DPP-4–to–SGLT2 inhibitor switch confers multiple benefits for patients with diabetes, hypertension

In the treatment of patients with type 2 diabetes mellitus and hypertension, switching from a dipeptidyl peptidase-4 (DPP-4) inhibitor to the sodium-glucose cotransporter-2 (SGLT2) inhibitor luseogliflozin appears to have favourable effects on blood pressure (BP), circadian rhythm, and night-time systolic BP (SBP) and pulse rate (PR), according to data from the open-label LUNA trial.

The changes achieved with the switching strategy should partly contribute to the cardiovascular event suppression reported in several large-scale cardiovascular trials on SGLT2 inhibitors, as pointed out by a team of Japan-based investigators. [N Engl J Med 2015;373:2117-2128; N Engl J Med 2017;377:644-657; N Engl J Med 2019;380:347-357]

LUNA included 56 patients (mean age 69 years, 69.6 percent male) with type 2 diabetes who had  glycated haemoglobin (HbA1c) levels of 6.0–9.0 percent (46–79 mmol/mol), been receiving ≥4 weeks of DPP-4 inhibitor treatment except for once-weekly agents, and a diagnosis of hypertension (BP >130/80 mm Hg) at baseline. These patients were randomized to either switch to luseogliflozin 2.5 mg/day (n=30) or continue their DPP-4 inhibitor treatment (n=26). The baseline demographic characteristics were similar in the two groups.

At week 8, the primary endpoint of a change in night-time SBP was more favourable in the luseogliflozin group than in the DPP-4 inhibitor group (mean, −4.0 vs 3.6 mm Hg; p=0.01). A similar pattern of results emerged for night-time PR (mean, −2.0 vs 0.9 bpm; p=0.03) and daytime SBP (mean, −4.4 vs 3.7 mm Hg; p=0.01). [Diabetes Res Clin Pract 2021;doi:10.1016/j.diabres.2021.109069]

Additionally, luseogliflozin exerted a positive effect on the BP circadian rhythm and reduced abnormal patterns. Significantly fewer patients who switched to the SGLT2 inhibitor vs continued with their DPP-4 inhibitor regimen showed abnormal BP circadian rhythms (nondipper pattern plus riser pattern; 36.6 percent vs 56.7 percent; p<0.05).

“A selective SGLT2 inhibitor blocks glucose reabsorption in the proximal tubules of the kidney and increases glucosuria, as well as blocking sodium resorption and leading to sodium excretion in the urine,” the investigators explained.

They pointed to sodium excretion and urinary volume caused by inhibition of sodium and glucose reabsorption at proximal tubules to potentially explain the mechanisms for the BP-lowering effect of SGLT2 inhibitors. [Nephrology 2017;13:11-26]

On the other hand, DPP-4 inhibitors neither affect BP nor reduce the prevalence of cardiovascular events, the investigators said. But these drugs are widely used due to their effectiveness for glycaemic control and acceptable safety. [Diabetes Care 2016;39:455-464; J Hypertens 2016;34:167-175; N Engl J Med 2013;369:1317-1326; JAMA 2019;321:69-79]

The present study had several limitations, the investigators acknowledged.

“First, the medication was open-label in clinical practice although the ABPM data were blinded. Second, all of the participants were Japanese, and thus the findings require confirmation in different ethnicities. Third, an inexplicable mild increase in BP was observed in the DPP-4i group,” they said.

Finally, the investigators stated that they excluded sleep apnoea syndrome (SAS) from the present study, although an improvement in SAS can alter BP circadian rhythm and BP.