Higher CV event risk with worse kidney function in TECOS, event rate unaffected by DPP4 inhibitor

Cornel JH, Bakris GL, Stevens SR, et al; TECOS Study Group­.
Diabetes Care 2016;published online ahead of print

Background

Type 2 diabetes mellitus (T2DM) is an important risk factor for macro-and microvascular complications, such as the development of chronic kidney disease (CKD). Moreover, CDK can further increase adverse CV outcomes [1,2]. It is therefore crucial to reduce CV risk by managing glycaemic control in T2DM patients. Glucose-lowering therapy in combination with managing multiple CV risk factors, has been previously been shown to lead to a reduction of adverse CV outcomes in T2DM patients [3,4].

Sitagliptin, a recently developed dipeptidyl peptidase 4 inhibitor (DPP-4i), improves glycaemic control in T2DM patients and its CV safety was investigated with the TECOS trial (Trial Evaluating Cardiovascular Outcomes With Sitagliptin). In this trial, 14,671 patients with T2DM and documented CV disease where randomised to sitagliptin or placebo, on top of standard therapies [5]. Results showed that sitagliptin did neither increase nor decrease CV events, heart failure hospitalisation, or adverse events in general.

In this post hoc analysis of the TECOS trial, the CV and CKD outcomes were evaluated in light of the estimated glomerular filtration rate (eGFR).

eGFR data was available for 14,525 patients, who were categorised into eGFR stages 1, 2, 3a, and 3b (≥90, 60–89, 45–59, or 30–44 mL/min/1.73 m², respectively). Baseline urinary albumin to creatinine ratios (UACR) were available for 5,148 patients. Median follow-up was 3 years.

Main results

• 22.9% of participants were categorised as eGFR stage 1, 54.2% as stage 2, 17.5% as stage 3a and 5.4% as stage 3b.
• The rates for the primary composite endpoint CV death, nonfatal myocardial infarction (MI), nonfatal stroke or hospitalisation for unstable angina (UA) increased with lower baseline eGFR values (3.52, 3.55, 5.74, and 7.34 events/100 patient-years, respectively, for stages 1–3b). The corresponding adjusted HRs, with stage 1 as the reference stage, were 0.93 (95% CI: 0.82–1.06) for stage 2, 1.28 (95% CI: 1.10–1.49) for stage 3a and 1.39 (95% CI: 1.13–1.72) for stage 3b (P<0.0001).
• The event rates increased similarly for all secondary endpoints (the composite endpoint CV death, nonfatal MI or nonfatal stroke and single endpoints CV death, nonfatal MI, nonfatal stroke, hospitalisation for UA or heart failure and all cause death), except for hospitalisation for UA.
• The absence of impact on the primary endpoint by sitagliptin treatment was irrespective of baseline eGFR stage.
• The modelled impact of continuous baseline eGFR and UACR values on the primary endpoint showed that event rates increased substantially with eGFR values <60 mL/min/1.73 m² and with UACR values >30 mg/g.
• The mean eGFR reduction over 4 years from baseline was greater in the sitagliptin group than in the placebo group (-4.0 ± 18.4 vs. -2.8 ± 18.3 mL/min/1.73 m²). Although the median eGFR was marginally lower in the sitagliptin group compared to placebo (mean difference -1.34, P<0.0001), which remained consistent over time, the 4-year between-treatment group differences were similar for each eGFR stage, with no significant interactions of treatment effect by eGFR stage (P interaction = 0.14).
• Also mean UACR was consistently lower in the sitagliptin group compared to placebo (mean difference -0.18, P=0.031), but the 4-year UACR between-treatment group differences were similar (P interaction = 0.68).

Conclusion

This post hoc analysis of the TECOS trial demonstrated that although reduced eGFR and increased UACR were associated with a significantly increased risk of CV events, sitagliptin had, irrespective of baseline eGFR, no clinically significant impact on CV or CKD outcomes.

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References

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3. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–865
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