Plasma metabolites can predict cardiorenal outcomes in patients with type 2 diabetes and high cardiovascular risk

Presenter: Michael K. Hansen, Janssen Research and Development, Spring House, PA.

Identification of circulating metabolites to predict cardiorenal outcomes in patients with type 2 diabetes (T2D). Abstract TH-PO174. Presented Nov 2, 2023.

Adverse cardiorenal outcomes can be predicted by levels of baseline metabolites in patients with type 2 diabetes and high cardiovascular (CV) risk. In particular, higher levels of xanthosine were predictive of a higher risk of an adverse renal outcome, heart failure, and CV death among participants in the CANagliflozin cardioVascular Assessment Study (CANVAS), reported Michael K. Hansen Janssen Research and Development, Spring House, PA, and colleagues.

The CANVAS Program integrated data from two trials1,2 involving a total of 10,142 participants with type 2 diabetes and high CV risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks (2.5 yrs). Patients enrolled had type 2 diabetes and an estimated glomerular filtration rate (eGFR) of greater than 30 mL/min/1.73 m2 and were either at least 30 years old with a history of symptomatic atherosclerotic CV disease or at least 50 years old with at least 2 risk factors for CV disease.

In the post hoc analysis presented here, plasma metabolites were assayed from a subset of 929 participants of the CANVAS study.

Cox proportional hazard regression analysis was used to examine the association of 105 baseline metabolites with the renal outcome (≥ 40% decline in eGFR, end-stage kidney disease, or renal death) and CV outcomes, including heart failure, CV death, and major adverse cardiac events (MACE). The predicted hazard ratio (HR) for a 1-unit increase in the log metabolite values were calculated.

The 929 participants had a mean age of 63 years, a mean BMI of 32.8 kg/m2, a mean HbA1c of 8.23, and a mean baseline eGFR of 75.7 mL/min/1.73 m2. Results showed that 60 patients (6.5%) had an adverse renal outcome, 157 (16.9%) had a MACE, 96 (10.3%) developed heart failure, and 155 (16.7%) developed heart failure with CV disease.

A 1-unit log increase in xanthosine was predictive of the adverse renal outcome (HR, 1.26; P = .016) in the overall cohort (randomized to either canagliflozin or placebo). Tropisetron (HR, 0.76; P = .007) and adenosine triphosphate-2 (HR, 0.81; P = .03) were protective of this outcome.

One-unit log increases in 3-hydoxykynurenine (HR, 1.54; P = .009), xanthosine (HR, 1.24; P = .003), uridine (HR, 1.64; P = .02), pyruvate (HR, 1.62; P = .032), phenylpyruvate (HR, 1.92; P = .003), phenyllactic acid (HR, 1.41; P = .049), lactate (HR, 2.15; P = .014), and biotin (HR, 1.89; P = .005) were significant predictors of the development of heart failure in the overall cohort, whereas glucose 6-phosphate was protective (HR, 0.67; P = .016).

Regarding the outcome of heart failure and CV death, increases in 3-hydoxykynurenine (HR, 1.44; P = .003), xanthosine (HR, 1.21; P = .002), rhamnose-2 (HR, 1.72; P = .003), pyrogluatmic acid (HR, 1.33; P = .02), lactate (HR, 1.85; P = .011), biotin (HR, 1.56; P = .01), and allantoin (HR, 1.51; P = .005) were all predictive of increased risk in the overall cohort whereas an increase in malonyl-CoA (HR, 0.78; P = .021) was protective.

Increases in 2-hydoxy-2-methyl butyrate (HR, 1.26; P = .05) rhamnose-2 (HR, 1.65; P = .004), and nicotinate (HR, 1.32; P = .046) were significant predictors of the development of MACE in the overall cohort, whereas increases in 2-ketohexanoic acid (HR, 0.56; P = .014), xanthurenate (HR, 0.84; P = .046), urate (HR, 0.75; P = .048), thymine d4 (HR, 0.64; P = .01), malonyl-CoA (HR, 0.69; P = .001), 5’ deoxyribose phosphate (HR, 0.78; P = .033), and adenosine triphosphate-1 (HR, 0.87; P = .034) were protective.

“Further research is required to better understand and validate these findings in additional patient populations and clinical cohorts,” the investigators concluded.

References

  1. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N EngI J Med 2017; 377(7):644-657.
  2. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380(24):2295-2306.

Michael K. Hansen is an employee of Janssen.

https://www.asn-online.org/education/kidneyweek/2023/program-abstract.aspx?controlId=394431

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