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NEW YORK (Reuters Health) – In patients with chronic kidney disease (CKD) and heart failure (HF), dapagliflozin curbed the incidence of new-onset type 2 diabetes without reducing HbA1c in a pooled analysis of the DAPA-CKD and DAPA-HF trials.

The fact that dapagliflozin did not reduce HbA1c “supports a direct beneficial effect of dapagliflozin on the pathogenesis of diabetes such as an improvement in beta-cell function or insulin sensitivity,” Dr. Hiddo Heerspink of University of Groningen in the Netherlands told Reuters Health by email.

“Further research is required in other populations, such as patients without CKD or heart failure and prediabetes, meri adalat cast to demonstrate that dapagliflozin also prevents progression to type 2 diabetes in these patients,” he said.

As reported in The Lancet Diabetes and Endocrinology Dr. Heerspink and colleagues did a pooled analysis of individual participant data from the multicenter DAPA-CKD and DAPA-HF phase 3, randomized, placebo-controlled trials. Participants had no history of diabetes and an HbA1c less than 6.5% (48 mmol/mol) at baseline.

New-onset type 2 diabetes was a prespecified exploratory endpoint in both trials.

A total of 4,003 participants (34.9% from DAPA-CKD and 65.1% from DAPA-HF) were included. Participants had a mean age of 63; 73% were men; 65%, white; and 29%, Asian.

Over a median follow-up of 21.2 months, 6.3% of patients in the placebo group (event rate, 3.9 per 100 patient-years) and 4.3% of those on dapagliflozin (event rate 2.6 per 100 patient years) developed type 2 diabetes (hazard ratio, 0.67).

There was no heterogeneity between studies and no clear evidence that the effect of dapagliflozin varied in prespecified subgroups – i.e., sex, age, glycemic status, BMI, glomerular filtration rate, systolic blood pressure, and baseline cardiovascular medication use.

More than 90% of those who developed type 2 diabetes had prediabetes at baseline (HbA1c 5.7% to 6.4%). As Dr. Heerspink noted, the mean HbA1c remained unchanged at 12 months (placebo-adjusted change in the dapagliflozin group of -0.01%/ -0.1 mmol/mol).

Dr. Alice YY Cheng of the University of Toronto, author of a related editorial, commented in an email to Reuters Health, “Lots of people with CKD or HF have prediabetes, so we should look for it in these populations.”

“Dapagliflozin was associated with less new-onset type 2 diabetes – interesting, given that there was no difference in HbA1c between the dapagliflozin and placebo groups and nearly 30% of the population had low eGFR, which limits the glucose-lowering effects of dapagliflozin,” she said.

“It remains unclear if the reduction in progression is true prevention with alterations of the pathophysiology of diabetes or, rather, a masking effect of the antihyperglycemic therapy,” she noted. “But does it matter to my clinical practice? Absolutely not!”

“There are plenty of reasons to be using SGLT2i in those with CKD or HF,” she said. “This would be a welcome bonus reason. So, bottom line – use SGLT2i in these patients!”

The study was funded by AstraZeneca. Six coauthors are employees and Dr. Heerspink and many other coauthors have received funds from the company. Dr. Cheng also received funds from the company.

SOURCE: and The Lancet Diabetes and Endocrinology, online November 29, 2021.

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