low risk of attrition bias for CV outcomes & death, but unclear for renal outcomes:
Low loss-to-follow-up (LTFU) of 0.3% for mortality & 1.3% for CV events, but high (12%) LTFU for kidney outcomes;
Modified intention-to-treat (mITT) including all patients as randomized who received study drug for at least 1 dose.