Dapagliflozin Reduces New Onset T2D, But Not HbA1c

Treatment with dapagliflozin—a sodium-glucose co-transporter-2 (SGLT2) inhibitor—reduced the incidence of new-onset type 2 diabetes in patients with chronic kidney disease and heart failure with reduced ejection fraction (HFrEF), according to a new pooled analysis of data from the DAPA-CKD and DAPA-HF studies. It did not, however, reduce HbA_1c levels.

The results were published in The Lancet Diabetes & Endocrinology.

“Dapagliflozin reduced a composite kidney endpoint of a 50% or more decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease or eGFR less than 15 mL/min per 1.73 m², or cardiovascular or kidney mortality in patients with chronic kidney disease irrespective of diabetes status in the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial. Dapagliflozin also reduced cardiovascular mortality or worsening heart failure in participants with and without diabetes with heart failure with reduced ejection fraction, in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial,” explained Peter Rossing, MD, of the Steno Diabetes Center Copenhagen, Gentofte, Denmark, and colleagues.

They conducted this first pooled analysis of individual patient data from the DAPA-CKD and DAPA-HF trials, including only those with no history of diabetes and HbA_1c less than 6.5% at baseline. The prespecified exploratory endpoint for both trials was new-onset type 2 diabetes, which was diagnosed via serial HbA_1c measurements (two consecutive values of ≥6.5%) of a clinical diagnosis of diabetes between study visits.

In all, Rossing and fellow researchers included 4,003 patients, of whom 49.8% had been treated with dapagliflozin, and 50.2% with placebo. Over the 21.2-month median follow-up, new-onset type 2 diabetes occurred in 4.3% of patients treated with dapagliflozin (event rate: 2.6/100 patient-years), compared with 6.3% of patients treated with placebo (event rate: 3.9/100 patient-years), for a hazard ratio of 0.67; (95% CI: 0.51-0.88; P=0.0040).

Researchers found neither heterogeneity between the two studies (P_interaction: 0.77), nor evidence that the effects of dapagliflozin differed in the prespecified subgroups, including sex, age, glycemic status, BMI, glomerular filtration rate, systolic blood pressure, and baseline cardiovascular medication use.

Over 90% of patients who developed type 2 diabetes were prediabetic at baseline, with HbA_1c levels ranging from 5.7% to 6.4%. In addition, mean HbA_1c levels did not change, with a placebo-adjusted change in dapagliflozin patients of −0.01 (95% CI: −0.03 to 0.01), −0.1 mmol/mol (95% CI: −0.3 to 0.1).

This finding was of particular import to editorialist Alice Y. Y. Cheng, of the University of Toronto, Ontario, Canada: “Of note, 60% of the population had prediabetes (HbA_1c 5.7%-6.4%) at baseline; more than 90% of the participants who developed type 2 diabetes had prediabetes at baseline. This underlines two important points: patients with prediabetes are at a high immediate risk of developing type 2 diabetes and that dysglycemia is common in patients with kidney disease or heart disease, which emphasizes the importance of metabolic screening in these patients,” she wrote in her accompanying editorial.

In conclusion, wrote Rossing and colleagues, “…treatment with dapagliflozin reduced the incidence of new-onset type 2 diabetes, an effect that was consistent across most subgroups and similar to that observed with the most commonly used medication for diabetes prevention, metformin. The effect was seen without a change in HbA_1c, which could suggest that this benefit is not merely a masking of diabetes but some fundamental effect on the pathogenesis of diabetes, perhaps improved β-cell function or enhanced insulin sensitivity. The diabetes prevention effects of SGLT2 inhibition we report should now be assessed in a broader prediabetes population, not necessarily with the comorbidities afflicting participants in the DAPA-HF and DAPA-CKD trials. Any long-term benefits of diabetes prevention remain to be shown in these and other populations.”

Like the authors, Cheng addressed the possible masking that may account for the preventive effects of dapagliflozin.

“Like other studies of diabetes prevention, the question remains whether the effects seen are due to masking or true prevention. In this case, it is of note that unlike, the other studies of diabetes prevention with pharmacotherapy, the HbA_1c was not changed by dapagliflozin compared with placebo. In addition, nearly 30% of the population had an estimated glomerular filtration rate of more than 45 mL/min per 1.73 m² at baseline, a renal threshold below which the glycemic efficacy of SGLT2 inhibitors is restricted. These observations support the possibility that the reduction of progression to type 2 diabetes might not just be a masking effect. However, this remains to be proven with a randomized controlled diabetes prevention trial that includes a washout period and tests of insulin sensitivity and β-cell function,” she wrote.

Ultimately, results of this analysis from Rossing and colleagues have practical implications, concluded Cheng.

“This analysis reminds us that people with kidney or cardiac disease have a high prevalence of dysglycemia so we should remember to screen for this. There are sufficiently compelling reasons to use SGLT2 inhibition in patients with chronic kidney disease and heart failure to reduce the risk of both cardiovascular and renal outcomes. The observation that use of SGLT2 inhibitors also leads to a reduction in progression to type 2 diabetes is a bonus. So, although it is intellectually stimulating to consider the why and how of the observed reduction in new onset type 2 diabetes in this pooled analysis, the real message is to use SGLT2 inhibition in this population,” she wrote.

Study limitations include lack of data on fasting or stimulated glucose concentration and insulin sensitivity or resistance assessments, and failure to assess glycemia after medication cessation, and trial differences that prevent subgroup analyses according to baseline ejection fraction, N-terminal pro-brain natriuretic peptide, or urine albumin-to-creatinine ratios.

1. In a pooled analysis of individual patient data from the DAPA-CKD and DAPA-HF randomized trials, dapagliflozin reduced the incidence of new-onset type 2 diabetes but did not lower HbA_1c levels.

2. In patients with chronic kidney disease and heart failure with reduced ejection fraction, treatment with the SGLT2 inhibitor dapagliflozin successfully reduced the number of patients who developed type 2 diabetes.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

The DAPA-CKD and DAPA-HF studies were funded by AstraZeneca.

Rossing reported funding to his institution from AstraZeneca for participating in the steering committee for DAPA-CKD; has received funding to his institution for advisory boards from Sanofi Avensis and Boehringer Ingelheim; from Bayer, Gilead and Novo Nordisk for steering committees; from Novo Nordisk, Bayer and Eli Lilly for lectures; has received grants from Novo Nordisk; and has held stock in Novo Nordisk in the past 3 years.

Cheng reports honoraria from Abbott, Astra Zeneca, Boehringer Ingelheim, Bayer, Bausch, Eli Lilly, Dexcom, Janssen, Insulet, HLS Therapeutics, Medtronic, Merck, Novo Nordisk, Sanofi, and Takeda.

Cat ID: 13

Topic ID: 76,13,730,3,13,127,411,669,918,925