GLP-1 receptor agonists improve kidney outcomes — and they do so independently of SGLT2 inhibitors

The FLOW trial brought GLP-1 receptor agonists (GLP-1 RAs) to the forefront of the discussion about chronic kidney disease and type 2 diabetes. A new subanalysis now sheds light on the concomitant use of GLP-1 RAs and SGLT2 inhibitors.

In May 2024, results were published from the FLOW trial, the first-ever dedicated renal outcomes study of a GLP-1 RA (semaglutide) in people living with type 2 diabetes (T2D) and chronic kidney disease (CKD). “The primary outcome was strikingly positive, with a 24 % relative risk reduction in the primary outcome of major clinical kidney events with semaglutide compared to placebo,” comments EASD member Katherine R. Tuttle from the University of Washington (USA). As principal investigator, she led a pre-specified analysis within the FLOW trial looking into the concomitant use of semaglutide and SGLT2 inhibitors (SGLT2i). The results have now been published in Nature Medicine.

Semaglutide may complement SGLT2i

“We found that the effect of semaglutide on the primary outcome was consistent regardless of SGLT2i use. In analyses of the decline of the estimated glomerular filtration rate, or eGFR, those who received an SGLT2i and semaglutide had at least as much effect on slowing loss of kidney function as those without an SGLT2i. These data support the plausibility of additive effects, as those taking SGLT2i are likely to have benefited from this therapy a priori,” says Tuttle.

While SGLT2i are the first choice for people with T2D and CKD according to the current ADA/EASD consensus report, GLP-1 RAs have been shown to provide substantial benefits for both renal and cardiovascular outcomes. Tuttle and the other authors consider that the molecular mechanisms behind both drug classes may complement each other, regardless of their glucose lowering effects. “In my opinion, guideline updates are in order in all diabetes, renal, and cardiovascular organisations. These are truly practice-changing findings that have the potential to save many kidneys, hearts, and lives,” says Tuttle about the FLOW results.

Primary endpoint shows no subgroup heterogeneity

In the current publication, Tuttle and her team discuss a number of previous studies on the combination of GLP-1 RAs and SGLT2i. However, CKD and the combination of the two drug classes were usually rare in these studies. In the FLOW trial, the researchers were able to randomise 3,533 participants, of whom 550 (15.6 %) were using an SGLT2i at baseline (277 in the semaglutide group and 273 in the placebo group). No statistically significant subgroup heterogeneity was found in the primary endpoint by SGLT2i use (p-interaction: 0.109), meaning that the effect of semaglutide was not biased by SGLT2i therapy.

Among participants taking an SGLT2i at baseline, the primary outcome occurred in 14.8 % (41/277) of the semaglutide group versus 13.9 % (38/273) of the placebo group (hazard ratio [HR]: 1.07; 95 % confidence interval [CI]: 0.69–1.67; p = 0.755). In participants not taking an SGLT2i at baseline, the primary endpoint occurred in 19.5 % (290/1,490) of the semaglutide group versus 24.9 % (372/1,493) of the placebo group (HR: 0.73; 95% CI: 0.63–0.85; p lt. 0.001).

Impact on eGFR, MACE and mortality

In addition to the primary endpoint, three confirmatory secondary endpoints were specified in the FLOW trial: total eGFR decline, major cardiovascular events (MACE; composite of nonfatal myocardial infarction, nonfatal stroke or death from cardiovascular causes) and all-cause death. For eGFR decline, the treatment difference in favour of semaglutide was not significantly different between the subgroups (p-interaction of 0.237), with values of 0.75 ml min–1/1.73 m2/year (CI: –0.01–1.5) in the SGLT2i subgroup and 1.25 (CI: 0.91–1.58) in the non-SGLT2i subgroup. MACE and all-cause death also occurred similarly regardless of SGLT2i use, with p-interactions of 0.741 and 0.901, respectively.

“In conclusion, semaglutide reduced risks of kidney, cardiovascular, and all-cause mortality outcomes without heterogeneity of those benefits by SGLT2i use in participants with T2D and CKD,” the authors summarise the results of their analyses. However, Tuttle notes that in the FLOW study the use of SGLT2i was not randomised and was present in only 15.6 % of participants at baseline. “It is important to recognise that FLOW was not powered for these analyses, and there are biases in who receives SGLT2i,” she remarks.

A feasible strategy for clinical practice?

As noted above, the current ADA/EASD consensus report on the management of hyperglycaemia in T2D recommends that in the presence of CKD, SGLT2i with primary evidence of reducing CKD progression should be prioritised. GLP1-RAs with proven cardiovascular benefit should be used in the second line, when SGLT2i are not tolerated or contraindicated, or in combination with SGLT2i if HbA1c levels are above target.

Nevertheless, Tuttle highlights the benefits of combining GLP-1 RA and SGLT2i in practice. “These agents work very well together for overall metabolic control of glycaemia – especially in those with preserved eGFR – and weight management, as well as providing heart and kidney protection.” With the new FLOW subanalysis, it is plausible that the benefits of semaglutide are independent of, and possibly additive to, SGLT2i. “However, the cost of SGLT2i and GLP-1 RA is a major barrier to providing them to many patients,” says Tuttle. “The most pressing issue now is to implement the results for the vast number of people who could benefit worldwide.”

To learn more about GLP-1 RA and the FLOW trial, watch the EASD e-learning feature on GLP-1-Based Therapy.