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Combination therapies in T2DM exert differential effect on intrarenal haemodynamics

Jairia Dela Cruz
20 Nov 2019
Dr Christian Ott from the Friedrich-Alexander University Erlangen-Nürnberg at Erlangen, Germany

Combination therapy with empagliflozin plus linagliptin (E+L) reduces glomerular filtration rate (GFR), whereas metformin plus insulin glargine (M+I) confers benefits for both GFR and renal plasma flow (RPF) in type 2 diabetes mellitus (T2DM). The haemodynamic mechanism underlying these effects involves a decrease in efferent resistance with E+L and an increase in afferent resistance with M+I, according to the results of a randomized controlled trial presented at the American Society of Nephrology (ASN) Kidney Week 2019.

“Combination of insulin with oral antidiabetic drugs is a valid option, but oral combination therapy emerged as an alternative treatment in T2DM,” said principal researcher Dr Christian Ott from the Friedrich-Alexander University Erlangen-Nürnberg at Erlangen, Germany. “However, the intrarenal and renal haemodynamic profile[s] of such combination therapies ha[ve] not been evaluated so far.”

To close the gap, Ott and his team examined the effect of a 3-month treatment course with E+L (10 mg and 5 mg orally, respectively) against that of M+I (dose adjustments performed according to glucose levels) on the renal and intrarenal haemodynamic profiles of 100 T2DM patients (mean age, 60.3 years; 73.0 percent male).

Renal haemodynamics were assessed using the current gold-standard of constant-infusion input-clearance technique with para-aminohippuric acid and inulin for RPF and GFR. Intrarenal haemodynamics were calculated according to the Gomez formula.

There was a greater reduction in HbA1c observed with M+I than with E+L group (p=0.001) due to the multiple dose adjustment of insulin glargine. For this reason, all analyses between M+I and E+L were HbA1c-adjusted to evaluate the glucose independent effects of the two therapies. E+L produced superior effects on body weight (p<0.001), body mass index (p<0.001), and both ambulatory 24-h systolic and diastolic BP (p=0.004 and p=0.036, respectively). [ASN 2019, abstract SA-OR083]

Results for renal haemodynamics revealed that in the E+L group, GFR decreased substantially (127 vs 120 ml/min; p=0.003) but RPF remained unchanged (623 vs 615 ml/min; p=0.536). In comparison, the M+I group achieved significant reductions in both GFR (127 vs 120 ml/min; p=0.001) and RPF (653±150 vs. 600±121 ml/min, p<0.001), and these effects were clearly more favourable than in the E+L group (p<0.001).

In terms of intrarenal haemodynamics, E+L treatment had no marked impact on resistance of afferent arteriole (RA; p=0.116) but led to a decrease in resistance of efferent arteriole (RE; p=0.001). Conversely, M+I yielded a reduction in RA (p=0.006) but had no significant effect on RE (p=0.538). This finding indicates that treatment effects on RA (p<0.001) and on RE (p<0.001) were significantly different between the two groups.

The study population included adult T2DM patients (age, 18–75 years) with HbA1c levels 6.5 percent. All patients had been using metformin (850 or 1,000 mg twice daily) for at least 2 months prior to screening visit.

Exclusion criteria were as follows: any other form of diabetes than T2DM, HbA1c levels >10.5 percent, fasting plasma glucose >240 mg/dl, urine albumin-to-creatinine ratio (UACR) 300 mg/g, estimated GFR <60 ml/min/1.73m2, congestive heart failure NYHA stage III and IV, and use of loop diuretics. None of the patients included were exposed to insulin, glitazone, gliptin or SGLT-2 inhibitor within the past 2 months.

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Pearl Toh, 31 Dec 2019
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