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CARMELINA: official trial data disclosure by members of the trial steering committee

CARMELINA subgroup analysis:
linagliptin and cardio–renal outcomes across eGFR subgroups in patients with T2D and CV and/or kidney disease

Why did we need the CARMELINA trial?

International guidelines now recommend therapies with a proven CV benefit profile to be used preferentially in patients with T2D and CV disease, marking a new era in diabetes management1–3

Reducing the risk of CV and kidney complications is an important treatment goal in patients with T2D who are at increased risk of these events4–6

However, a need remains for additional glucose-lowering medications with a proven long-term CV safety profile, and DPP-4 inhibitors represent a common add-on treatment choice2,3

The CARMELINA (CArdiovascular safety and Renal Microvascular outcomE with LINAgliptin in patients with T2D at high vascular risk) CVOT investigated the long-term CV and kidney safety profile of linagliptin versus placebo, on top of standard of care7

CARMELINA was a multinational, randomised, double-blind, placebo-controlled CVOT7

Study medication was given on top of stable background glucose-lowering therapy and patients were treated for CV risk factors in accordance with local guidelines

CARMELINA was specifically designed to evaluate the CV (3P-MACE) and kidney safety profile of linagliptin7

The CV safety profile of linagliptin was assessed using 3P-MACE (CV death, non-fatal MI, non-fatal stroke)

CARMELINA is the first CVOT to specifically assess the kidney safety profile of a DPP-4 inhibitor

CARMELINA studied a patient population that is relevant to clinical practice7

  • CARMELINA was designed to recruit patients with T2D, including those with CV and/or kidney disease:
    a population that has previously been underrepresented in other CVOTs in diabetes

  • The characteristics of patients enrolled in CARMELINA are representative of those seen in clinical practice...

  • ...and the trial included patients across a broad range of kidney function, with a high proportion of patients with kidney disease

CARMELINA provided data for the long-term CV and kidney safety profile of linagliptin7

Cardiovascular

Long-term CV safety profile demonstrated7

The 3P-MACE primary outcome occurred in 434/3494 (12.4%) and 420/3485 (12.1%) patients in the linagliptin and placebo groups, respectively

The treatment effect of linagliptin on the 3P-MACE outcome was consistent across eGFR subgroups‡§7

Hospitalisation for
heart failure

No increased risk of hospitalisation for heart failure§7

The rates of hospitalisation for heart failure did not differ between treatment groups: 209/3494 (6.0%) and 226/3485 (6.5%) patients in the linagliptin and placebo groups, respectively

No increased risk of hospitalisation for heart failure across eGFR subgroups, which was consistent with the overall population§8

Kidney

Long-term kidney safety profile demonstrated7

The key kidney outcome occurred in 327/3494 (9.4%) and 306/3485 (8.8%) patients in the linagliptin and placebo groups, respectively

The treatment effect of linagliptin on the composite kidney outcome was consistent across eGFR subgroups§8

The risk of progression to albuminuria was significantly reduced, with consistent effects seen across eGFR subgroups§**8

Overall safety

The overall safety profile of linagliptin (including risk of hypoglycaemia) was consistent across eGFR subgroups and with the overall study population of CARMELINA7,8

What is the meaning of the CARMELINA results?7

CARMELINA provided data for the long-term CV safety profile of linagliptin in patients with T2D, including those with CV and/or kidney disease7

Linagliptin showed no increase in the risk of hospitalisation for heart failure7

Linagliptin demonstrated a reassuring long-term kidney safety profile7

The CV, kidney and overall safety profile of linagliptin across eGFR subgroups, including in patients with reduced kidney function, was consistent with its safety profile in the overall study population of CARMELINA7,8

Want to know more about the CARMELINA trial? Click here for further resources

For information on the CAROLINA trial, please click here

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A robust CVOT programme assessing the long-term
CV and kidney safety profile of linagliptin
Patients eligible for enrolment in CARMELINA were adults with T2D, HbA1c values of 6.5–10.0% and high CV and renal risk
*The trial was event-driven, therefore the median study duration of 2.2 years was not fixed at the start, but continued until at least 611 participants had an adjudication-confirmed primary outcome event; Established kidney disease was defined in CARMELINA as eGFR of 15–<45 ml/min/1.73 m2 regardless of UACR or eGFR ≥45-76 ml/min/1.73 m2 with UACR >200 mg/g. High CV risk was defined as a history of coronary artery disease, stroke or peripheral vascular disease, and microalbuminuria or macroalbuminuria, defined as UACR >30 mg/g or equivalent; Time to first occurrence of CV death, non-fatal MI or non-fatal stroke; §Because both the parallel confirmatory tests for superiority of the primary outcome (3P-MACE) and the key secondary outcome (composite kidney outcome) in the overall population were not significant (p=0.74 and p=0.62 for superiority, respectively), all subsequent analyses and outcomes are considered exploratory; Time to first occurrence of sustained eGFR decrease by ≥40%, progression to sustained ESKD or death due to kidney disease (key secondary outcome)7; **Linagliptin is not indicated for the treatment of albuminuria
3P-MACE, 3-point major adverse cardiovascular events; CV, cardiovascular; CVOT, cardiovascular outcomes trial; DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; MI, myocardial infarction; T2D, type 2 diabetes; UACR, urine albumin-to-creatinine ratio
1. Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2018;42:S162; 2. American Diabetes Association. Diabetes Care 2021;44:S1; 3. Buse JB et al. Diabetes Care 2020;43:487; 4. Sarwar N et al. Lancet 2010;375:2215; 5. Thomas M et al. Nat Rev Nephrol 2016;12:73; 6. Diabetes Canada. Can J Diabetes 2018;42:S201; 7. Rosenstock J et al. JAMA 2019;321:69; 8. Perkovic V et al. Diabetes Care 2020;43:1803

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