Comparison of Serum Ketone Levels and Cardiometabolic Efficacy of Dapagliflozin versus Sitagliptin among Insulin-Treated Chinese Patients with Type 2 Diabetes Mellitus

Abstract

Background: Insulin-treated patients with long duration of type 2 diabetes mellitus (T2DM) are at increased risk of ketoacidosis related to sodium-glucose co-transporter 2 inhibitor (SGLT2i). The extent of circulating ketone elevation in these patients remains unknown. We conducted this study to compare the serum ketone response between dapagliflozin, an SGLT2i, and sitagliptin, a dipeptidyl peptidase-4 inhibitor, among insulin-treated T2DM patients.Methods: This was a randomized, open-label, active comparator-controlled study involving 60 insulin-treated T2DM patients. Participants were randomized 1:1 for 24-week of dapagliflozin 10 mg daily or sitagliptin 100 mg daily. Serum β-hydroxybutyrate (BHB) levels were measured at baseline, 12 and 24 weeks after intervention. Comprehensive cardiometabolic assessments were performed with measurements of high-density lipoprotein cholesterol (HDL-C) cholesterol efflux capacity (CEC), vibration-controlled transient elastography and echocardiography.Results: Among these 60 insulin-treated participants (mean age 58.8 years, diabetes duration 18.2 years, glycosylated hemoglobin 8.87%), as compared with sitagliptin, serum BHB levels increased significantly after 24 weeks of dapagliflozin (P=0.045), with a median of 27% increase from baseline. Change in serum BHB levels correlated significantly with change in free fatty acid levels. Despite similar glucose lowering, dapagliflozin led to significant improvements in body weight (P=0.006), waist circumference (P=0.028), HDL-C (P=0.041), CEC (P=0.045), controlled attenuation parameter (P=0.007), and liver stiffness (P=0.022). Average E/e’, an echocardiographic index of left ventricular diastolic dysfunction, was also significantly lower at 24 weeks in participants treated with dapagliflozin (P=0.037).Conclusion: Among insulin-treated T2DM patients with long diabetes duration, compared to sitagliptin, dapagliflozin modestly increased ketone levels and was associated with cardiometabolic benefits.

Effect of sodium-glucose cotransporter protein-2 inhibitors on left ventricular hypertrophy in patients with type 2 diabetes: A systematic review and meta-analysis

“…The normal value is E/A > 1, and E/A < 1 is the manifestation of reduced ventricular diastolic function. In the present study, no statistically significant difference between the two groups was observed in the included studies ( 10 – 13 ). In contrast, some researchers believe that SGLT-2i could increase E/A after taking SGLT-2i.…”

“…A total of four articles ( 10 – 13 ) were included in the E/A study. There was no significant difference in E/A between the experimental and control groups (SMD −0.01, 95% CI −0.22 to 0.20, I 2 = 0%, p = 0.908) ( Figure 5D ).…”

“…Five articles (9,(12)(13)(14)19) recorded the changes of LVM. The SGLT-2i group had a significant reduction in LVM compared with the placebo group (SMD −0.23, 95% CI −0.44 to −0.02, I 2 = 22.6%, p = 0.034) (Figure 3A).…”

Serum thrombospondin‐2 level changes with liver stiffness improvement in patients with type 2 diabetes

“…All participants were T2D patients on background insulin therapy, and were randomized in a 1:1 ratio to an open‐label SGLT2i or DPP4i treatment to compare the serum ketone response and other metabolic changes. In this post‐hoc analysis, all DISTINCTION participants were included and their inclusion/exclusion criteria were described in detail previously 11 . The primary endpoint of the current study was the change in LS measured by vibration‐controlled transient elastography (VCTE).…”

“…XL probe was used only when M probe failed to produce valid and reliable measurements. LS and controlled attenuation parameter (CAP), which reflected hepatic fibrosis and steatosis, respectively, were measured by experienced operators with satisfactory interobserver reliability 11 . Both measurements were represented by the median of 10 reliable measurements.…”