Can Older Patients Tolerate Canagliflozin?

Canagliflozin improves glycemic control, blood pressure, and body weight in adults 75 years and over, though they may experience more volume depletion-related adverse events, genital mycotic infections, and urinary tract infections than younger patients, according to a study published in the Journal of the American Geriatric Society.¹

“This analysis demonstrates that canagliflozin may offer multiple benefits for older adults with T2DM, including favorable glycemic efficacy and low risk of hypoglycemia,” wrote first author Alan Sinclair, MSc, MD, of the Foundation for Diabetes Research in Older People (Bucks, UK), and colleagues.

Because older patients have may higher comorbidity burdens, decreased functional status, and limited life expectancy, the American Diabetes Association and the American Geriatrics Society have recommended customized HbA1c goals for older adults. These include higher HbA1c targets if the risks such as hypoglycemia outweigh the benefits of tighter glycemic control.²

SGLT2 inhibitors like canagliflozin increase urinary glucose excretion, causing a net loss in calories and mild weight loss, as well as osmotic diuresis that may mildly decrease blood pressure. Because SGLT2 inhibitors act on the kidney, they may be less effective in those with a lower estimated glomerular filtration rate, such as older patients and those with renal impairment. Older adults may also be at increased risk of volume depletion-related adverse effects during canagliflozin treatment.

In the study, researchers used pooled efficacy data from six randomized, double-blind, placebo-controlled trials covering 4158 patients < 75 years, and 183 patients ≥75 years. They used safety data from adverse event reports for eight randomized, double-blind, placebo- and active-controlled studies covering 9439 patients under age 75 and 490 patients ≥ 75 years. Pooled analyses included one study with patients at high cardiovascular risk, one in patients with moderate renal impairment, and one in patients aged 55 to 80.

Key Results:

• Median reduction in HbA1c for canagliflozin 100 mg:

♦ < 75 years: -0.70%

♦ ≥ 75 years: -0.50%

• Median reduction in HbA1c for canagliflozin 300 mg:

♦ < 75 years: -0.90%

♦ ≥ 75 years: -0.50%

• Overall adverse event incidence for canagliflozin 100 mg:

♦ < 75 years: 67.1%

♦ ≥ 75 years: 72.4%

• Overall adverse event incidence for canagliflozin 300 mg

♦ < 75 years: 68.6%

♦ ≥ 75 years: 79.1%

• Volume-depletion adverse events with canagliflozin 100 mg

♦ < 75 years: 2.2 %

♦ ≥ 75 years: 4.9%

• Volume-depletion adverse events with canagliflozin 300 mg

♦ < 75 years: 3.1%

♦ ≥ 75 years: 8.7%

• Hypoglycemia episodes with canagliflozin 100 mg

♦ < 75 years: 5.3%

♦ ≥ 75 years: 4.3%

• Hypoglycemia episodes with canagliflozin 300 mg

♦ < 75 years: 4.9%%

♦ ≥ 75 years: 4.8%

• Low incidence of severe hypoglycemia across treatment groups, ages, and background antihyperglycemic therapy

• Both age groups showed reductions in fasting plasma glucose, body weight, and blood pressure

• Numerically higher urinary tract infections, genital mycotic infections, and osmotic-diuresis-related adverse events in patients ≥ 75 years compared to <75 years

Most volume depletion-related adverse events were mild to moderate, and more participants aged 75 and over were on loop diuretics than younger patients, the authors noted.

To minimize volume depletion-related adverse events, they advised closer monitoring of patients on concomitant loop diuretics and SGLT2 inhibitors, careful management of antihypertensives, and careful dose escalation.

They also pointed out that canagliflozin’s decreased efficacy in older patients in terms of reduction in HbA1c may be related to lower mean baseline estimated glomerular filtration rate.

“Together, these findings support canagliflozin, starting with the 100-mg dose, as a safe and efficacious therapeutic option for individuals aged 75 and older with T2DM,” they concluded.

Take-home Points

• Pooled analysis of RCTs found that canagliflozin lowers HbA1c in patients ≥75 years, but to a lesser extent than in younger patients.

• Canigliflozin also lowers fasting plasma glucose, body weight, and blood pressure in older patients.

• Older patients experienced more genital mycotic infections, urinary tract infections, and volume depletion-related adverse events with canagliflozin, compared to younger patients.

• Closer monitoring of patients on concomitant loop diuretic and SGLT2 inhibitor therapy, careful management of antihypertensives, and careful dose escalation of SGLT2 inhibitors are advisable in older patients.

References:

1. Sinclair AJ, et al. Efficacy and safety of canagliflozin in individuals aged 75 and older with type 2 diabetes mellitus: a pooled analysis. J Am Geriatr Soc. 2016 Mar;64(3):543-552. doi: 10.1111/jgs.14028.

2. Kirkman MS, et al. Diabetes in older adults. Diabetes Care. 2012 Dec;35(12):2650-2664.