Two Glucose-Lowering Mechanisms of Canagliflozin Depending on Body Weight Changes in Drug-Naïve Subjects with Type 2 Diabetes

Abstract

ObjectivesThe aim of this study was to investigate the relations between the changes in body weight and those of glycemic and non-glycemic parameters in drug-naïve subjects with type 2 diabetes mellitus (T2DM) treated with canagliflozin monotherapy.MethodsSubjects received 50–100 mg/day canagliflozin monotherapy for 3 months (n = 36), and were then divided into two groups: (1) those who lost weight [changes in (Δ)BMI ≤ − 0.45, p < 0.00001: Group L(ost), n = 20); and (2) those who did not lose weight [ΔBMI > − 0.45, p = non-significant: Group N(eutral), n = 16]. At 3 months, the levels of glycemic and non-glycemic parameters were compared with those at baseline.ResultsSignificant reductions of BMI levels (− 2.1%, p < 0.00001) were observed for the overall subjects. At baseline, fasting blood glucose (FBG) and HbA1c levels were significantly higher, and homeostasis model assessment-B (HOMA-B) levels were significantly lower in Group N versus Group L. Similar reductions of HbA1c (Group L: 9.54 ± 2.58% to 7.54 ± 1.27%, p < 0.05; Group N: 11.23 ± 2.27% to 9.19 ± 1.64%, p < 0.0002) and homeostasis model assessment-R (HOMA-R; Group L: − 32.3%, p < 0.005; Group N: − 36.5%, p < 0.02) levels were seen in these two groups. However, other parameters showed distinct regulatory patterns. (1) Group L: significant reductions in uric acid (UA) levels (− 6.9%, p < 0.02) were observed. Significant correlations between the changes in FBG and HOMA-R (R = 0.458, p < 0.05) were seen. (2) Group N: significant increases in HOMA-B (+ 69.4%, p < 0.007) and reductions in free fatty acid (FFA; − 25.8%, p < 0.02) levels were observed. Significant negative or positive correlations between the changes in (Δ)FBG and ΔHOMA-B (R = − 0.557, p < 0.03), and between ΔFBG and ΔHOMA-R (R = 0.458, p < 0.05) were seen.ConclusionsThese results indicate that (1) body weight changes with canagliflozin were not associated with its glycemic efficacy; and (2) distinct glucose-lowering pathways may exist with canagliflozin, reducing insulin resistance in those who lose weight and enhancing β-cell function, as well as reducing insulin resistance, possibly via the decreased FFA levels, in those who do not lose weight.

Regulations of Free Fatty Acids and Diabetic Parameters in Drug Naïve Subjects with Type 2 Diabetes Treated with Canagliflozin Monotherapy

“…No other drugs were administered. The subjects were encouraged to follow exercise and diet as described [11,12]. The Ethics Committee of Gyoda General Hospital and Kumagaya Surgery Hospital approved execution of this study.…”

“…The secondary end point included HbA1c, FBG, insulin, HOMA-R, HOMA-B, adipose insulin resistance (adipose-IR), total cholesterol (T-C), triglyceride (TG), HDL-C, non-HDL-C, low density lipoprotein (LDL)-C, UA and BMI. Blood was collected at the fasting state in the morning and standard techniques were used to measure or calculate these parameters as described previously [11,12]. FFA concentrations were determined by colorimetry with enzymatic reactions as described [11,12].…”

“…Blood was collected at the fasting state in the morning and standard techniques were used to measure or calculate these parameters as described previously [11,12]. FFA concentrations were determined by colorimetry with enzymatic reactions as described [11,12]. Adipose-IR was calculated as follows: FFA × insulin [19].…”

“…Most of the statistical analysis was performed as described previously [11,12] using PAST program from the University of Oslo (https://folk.uio.no/ohammer/past/). Multiple regression analysis was undertaken to identify any contributing factors for the changes of FFA levels with canagliflozin.…”

“…For example, no changes of FFA levels with dapagliflozin were reported [8,9]. On the other hand, decreases of FFA levels were reported with ipragliflozin in obese type 2 diabetic db/db mice [10] or with canagliflozin in patients with T2DM who respond efficiently or who do no lose weight with this drug [11,12]. While the precise mechanisms of how SGLT-2 inhibitors regulate FFA levels remains to be investigated, this regulation could be by stimulating fat oxidation through modulations of genes related to FFA metabolisms in adipose tissues including uptake, binding, β-oxidation and oxidative phosphorylation [13].…”