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Expanding the Role of Canagliflozin

Sep 24, 2016

Canagliflozin can decrease blood sugar and provide control, but what other metabolic effects can it provide?

Canagliflozin (Invokana) has been widely used since its approval in 2013. Various studies favor its use due to new evidence showing cardiovascular benefits in patients with diabetes. Significant reductions in HbA1c, fasting blood glucose, weight, and blood pressure have been documented. The unique mechanism of action of canagliflozin and other SGLT-2 inhibitors increase diuresis to promote excretion of excess glucose and providing an euglycemic state in these patients. However, researchers now question the use of canagliflozin and other agents within its class due to the potential of impairing mineral homeostasis. Mehul Desai from Janssen Research and Development, LLC and colleagues conducted a meta-analysis where the preclinical and clinical effects of canagliflozin were examined. Canagliflozin increased serum concentrations of phosphate and magnesium in patient receiving treatment with this agent.  This increase in magnesium can predispose for neuromuscular complications. Conversely, low levels of magnesium can predispose for life-threatening arrhythmias.


Recently, at the ADA 76th Scientific Session, a study that was presented looked into these effects in more detail. Richard E. Gilbert, MD, PhD FRCPC from the University of Toronto expanded on the topic. The proportion of patients with low levels of magnesium, defined as <1.8 mg/dL, were examined from pooled data from 4 different studies. All of these studies included canagliflozin 100 mg and 300 mg along with placebo. These studies were 26 in duration and the data that was collected showed increases in serum magnesium in those patients with low magnesium levels.  Gilbert states that “patients treated with canagliflozin are 10-14 times more likely to achieve magnesium levels of greater than 1.8 mg/dL when compared to placebo.” These findings provide a feasible option for patients who have low magnesium levels and other risk factors for arrhythmias. Thus, highlighting the benefits in preventing certain cardiovascular complications.

Another concern that raises from the use of these agents includes the effects on bone mineral density and homeostasis of other minerals. Desai and colleagues saw in their study that there were meaningful changes in calcium and vitamin D as it relates to bone mineral density. However, these changes in vitamin D and calcium does not affect bone turnover on bone mineral density. Nonetheless, a 1.2% decrease in bone mineral density has been observed in studies, therefore, explaining that there is still a risk of fracture with the use of canagliflozin.

Based on these findings, the role of canagliflozin can be further expanded in patient populations who suffer from electrolyte and mineral imbalances. The elderly population has some predisposing conditions for these imbalances that may limit the application of these agents in their disease state management. Previous studies have looked at these implications and the risk of related adverse events that can lead to fractures. Debate still exists in terms of the risk of bone mineral density with its use. Different studies hypothesize that an increase in urine glucose excretion and weight loss may contribute to fractures. However, this needs to be further evaluated. However, one thing to consider is the volume depletion effects of canagliflozin and other SGLT-2 inhibitors due to increased diuresis that predisposes these patients to experience orthostasis and eventually lead to falls. The risk of orthostasis increases if other antihypertensive medications are being used for other comorbidities. Despite these risks, the long-term benefits need to be taken into consideration when utilizing these and other antidiabetic agents. In conclusion, canagliflozin provides great benefits when added on to other treatments in regimens in diabetes, which makes it a feasible option to obtaining target glycemic control. Improvement in magnesium levels can be obtained with it use.

Practice Pearls:

  • Canagliflozin 100 mg and 300 mg can increase serum magnesium levels in patients.
  • Diabetes patients with hypomagnesemia are at an increased risk for arrhythmias, therefore, treatment with canagliflozin can help prevent these arrhythmias.
  • Bone mineral density is not greatly impacted from the use of canagliflozin.


Alba, Maria, John Xie, Albert Fung, and Mehul Desai. “The Effects of Canagliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, on Mineral Metabolism and Bone in Patients with Type 2 Diabetes Mellitus.” Current Medical Research and Opinion 32.8 (2016): 1375-385. Web.

Gilbert, Robert, Mende Christian, Vijapurkar Ujjwala, Sha Sue, Davies Michael J., Desai Mehul. Effects of Canagliflozin (CANA) on Serum Magnesium (Mg) in Patients with Type 2 Diabetes Mellitus (T2DM. Poster session presented at: 76th Scientific Session of the American Diabetes Association; 2016 Jun 10-14; New Orleans, LA.

Blau, Jenny E., Bauman Viviana, Piaggi Paolo, Collins Michael T., Taylor Simeon I.. Rother Kristina I. Acute Effects of Canagliflozin on Bone Metabolism: Preliminary Results from a Randomized, Placebo-Controlled Trial. Poster session presented at: 76th Scientific Session of the American Diabetes Association; 2016 Jun 10-14; New Orleans, LA.


Pablo A. Marrero-Núñez – USF College of Pharmacy Student Delegate –  Doctor of Pharmacy Candidate 2017 – University of South Florida – College of Pharmacy