Two-Year Results Support Use of Canagliflozin in the Elderly

Short-term clinical trials of 26- and 52-weeks duration suggest that canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor approved in 2013, lowers HbA1c and results in modest decreases in weight and blood pressure. As with all new medications, however, questions arise about longer-term results-both positive and negative. 

An important line of inquiry centers on the role of the kidney as one of the body’s primary organs involved in homeostasis. Will homeostatic mechanisms compensate over time? Do patients eventually reach a new steady state, whereby they no longer experience the same benefits?  Moreover, the use of SGLT2 inhibitors is associated wtih urinary tract and genital mycotic infections and canagliflozin has been linked to increased incidence of fractures. How do these side effects play out over the long term, particularly in elderly patients who might be at increased risk?

Recent results from a randomized, placebo controlled phase 3 study suggest that the benefits of canagliflozin do extend over the long-term, and that the medication is generally well tolerated in elderly patients. The study was published ahead of print in December 2014, in Diabetes Obesity and Metabolism.

“This study…demonstrates that the glycemic improvements associated with canagliflozin treatment are sustained over a 2-year period,” wrote first author Bruce Bode, MD, FACE, of the Atlanta Diabetes Associates, and colleagues. “Canagliflozin significantly improved glycemic control and reduced body weight and systolic blood pressure compared with placebo over 104 weeks in patients aged 55 to 80 years who had T2DM that was inadequately controlled on their current regimen.”

The study took place at 90 clinical centers in 17 countries. Researchers randomized 714 patients aged 55 to 80 years to canagliflozin 100 mg or 300 mg daily vs. placebo.  Mean age of participants was 63.6 years and mean baseline HbA1c was 7.7%. The study design included a 2-week single blind run-in period;  24-week core period; 78-week double-blind extension period; and 30-day follow-up.

Key Results at 104 weeks

Changes in HbA1c, fasting plasma glucose, and body weight for canagliflozin 100 mg and 300 mg were similar to pooled analyses of 26-week results. HbA1c levels decreased most markedly at week 12, then showed stable reductions through week 52, and small, progressive increases by week 104. The placebo group showed a similar pattern.

All treatment groups had stable mean estimated glomerular filtration rates (eGFRs), suggesting that efficacy changes were unrelated to declining eGFR over time, according to the authors.

The canagliflozin groups experienced more genital mycotic infections, of which the incidence was higher among women. Most were reported during the first 52 weeks. Up to one-third of participants who developed genital mycotic infections experienced a recurrence. Likewise, the canagliflozin groups experienced more urinary tract infections, of which most occurred in the first 26 weeks. Of those who developed a UTI, about half experienced a recurrence.

Both doses of canagliflozin were linked to statistically significant decreases in bone mineral density in the total hip, compared to placebo. These results are of “uncertain clinical significance,” according to the authors, with further details forthcoming in a future publication.

“[M]ost adverse effects were mild to moderate in severity and infrequently led to study discontinuation. These findings provide further support for canagliflozin for the long-term treatment of older patients with T2DM,” concluded Dr Bode and colleagues.

Canagliflozin 100 mg

Canagliflozin 300 mg

Placebo

Change in HbA1c

-0.32%

-0.43%

0.17%

Percent of patients Achieving HbA1c <7%

35.8%

41.9%

20.3%

Percent achieving >5% reduction in body weight

27.8%

33.1%

10.5%

LS mean change in Systolic Blood Pressure compared to baseline

-3.0 mmHg

-1.2 mmHg

+4.5 mmHG

LS mean change in Fasting Plasma Glucose compared to baseline

-0.6 mmol/l

-0.7 mmol/l

+0.6 mmol/l

LS mean change in LDL from baseline

+0.05 mmol/l

+0.11 mmol/l

+0.03 mmol/l

Genital mycotic infections

Women: 4.3%

Men: 1.4%

Women: 23.9%

Men: 5.6%

Women:18.7%

Men: 10.9%

UTIs

14.5%

16.5%

10.1%

Osmotic-diuresis-adverse events

9.1%

12.3%

5.5%

Volume depletion Adverse events

5.4%

5.9%

1.7%

Fracture adverse events

2.9%

4.2%

2.1%

Discontinuation Rates

23.7%

24.6%

33.3%

Adverse events leading to discontinuation

4.6%

10.2%

6.8%

Disclosures:

The study was sponsored by Janssen Research & Development, LLC, the maker of canagliflozin.

Drs Sullivan, Fung, Usiskin, and Meininger are employees of Janssen Research & Development, LLC.Dr Bode reports grant support from Janssen. Dr Harris reports serving on the advisory board and being a speaker for Sanofi-Aventis, Janssen, Novo Nordisk, Takeda, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Merck, and Boehringer Ingelheim. Dr Stenlof reports no conflicts of interest.

References:

Bode B, Stenlof K, Harris S.  Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55 to 80 years with type 2 diabetes. Diabetes Obes Metab. 2014 Dec 13. doi: 10.1111/dom.12428. [Epub ahead of print]