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

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

Why do 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 type 2 diabetes 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 and had a high proportion of patients with kidney disease

CARMELINA demonstrated data for the long-term CV and kidney safety profile of linagliptin

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

Consistent CV safety profile in Asian patients§8

Hospitalisation for
heart failure

No increased risk of hospitalisation for heart failure§7

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 in Asian patients§8

Differences in the treatment effect among different regions were suggested for HHF (p = 0.0368 for treatment by region interaction). However, consistent with the overall population, there was no increase in the risk of HHF with linagliptin versus placebo in Asian patients

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

Consistent kidney safety profile in Asian patients§8

Overall safety

The overall safety profile of linagliptin in Asian patients was consistent with its profile in the overall study population of CARMELINA8

What is the meaning of the CARMELINA results?7, 8

In CARMELINA, linagliptin demonstrated a long-term CV safety profile in patients with T2D, including those with CV and/or kidney disease

Linagliptin showed no increase in risk of hospitalisation for heart failure, even in patients at high risk of heart failure

Linagliptin demonstrated a reassuring long-term kidney safety profile

The CV, kidney and overall safety profile of linagliptin in Asian patients was consistent with its safety profile in the overall study population of CARMELINA

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
*Asian patients in CARMELINA were patients from Asian study sites (China, Japan, Malaysia, South Korea and Taiwan) who self-identified as being of Asian race8; Established kidney disease was defined in CARMELINA as eGFR of 15–<45 ml/min/1.73 m2 or eGFR ≥45–75 ml/min/1.73 m2 with UACR >200 mg/g or equivalent; proportion of patients with established kidney disease was not reported in the elderly subgroup analysis. 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 equivalent7; 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 exploratory7Time to first occurrence of sustained eGFR decrease by ≥40%, progression to sustained ESKD or death due to kidney disease (key secondary outcome)
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; HbA1c, glycated haemoglobin; 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 2020;43: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 CanadaCan J Diabetes 2018;42:S201; 7. Rosenstock J et al. JAMA 2019;321:69; 8. Inagaki N et al. Diabetol Int 2019;11:129

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