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Renal Outcomes With DPP-4 Inhibitors, SGLT-2s, and GLP-1 Agonists

Data from 2 trials show long-term use can improve albumin/creatinine ratio, but not other renal outcomes.

Renal data from the cardiovascular-outcomes trials TECOS and SAVOR-TIMI 53 show that long-term use of saxagliptin (Onglyza) improved the albumin/creatinine ratio (ACR) but not other renal outcomes, while in TECOS, there was no clinically significant impact of sitagliptin (Januvia) on renal end points.

Senior author Rury Holman, FMedSci, professor of diabetic medicine and diabetes trials unit director at the University of Oxford, United Kingdom, stated that:

“Essentially, TECOS shows that sitagliptin can be used safely to help manage glucose levels knowing that it has no clinically significant effects on cardiovascular or chronic kidney disease outcomes and is well tolerated.

“The results from the studies are letting us feel more comfortable in prescribing DDP-4 inhibitors, like the [glucagon-like peptide 1] GLP-1 analogs and the [sodium-glucose cotransporter 2] SGLT-2 inhibitors in knowing that these are safe with respect to both renal and cardiovascular toxicities.

“Plus, that the improvement in ACR in the SAVOR-TIMI 53 study should translate into improvement in renal function over the long haul. Which could mean a significant long-term kidney benefit.”

Results of the Savor-TIMI study with a total of renal outcomes of the study population of SAVOR-TIMI 53 in 16,492 patients (saxagliptin: 8280; placebo: 8212) reported that a majority of patients (> 95%) had an ACR measurement at baseline. Most patients (60%) had normoalbuminuria, 27% had microalbuminuria, and 10% had macroalbuminuria.

A higher percentage of saxagliptin patients shifted to a lower ACR category and a smaller percentage had increased ACR, compared with placebo patients, irrespective of baseline ACR category and treatment with saxagliptin improved ACR, even in the normo albuminuric range, without affecting estimated glomerular filtration rate (eGFR); this change was mainly driven by the larger change in ACR in the group that had ACR > 300 mg/g at baseline.

Plus, when the investigators looked at ACR as a continuous variable, treatment with saxagliptin, compared with placebo, was associated with decreased albuminuria at all times (P < .05 at 1 year, 2 years, and end of study).

They noted that the HbA1c did not affect the reduction in ACR. Saxagliptin did not affect renal safety outcomes, however, including doubling of serum creatinine, initiation of chronic dialysis, renal transplant, or serum creatinine > 60 mg/dL, all of which were similar between the active treatment and placebo arms.

To help better define the renal outcomes with DPP-4 inhibitors, further studies of longer duration are needed.

In the TECOS study with a population comprised of 14,671 patients (sitagliptin: 7332; placebo: 7339), an eGFR analyses were performed on a subset of 13,604 patients who had baseline eGFR measured and at least one post-baseline value. But ACR outcomes analyses were performed on just 3,831 patients who had baseline and post-baseline measurements for eGFR and ACR.

From the results they found that kidney function declined at the same rate in both the sitagliptin and placebo groups, but with a slightly lower and constant eGFR difference in those assigned to receive sitagliptin.

Mean ACR was also marginally lower in patients on sitagliptin compared with those on placebo, when analyzed in the 26% of patients in TECOS for whom these data were available.

The TECOS investigators wrote that, “It is uncertain whether these small offsets in eGFR and urinary ACR would have any long-term clinical implications.”

The renal data from TECOS and SAVOR-TIMI 53 are very different from the EMPA-REG OUTCOME, which showed that the SGLT-2 inhibitor empagliflozin (Jardiance) slowed progression of kidney disease over 3 years. Plus to a lesser extent there was some renal benefit with the GLP-1 agonist liraglutide (Victoza) from the LEADER study.

Unlike DPP-4 inhibitors, SGLT-2 inhibitors and GLP-1 agonists have a number of favorable effects on other risk factors such as blood pressure and weight, which may go toward providing some explanation as to the differences in renal outcomes.

All these results from these cardiovascular-outcomes studies with type 2 diabetes drugs  could change our guideline dramatically.

In summary, empagliflozin and liraglutide have a leg up over the DPP-4 inhibitors because they have also demonstrated benefit in terms of cardiovascular outcomes.

Results from the TECOS trial showed that impaired kidney function is associated with worse cardiovascular outcomes, and that sitagliptin has no clinically significant impact on cardiovascular or CKD outcomes, irrespective of baseline eGFR.

Results from the SAVOR-TIMI 53 Trial showed that treatment with saxagliptin improved ACR, even in the normo-albuminuric range, without affecting eGFR. The beneficial effect of saxagliptin on albuminuria could not be explained by its effect on glycemic control.

Practice Pearls:

  • Impaired kidney function is associated with worse cardiovascular outcomes.
  • Saxagliptin improved ACR, even in the normo albuminuric range, without affecting eGFR.
  • Empagliflozin and liraglutide have shown better outcomes over DPP-4 inhibitors because they have also demonstrated benefit in terms of cardiovascular outcomes.

The renal analysis from TECOS was published online October 14 in Diabetes Care and that from SAVOR-TIMI 53 was published 3 days later, October 17, also in Diabetes Care.