Efficacy of Additional Canagliflozin Administration to Type 2 Diabetes Patients Receiving Insulin Therapy: Examination of Diurnal Glycemic Patterns Using Continuous Glucose Monitoring (CGM)

Abstract

IntroductionThe efficacy of administering a sodium–glucose cotransporter 2 inhibitor during insulin therapy has not been established. In this study, we examined its effects based on diurnal glycemic patterns using continuous glucose monitoring (CGM).MethodsThe subjects were 15 patients who had received insulin therapy for 1 year or more. A CGM device was attached to all subjects for 1 week. The administration of canagliflozin at 100 mg was started 4 days after attachment. The mean glucose concentrations, standard deviation (SD), mean amplitude of glycemic excursions (MAGE), mean of daily difference of blood glucose (MODD), and area under the curve (AUC) (≥180, <70 mg h/dL) after the start of administration were compared with the pretreatment values. In addition, we compared changes in the number of insulin units between basal and bolus insulin. Furthermore, we investigated the influence of canagliflozin on oxidative stress markers and cytokines using 8-hydroxy-2′-deoxyguanosine (8-OHdG), tumor necrosis factor-α (TNF-α), and adiponectin as parameters.ResultsThe mean glucose concentrations decreased from 161.1 to 139.1 mg/dL (P < 0.01). The SD decreased from 36.5 to 29.6 mg/dL (P = 0.05). The MAGE decreased from 89.2 to 77.4 mg/dL (P < 0.01), and the MODD decreased from 34.3 to 25.5 mg/dL (P < 0.05). All parameters showed significant improvements in diurnal changes. AUC of ≥180, i.e., the total area of blood glucose levels at or above 180 on the blood glucose curve of CGM, decreased from 339.1 to 113.6 mg/dL (P < 0.05). AUC of <70, i.e., the total area of blood glucose levels below 70 on the blood glucose curve of CGM, slightly decreased from 1.6 to 0.3 mg/dL (P = 0.08). The total number of basal insulin units decreased from 128 to 76, and that of bolus insulin decreased from 266 to 154; the dose of insulin could be markedly decreased. In addition, the mean 8-OHdG level decreased from 11.4 to 10.8 ng/mg Cre (P < 0.05), and the mean TNF-α level decreased from 2.31 to 1.79 pg/mL (P = 0.10). The mean adiponectin level increased from 5.01 to 5.53 μg/mL (P < 0.05).ConclusionCanagliflozin improved blood glucose changes in type 2 diabetes using insulin. In addition, the results suggest its antioxidant actions.Trial RegistrationUniversity Hospital Medical Information Network (UMIN no. 000019429).

Effects of canagliflozin versus glimepiride on adipokines and inflammatory biomarkers in type 2 diabetes

“…Thus, the ability of canagliflozin treatment to increase adiponectin independent of weight loss or improvements in glycemia, together with a decrease in leptin and IL-6, may be indicative of a primary improvement in adipose tissue function with direct implications related to metabolic health. Of note, increases in adiponectin have recently been seen with canagliflozin treatment (100 mg dose) in a small study of patients with type 2 diabetes on background insulin [22].…”

“…Certain adipokines, pro-inflammatory cytokines, and chemokines regulate adipose tissue function and metabolic processes that contribute to cardiovascular risk in patients with type 2 diabetes and obesity. While studies have shown that treatment with glimepiride is not associated with meaningful changes in most of these biomarkers [18,19], there is some limited evidence to suggest that SGLT2 inhibitors may have favorable effects on serum leptin, adiponectin, IL-6, TNFα, CRP, and MCP-1 levels [9,[20][21][22]. Our analyses were the first to assess changes in adipokines, inflammatory biomarkers, and chemokines based on data from a large, randomly selected subset of patients with type 2 diabetes enrolled in an active-controlled trial [14].…”

Improvements of ambient hyperglycemia and glycemic variability are associated with reduction in oxidative stress for patients with type 2 diabetes

“…Yamazaki et al reported that glinide treatment was more beneficial than SU for decreasing daily glucose variability; comparisons were also made to determine the effects of glinide and SU treatments on oxidative stress [32]. Recent studies have reported that SGLT2 inhibitors, which decrease plasma glucose levels in an insulin-independent manner by selectively inhibiting renal glucose reabsorption and increasing urinary glucose excretion, improved daily and day-to-day glucose variability and reduced oxidative stress [33]. Although improvement of glucose variability is important for reducing oxidative stress, treatment of glucose variability without stimulating insulin secretion may be preferable.…”

Type 2 Diabetes and Glycemic Variability: Various Parameters in Clinical Practice

“…Although previously it was difficult to clarify at which point within a 24-h time frame the effects of such drugs were exerted, this information has become clear with the advent of the CGM system. This system allows greater ease in determining the effects of existing drugs and the effect of additional administration of other anti-diabetes drugs [ 26 , 27 ]. Furthermore, detection of hypoglycemia related to CV events has become possible [ 10 , 28 , 29 ].…”