Canagliflozin as an Initial Therapy in Drug-Naïve Subjects with Type 2 Diabetes Mellitus: A Potential Involvement of Atherogenic Lipids in its Glycemic Efficacy

Abstract

Background and ObjectivesThe aim of this study is to investigate canagliflozin as an initial therapy in type 2 diabetes mellitus and to explore the effects on metabolic parameters in relation to effects on glycemic control.Subjects and MethodsTreatment-naïve subjects with type 2 diabetes mellitus received canagliflozin 50–100 mg/day monotherapy. At 3 months, levels of glycemic and non-glycemic parameters were compared with those at baseline (n = 39). As a comparator, our previous data of baseline glycosylated hemoglobin (HbA1c)-matched treatment-naïve subjects with ipragliflozin 25–50 mg monotherapy (n = 27) were employed.ResultsSignificant reductions in HbA1c (from 9.96 to 8.33%), fasting blood glucose (−23.9%), homeostasis model assessment-R (HOMA-R, −33.5%), body mass index (−1.8%), and uric acid (UA, −5.2%) levels and significant increases in homeostasis model assessment-B (HOMA-B, 30.1%) levels were observed. Approximately one third of the subjects experienced certain adverse events. Similar results were obtained with ipragliflozin. Baseline levels of HbA1c, triglycerides, non-high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) were chosen as significant contributing factors for the changes in HbA1c levels with canagliflzoin, while only baseline HbA1c levels were selected as such a factor with ipragliflozin. Significant positive correlations between the changes in HbA1c and changes in non-HDL-C (R = 0.3954) or between changes in HbA1c and changes in LDL-C (R = 0.4317) were observed with canagliflozin. With ipragliflozin, no such correlations were noted. No correlations between the changes in HbA1c and changes in body mass index were seen with both drugs.ConclusionsThese results suggest that (1) canagliflozin appears to offer clinically beneficial outcomes as an initial therapy in subjects with type 2 diabetes mellitus, although with certain adverse events. (2) Atherogenic cholesterols including non-HDL-C and LDL-C could be involved in the glycemic efficacy of canagliflozin. This was not the case with ipragliflozin. (3) Unexpectedly, weight reductions with canagliflozin are not associated with its glycemic efficacy.

Characterization of metabolic parameters in responders and nonresponders treated with canagliflozin monotherapy in drug-naive subjects with Type 2 diabetes

“…[ 10 18 ] Simply, dividing the patients in this fashion may constitute a fundamental problem since the changes of HbA1c levels were shown to be dependent on the baseline HbA1c levels in many drugs including canagliflozin. [ 9 ] Thus, we previously used a novel index called “A1c index” to overcome this problem. [ 10 18 ] However, the validity of A1c index would require further well-designed studies.…”

“…[ 19 ] Many diabetes drugs, including insulin, sulfonylureas, and thiazolidinediones cause weight gain. [ 9 ] Therefore, drugs that possess reducing effects on body weight are particularly important. So far, few studies report the relationship between the body weight reductions with canagliflozin and its effects on glycemic control.…”

“…However, it could also be used as alternative first-line options in patients with contraindications or intolerance to metformin. [ 9 ]…”

“…As an initial step toward investigating this question, canagliflozin 50–100 mg/day monotherapy was performed with drug-naïve patients with T2DM, and the effects on a number of glycemic and nonglycemic parameters were investigated in two groups representing distinct response to canagliflozin (responders and nonresponders). Since the response to canagliflozin was shown to be baseline glycated hemoglobin (HbA1c) dependent,[ 9 ] we used a novel index called A1c index[ 10 ] to evaluate the glycemic efficacy of canagliflozin.…”

Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice

“…Paradoxically, today there are more clinical than experimental data regarding the beneficial effects of SGLT2i on CVD, evaluating endothelial function, arterial stiffness, atherogenic cholesterols in patients with DM type 2 etc. [11][12][13]; however, although various SGLT2i such as empagliflozin, dapagliflozin, ipragliflozin and luseogliflozin have been evaluated in animal experimental studies regarding their the anti-atherogenic effects, there is paucity of evidence regarding canagliflozin.…”