Is the SGLT-2 inhibitor ideal used along along with metformin, or is canagliflozin as a monotherapy an excellent choice?
Type 2 diabetes mellitus is a chronic health problem that develops as a result of defective insulin secretion and is often associated along with obesity-related insulin resistance. Type 2 diabetes is steadily decreased beta cell function over time. Glucose lowering agents are continuously implemented to regulate hyperglycemia once way of living changes are not enough. In people along with hyperglycemia, plasma glucose levels can easily be lowered by inhibiting sodium glucose co-transporter 2 (SGLT-2). The kidney plays an crucial role in glucose homeostasis, in large portion through reabsorption of filtered glucose at the proximal tubule. Majority of renal glucose reabsorption is mediated by SGLT-2. Canagliflozin is an SGLT-2 inhibitor which lowers the renal threshold for glucose, thereby promoting urinary glucose excretion (UGE). Increased UGE along with SGLT-2 inhibition is associated along with a mild osmotic diuresis and a loss of gram calories leading to physique weight reduction. Canagliflozin improved glycemic control, reasonable physique weight and systolic blood pressure. It was generally well tolerated in a broad range of patients along with type 2 diabetes inadequately controlled by their current regimens. It likewise activates AMP- activated healthy protein kinase (AMPK), which signals a pathway much like metformin mechanism.
The make every effort of this study is to evaluate the pharmacodynamics effects and safety /tolerability of solitary and multiple ascending oral doses of canagliflozin in patients along with type 2 diabetes mellitus. A randomized double blind placebo controlled, solitary and multiple ascending dose was conducted in the United States, Germany and South Korea. Eligible patients were men, postmenopausal or surgically sterile women from 25 to 65 years along with BMI between twenty to 40 kg/m2. Patients meeting criteria were assigned to cohorts according to randomization (4:1) within each cohort. They received canagliflozin or placebo and patients were accepted from day 3 to day 20. Patients received placebo after an over night fast and canagliflozin increment doses of 30,100, 200 or 400 mg QD or 300 mg two times day-to-day BID. Various doses were offered at personal times and they were discharged on day twenty for subsequent safety assessment on day 21 and 22. ANCOVA model is the statistical analyses used.
116 patients were randomized to canagliflozin (n=93) and placebo (n=23). Canagliflozin treatment made dose dependent raises in UGE on the 2 day 1 and day 16 as compared to placebo. The effect of canagliflozin on 24-hr UGE observed on Day 1 was sustained after the last dose of canagliflozin. Doses of ≥200 mg near maximal suppression of renal threshold for reduction (RTG) was sustained throughout the 24 hr dosing period. 100 mg dose of canagliflozin offered likewise offered near maximal reduction in RTG for the initial 13 hrs after dosing along with a modest waning of the effect in the over night period, for the 100 mg dose on day 16. 30 mg but offered submaximal reductions in RTG. Canagliflozin was generally well tolerated along with no clinically notable imbalances among treatment; no hypoglycemia was reported.
Another short article hoc was done to analyze the effects of canagliflozin on HbA1c by baseline HbA1c and known duration of type 2 diabetes mellitus. Data was pooled from patients along with type 2 diabetes enrolled in four 26 week placebo controlled phase 3 studies of canagliflozin (N=2313). Adjustment in HbA1c from baseline to week 26 was assessed in the overall population and in subgroups by baseline HbA1c and known duration of type 2 diabetes. Statistical analysis used is the ANCOVA model. Canagliflozin 100 and 300 mg offered higher HbA1c reduction as compared to the placebo. the 2 canagliflozin doses were generally well tolerated across subgroups along with a safety and tolerability profile consistent along with that seen in phase 3 studies. The restriction of this study was that that there was no pre-explained statistical testing across subgroups based on baseline HbA1c and known duration of type 2 diabetes. Yet Yet another study led by Professor Grahame Hardie showed that canagliflozin likewise activates AMPK, and therefore it is not vital to usage it as include on therapy to metformin because the 2 act through AMPK mechanism.
In conclusion, it was revealed that treatment along with canagliflozin at doses ≥ 100mg QD for 2 weeks was associated along with increased UGE and a decreased RTG. likewise it is not vital to combine canagliflozin to metformin because they the 2 act through the exact same mechanism of action.
Practice Pearls:
- Canagliflozin is an SGLT-2 inhibitor produced for the treatment of adults along with type 2 diabetes which lowers the renal threshold for glucose, thereby promoting urinary glucose excretion.
- Canagliflozin is well tolerated and treatment showed an improvement in glycemic regulate and reductions in physique weight.
- It is not truly vital to combine canagliflozin along with metformin because they the 2 act through the exact same AMPK mechanism
References:
The PLOS ONE Staff. “Correction: Pharmacodynamic Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, from a Randomized Study in Patients along with Type 2 Diabetes.” PLoS ONE 9.9 (2014): e110069. PMC. Web. 12 July 2016.
Wilding John P.H et al. “Efficacy and safety of canagliflozin by baseline HbA1c and known duration of type 2 diabetes mellitus.” Diabetes and its complications 29 (2015). Web. 12 July 2016.
Hardie Grahame et al. “Effectiveness in treating type 2 diabetes”. Medical press. July 6 2016. Web 12 July.
