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Empagliflozin may benefit long-term kidney function in type 2 diabetes
In patients with type 2 diabetes and preserved renal function, the substantial glucose loss following treatment with the SGLT2 inhibitor empagliflozin induces renal metabolism changes that may benefit long-term kidney function, according to published findings.
“In patients with preserved renal function, the modest hyperketonemia induced by SGLT2 inhibition is primarily the result of enhanced ketogenesis and is not due to impaired urinary ketone excretion,” Ele Ferrannini, MD, professor of medicine at Consiglio Nazionale della Ricerche Institute of Clinical Physiology in Pisa, Italy, told Endocrine Today. “More broadly, the osmotic diuresis induced by the SGLT2 blockade changes the handling of other solutes (eg, sodium and lactate, as described in the paper) and, likely, proteins.”
Ferrannini and colleagues analyzed the fasting and postmeal urinary excretion of glucose, beta-hydroxybutyrate, lactate and sodium in 66 patients with type 2 diabetes and preserved renal function, as well as in 25 healthy adults with normal glucose tolerance or prediabetes (controls). Patients with type 2 diabetes and prediabetes underwent three open-label studies: baseline measurements, acute (single dose of 25 mg empagliflozin [Jardiance, Boehringer Ingelheim]), and chronic (25 mg empagliflozin for 28 days). Controls did not participate in the chronic study. Each study consisted of a 3-hour basal period followed by a 5-hour meal tolerance test (one egg, 50 g parmesan cheese, 50 g white bread and 75 g of glucose in water) combined with a double-tracer technique. Empagliflozin was ingested 30 minutes before the tracer infusion. Blood was drawn at timed intervals; urine was collected separately during the basal period and again during the meal.
After 28 days of chronic therapy, fractional glucose excretion rose from 0.2% at baseline to 38% in the fasted state, and from 1.8% to 46% during the fed state (P < .0001 for both); changes were observed over a range of BMI and creatinine clearance rates.
Excretion of beta-hydroxybutyrate in the fasted state rose from a mean 0.08 µmol/min–1 to 0.31 µmol/min–1; the lactate excretion rate rose from 0.06 µmol/min–1 to 0.28 µmol/min–1; the sodium excretion rate in the fed state rose from 0.27 mEq/min–1 to 0.36 mEq/min–1; all measures were positively related to glycosuria (P < .001).
Results were similar for patients without diabetes, although the changes were smaller, according to the researchers. Plasma erythropoietin concentrations also increased by 31% (P = .0078).
The researchers noted several unexpected findings. Creatinine clearance was 35% lower in lean patients vs. those with obesity, but renal glucose clearance in response to the chronic dose was only 23% lower in lean adults in the fasted state and 16% lower during the fed state. In lean adults, severe carbohydrate restriction may enhance hyperketonemia during SGLT2 inhibitor therapy, Ferrannini said.
“This calculation highlights the fact that SGLT2 inhibition induces a degree of glycosuria, relative to the filtered glucose load, that is essentially independent of body size, thereby exposing the lean person to a substantially higher degree of carbohydrate deficit than the obese individual,” the researchers wrote. “This may represent an additional circumstance predisposing less obese patients with [type 2 diabetes] on SGLT2 [inhibitor] treatment on a low-carbohydrate diet to an augmented reliance on fat use for energy production, hyperketonemia and, occasionally, ketoacidosis.”
In addition, although creatinine clearance was consistently higher during the mixed meal vs. the fasted state, both acute and chronic doses of empagliflozin were associated with a 10% decrease in fasting and postmeal creatinine clearance in patients with and without diabetes. This change has been typically related to blood-volume depletion; however, “in our subjects, volume contraction, as judged from the plasma albumin concentrations, was very small over the few hours following single-drug administration,” the researchers wrote.
“These findings, and the increase in [erythropoietin] production, indicate that substantial glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism that, taken together, may be beneficial for kidney function in the long term,” the researchers wrote.
Ferrannini added that, going forward, researchers must characterize the clinical circumstances and mechanisms of SGLT2 inhibitor-induced shifts in substrate utilization. – by Regina Schaffer
For more information:
Ele Ferrannini, MD, can be reached at the Consiglio Nazionale della Ricerche Institute of Clinical Physiology, Piazzale Aldo Moro, 7-00185 Rome, Italy; email: ferranni@ifc.cnr.it.
Disclosure: Ferrannini reports receiving speaking and consultant fees from for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson and Merck.