Canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is used to treat type 2 diabetes. This article delves into the mechanisms by which canagliflozin promotes weight loss, drawing upon clinical studies and experimental data.
Introduction
Overweight and obesity are significant comorbidities in individuals with type 2 diabetes mellitus. Weight loss of 5-10% can improve glycemic control and cardiovascular disease (CVD) risk factors. However, achieving and maintaining weight loss is difficult, especially since some anti-hyperglycemic agents (AHAs) are associated with weight gain. Canagliflozin, an SGLT2 inhibitor, has emerged as a treatment option that addresses unmet clinical needs, including weight loss, beyond improving glycemic control.
Canagliflozin: An SGLT2 Inhibitor
Canagliflozin lowers the renal threshold for glucose and increases urinary glucose excretion (UGE). This results in decreased plasma glucose in patients with hyperglycemia and a mild osmotic diuresis.
How Canagliflozin Works
Canagliflozin inhibits SGLT2 in the kidneys, reducing the reabsorption of glucose and increasing its excretion through urine. SGLT2 is a protein located in the proximal tubules of the kidneys, playing a key role in reabsorbing glucose from the glomerular filtrate back into the bloodstream. By blocking this transporter, canagliflozin reduces glucose reabsorption, leading to glucosuria and lower blood glucose levels.
Clinical Evidence of Weight Loss
Pooled data from four placebo-controlled Phase 3 studies (N=2,250) in patients with type 2 diabetes showed that canagliflozin 100 and 300 mg reduced mean body weight compared with placebo (p<0.001). More patients had body-weight reductions >0%, ≥5% and ≥10% with canagliflozin treatment than with placebo.
Read also: Weight Loss Guide Andalusia, AL
Dose-Dependent Reductions
Dose-dependent reductions were seen in body weight, HbA1c, and SBP with canagliflozin compared to placebo. Most canagliflozin-treated patients experienced weight loss, with 82% and 85% of patients on 100 mg and 300 mg, respectively, experiencing weight loss compared to 55% of placebo-treated patients.
Weight Loss Quartiles
Body-weight reductions were seen in the highest three quartiles of weight loss with canagliflozin 100 and 300 mg compared with a small increase in the lowest quartile. Decreases in body weight vs. placebo were seen with both canagliflozin doses across quartiles.
Mechanisms of Weight Loss
The weight loss associated with canagliflozin is attributed to both weight-loss-associated and weight-loss-independent mechanisms.
Weight-Loss-Independent Effects
Approximately 85% of the placebo-subtracted reductions in HbA1c with canagliflozin were weight-loss-independent, likely due to increased UGE. The exact mechanism of weight-loss-independent BP reduction is not completely understood but may partially be related to the mild osmotic diuresis or alterations in sodium reabsorption.
Weight-Loss-Associated Effects
Weight loss contributed ~40% to the overall reduction in SBP seen with canagliflozin. Patients with greater weight loss had greater reductions in HbA1c and SBP. Each 1% reduction in body weight was associated with a 0.045% (0.5 mmol/mol) reduction in HbA1c and a 0.62 mmHg reduction in SBP.
Read also: Beef jerky: A high-protein option for shedding pounds?
Canagliflozin vs. Other AHAs
Most AHA therapies are either weight-loss neutral (e.g., biguanides, dipeptidyl peptidase-4 inhibitors) or potentially increase body weight (e.g., sulfonylureas, insulin, pioglitazone). Prior to the introduction of SGLT2 inhibitors, glucagon-like peptide-1 receptor agonists were the only class consistently associated with body-weight reduction in patients with type 2 diabetes.
Canagliflozin in Obese Mice
Studies in high-fat diet-induced obese mice demonstrated that canagliflozin reduced body weight, liver weight, and the ratio of liver weight to body weight. It also lowered serum levels of total cholesterol (TC) and triglycerides (TG) and ameliorated liver steatosis.
Impact on Signaling Molecules
During canagliflozin treatment, SGLT2, diacylgycero1 acyltransferase-2 (DGAT2), PPARγ1, and PPARγ2 were inhibited, and PPARα1 was elevated in the liver tissues. This may explain why body weight was reduced and secondary liver injury was ameliorated.
Differential Glucose-Lowering Mechanisms
Canagliflozin may possess distinct, dual glucose-lowering mechanisms depending on body weight changes. In subjects who lose weight, the degrees of insulin resistance decrease.
Subjects Who Lost Weight
In those who lost weight, the degrees of insulin resistance (assessed by HOMA-R) were significantly reduced, and good correlations were seen between the changes in HOMA-R and FBG. Significant reductions in uric acid (UA) levels were observed.
Read also: Inspiring Health Transformation
Subjects Who Did Not Lose Weight
In those who did not lose weight, levels of β-cell functions (assessed by HOMA-B) were significantly elevated, and good negative correlations were observed between the changes in HOMA-B and FBG. Significant increases in HOMA-B and reductions in free fatty acid (FFA) levels were observed.
Impact on Cardiovascular Risk Factors
In subjects who lost weight, canagliflozin was associated with improvements in the levels of metabolic parameters related to cardiovascular risk factors, including uric acid and triglyceride levels.
Canagliflozin and SGLT2 Upregulation
In T2DM, renal glucose reabsorption is increased potentially due to upregulation of SGLT2/GLUT2 transporter expression and activity. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers RTG, thereby increasing UGE.
Potential Side Effects
It's important to acknowledge potential side effects associated with canagliflozin. The increased glucose excretion creates a more favorable environment for urinary tract infections and genital yeast infections due to the higher glucose content in the urine. Electrolyte imbalances can also occur as a result of the drug's mild diuretic effect.
tags: #canagliflozin #weight #loss #mechanism