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Expanding the Role of Canagliflozin in the Elderly

What benefits can medication provide in elderly patients with uncontrolled type 2?

Managing diabetes in the elderly is challenging due to the complexity of the physiologic changes that take place with aging. Uncontrolled diabetes in this patient population is greatly impacted by decreases in muscle mass and an increase in adipose tissue, which can impair glucose uptake.

Greater challenges arise in proper diabetes management when the changes and other comorbidities increase the risk of other complications. For instance, there has been evidence suggesting that uncontrolled blood glucose that lead to oxidative stress can have an effect on cognition, thus, predisposing to Alzheimer’s disease. Furthermore, the impact of the complexity of diabetes in the elderly expands to decreased hepatic and renal function, which hinders the ability to use certain medications (e.g. SGLT-2 inhibitors). SGLT-2 inhibitors have shown great benefits in offering glucose control, but also providing modest improvements in blood pressure and weight reduction. Various clinical trials have looked into the use of canagliflozin for management of diabetes in the elderly. However, the increase in urination seen with the use of canagliflozin and other SGLT-2 inhibitors has raised concerns in those individuals age 75 years and older due to increase in adverse events secondary to volume depletion.

Recently, in a meta-analysis from various randomized phase 3 trials, Alan J. Sinclair, MSc, MD and colleagues from the Foundation for Diabetes Research in Older Adults, looked to compare the safety and efficacy of canagliflozin in patients younger than 75 years of age and those 75 years old and older. To better understand the efficacy of canagliflozin in this study population, six controlled trials were analyzed. Each trial was 18-26 weeks in duration with a total combined population of 4,158 patients. In these trials, canagliflozin was used as monotherapy or in combination with other agents. Particularly, the CANVAS trial studied 183 patients age 75 years and older who received canagliflozin 100 or 300 mg once daily. Moreover, the safety and tolerability analyses were done using eight clinical trials with a total combined population of 9,439 patients. The majority of patients in all of these studies had the following baseline characteristics: A1C 7-10.5%, fasting plasma glucose of less than 270 mg/dL. The efficacy endpoints of the study included changes in A1c, fasting blood glucose, body weight, and blood pressure. Consequently, the incidence of side effects was evaluated as secondary endpoint for tolerability analysis.

Results from the study illustrated greater reductions in both age groups with canagliflozin 100 mg and canagliflozin 300 mg (-0.85%; 95% CI: -0.91, -0.78 in patients <75 years vs. -0.55%; 95% CI: -0.85, -0.28 in patients >75 years). From baseline, fasting blood glucose levels were also improved in patients receiving canagliflozin 100 mg and canagliflozin 300 mg  (<75 years -26.9 and -35.4 mg/dL, respectively vs >75 years -14.6 and -21.7 mg/dL, respectively). In terms of body weight, canagliflozin provided greater weight reduction in patients older than 75 years than those patients younger than 75 years (-3.1% vs -2.6%, respectively). Significant blood reductions were also seen with canagliflozin use among both groups. Subsequently, the incidence of adverse event was greater in those receiving canagliflozin 300 mg, which led to increased rates of discontinuation. This was seen to a greater extent in patients 75 years of age and older with canagliflozin 100 mg. The most common side effects included genital fungal infections and urinary tract infections. Volume depletion was observed predominantly in patients age 75 years or older receiving canagliflozin 300 mg.

In conclusion, canagliflozin 100 and 300 mg provides significant improvements in glycemic control, blood pressure reductions, and weight reductions. The marked increase in adverse effects associated to volume depletion can be linked to renal function and glomerular filtration rate. One thing to take into consideration when dealing with elderly patients is estimated glomerular filtration rate, as those patients with low eGFR may not experience adequate glycemic control. Therefore, patients older than 75 years of age warrant closer monitoring for renal function as opposed to younger individuals.

Practice Pearls:

  • Canagliflozin provides significant reductions in glucose levels, specifically HbA1c and FPG.
  • Adverse events associated with volume depletion warrant closer monitoring in elderly patients.
  • If increasing the dose of canagliflozin, renal function should be monitored routinely.

References:

Kandimalla, Ramesk, Vani Thirumala, and P. Hemachandra Reddy. “Is Alzheimer’s Disease a Type 3 Diabetes? A Critical Appraisal.” Biochimica Et Biophysica Acta (BBA) – Molecular Basis of Disease (2016): n. pag. Web.

Rosenthal, Norm, Gary Meininger, Kirk Ways, David Polidori, Mehul Desai, Rong Qiu, Maria Alba, Frank Vercruysse, Dainius Balis, Wayne Shaw, Robert Edwards, Scott Bull, Nicholas Di Prospero, Sue Sha, Paul Rothenberg, William Canovatchel, and Keith Demarest. “Canagliflozin: A Sodium Glucose Co-transporter 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus.” Ann. N.Y. Acad. Sci. Annals of the New York Academy of Sciences 1358.1 (2015): 28-43. Web.

Sinclair, Alan J., Bruce Bode, Stewart Harris, Ujjwala Vijapurkar, Wayne Shaw, Mehul Desai, and Gary Meininger. “Efficacy and Safety of Canagliflozin in Individuals Aged 75 and Older with Type 2 Diabetes Mellitus: A Pooled Analysis.” Journal of the American Geriatrics Society J Am Geriatr Soc 64.3 (2016): 543-52. Web.

 

Researched and prepared by Christian Gill, Pharm.D. Candidate, Class of 2017. Reviewed by Michelle Caetano, Pharm.D., BCPS, BCACP, CDOE, CVDOE