Liraglutide and Renal Outcomes in Type 2 Diabetes

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Mann JFE, et al. "Liraglutide and Renal Outcomes in Type 2 Diabetes". New England Journal of Medicine. 2017. 377(9):839-848.
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Clinical Question

In adult patients with type 2 diabetes mellitus, does the use of liraglutide when compared to usual care alone result in decreased progression or development of diabetic kidney disease.

Bottom Line

With addition to usual care, liraglutide resulted in lower cases of the development and progression of diabetic kidney disease than placebo.

Major Points

A previous randomized, controlled trial showed Liraglutide resulted in lower risk of cardiovascular end points, but renal effects were unknown. This randomized, controlled trial used a ratio of measured creatinine and urinary albumin concentrations to assess patients with type 2 diabetes’ kidney function over a course of a minimum 42 months, comparing liraglutide to placebo in addition to usual treatment.

It was found that liraglutide resulted in better composite renal outcome than placebo, and this was primarily due to a lower rate of new-onset persistent macroalbuminuria in patients.

Design

  • Randomized, double-blind, placebo-controlled trial (n=9,340)
    • Liraglutide (n=4,668)
    • Placebo-control (n=4,672)
  • Setting: Laboratory tests performed centrally, ICON in Warrington, PA
  • Mean follow-up: 3.84 years
  • Analysis: time-to-event analyses with an intention-to-treat approach
  • Primary outcome: Composite renal outcomes (new-onset persistent macroalbuminuria, persistent doubling of serum creatinine level and and estimated GFR of 45ml or less per minute per 1.73m^2 of BSA, the need for continuous renal-replacement therapy, or death from renal disease).

Population

Inclusion Criteria

  • Type 2 diabetes mellitus
  • Risk of cardiovascular disease as defined by meeting at least one of their defined criteria (a full description of inclusion and exclusion criteria may be found in the supplementary materials)

Exclusion Criteria

  • Type 1 diabetes mellitus
  • Use of GLP-1 receptor agonist or any DPP-4 inhibitor within the previous 3 months.
  • An eGFR of <30 mL/min/1.73m2 at screening

Baseline Characteristics

Population Baseline Characteristics (liraglutide vs placebo-control)

  • Mean age: 64; 64
  • Mean BMI: 33; 33
  • Mean HbA1c%: 8.7; 8.7
  • Mean GFR: 80.2; 80.6

Interventions

  • Randomized to liraglutide or placebo in addition to usual care. Renal outcomes were ascertained every 12 months and at the end of the trial.

Outcomes

The following outcomes are listed as liraglutide vs. placebo-control

Primary Outcomes

Composite renal outcome
15% vs. 19% (HR 0.78 ; 95% CI 0.67-0.92 P=0.003; NNT=25)

Secondary Outcomes

New-Onset persistent macroalbuminuria
9.0% vs 12.1% (HR 0.74 ; 95% CI 0.60-0.91 P=0.004; NNT=33)
Persistent doubling of serum creatinine level
4.9% vs 5.5% (HR 0.89 ; 95% CI 0.67-1.19 P=0.43)
Renal replacement therapy
3.1% vs 3.6% (Hr 0.87; 95% CI 0.61-1.24 P=0.44)
Death due to renal disease
0.4% vs 0.3% (HR 1.59; 95% CI 0.52-4.87 P=0.41)

Subgroup Analysis

In the subgroup analysis, liraglutide demonstrated efficacy over placebo in those with a GFR ≥60ml/min/1.73m^2 and those with micro- and macroalbuminuria

Adverse Events

Acute Kidney injury
2.4% vs 2.1%
Proteinuria
1.4% vs 2.0%
Renal failure
0.5% vs 0.8%

Criticisms

  • Although trial prespecified renal outcomes as secondary outcomes, it was not powered for analyses of the individual renal outcomes.
  • Patients were only followed up to a maximum of 5.0 years so longer-term effects can not be determined.
  • Exclusion criteria either not employed or not described.

Funding

  • Novo Nordisk - Manufacturer of Victoza (liraglutide)
  • National Institutes of Health

Further Reading