The Role of Kidney in Glucose Homeostasis — SGLT2 Inhibitors, a New Approach in Diabetes Treatment

Vasileios Andrianesis; John Doupis


Expert Rev Clin Pharmacol. 2013;6(5):519-539. 

In This Article

Adverse Events

According to the Phase III clinical studies on canagliflozin, which were summarized in the FDA briefing document, there were no reported cases of pheochromocytoma or malignant adrenal tumor. One case of testicular cancer was not related to the administration of canagliflozin, the overall incidence of renal, bladder and breast cancers did not differ between the canagliflozin treated and the placebo control groups.[110] Osmotic diuresis due to increased urinary glucose excretionwasan expected result of canagliflozin mechanism of action. Further more, the rate of osmotic diuresis related adverse events, and especially pollakiuria, thirst and polyuria, were significantly increased in the canagliflozin treatment groups (6.7 and 5.6% in 100 and 300 mg canagliflozin treatment groups versus 0.8% in placebo group) and infrequently led to discontinuation.[81,82,110,111] In other studies, the incidence of these events appeared to be similar to the placebo group.[79]

The mechanism of action of canagliflozin also explains the increased incidence of volume depletion events related to the reduced intravascular volume.[79,111] Hypotension, dizziness postural and orthostatic hypotension were the most commonly reported adverse events of this category. The rate of these events were higher in the canagliflozin treatment groups compared with the placebo (2.6, 5.0 and 8.5% in placebo, canagliflozin 100 mg, canagliflozin 300 mg groups, respectively).[110] Regarding the effect on renal function, in Phase III trials, it was demonstrated that canagliflozin may beresponsible for an early and dose-dependent decrease in eGFR and an increase in creatinine and BUN levels, which did not appear to be worsen with the continuation of the therapy.[79,81,110] Furthermore, in placebo-controlled trials, the levels of these renal function markers were similar in the placebo and the group receiving 100 mg of canagliflozin.[110] Abnormal renal function markers were reportedonly in the group receiving 300 mg of canagliflozin. In subjects with moderate renal impairment, the renal-related adverse events were increased even from the 100 mg dose.[82,110] Hemoconcentration, exhibited in the canagliflozin-treated arms, resulted in a mild increase in hemoglobin concentration and hematocrit (3.5% and 3.8% increase of hemoglobin in canagliflozin 100 and 300 mg, respectively, compared with a slight decrease in placebo group −1.1%).[79–82,110] In Phase III clinical trials, 18 venous thromboembolic events and 3 fatal events that were determined as cardiovascular event-related deaths were reported. Five of these events (0.2%) were exhibited in the canagliflozin 100 mg group, eight (0.3%) in canagliflozin 300 mg group and 5 (0.2%) in the placebo group.[110] Additionally, slight and no meaningful changes in serum calcium levels, a small-to-moderate increase in serum phosphate levels,[82] a moderate reduction in parathormone (PTH) and a moderate increase in 25-hydroxyvitamin D were observed in canagliflozin arms of the trials compared to placebo.[110] Moreover, although, it was reported that an increase in overall fractures in the canagliflozin-treated groups compared to placebo, this increase did not reach statistical significance apart from a borderline – significance of the overall fractures at all sites. (Overall, fracture incidence rate was 2.5, 2.3 and 1.7% for canagliflozin 300, 100 mg and control, respectively). Overall, upper extremity fractures rates were 0.9, 0.9 and 0.5% for canagliflozin 300,100 mg and placebo, respectively).[110]

Regarding the hepatic safety of canagliflozin, although, there were some studies presenting few cases of elevated alanine transaminase or aspartate transaminase most of them were related to other causes like cholecystitis or cholangiocarcinoma, thus, FDA advisory committee was concluded that there was no signal for hepatotoxicity from canagliflozin treatment.[110]

Although GIs both in women and men were the most frequent reported adverse events of canagliflozin administration as a result of its glucosuric effect, they were mild to moderate in severity, they were easily treated with topical and/or oral antifungal therapies and rarely led to discontinuation.[78–82,111] Vulvovaginal mycotic infection and vulvovaginal candidiasis were the most commonly reported events of this category in women. In placebo-controlled studies, genital mycotic infections in women were significantly increased in both canagliflozin treatment arms compared withplacebo without dosedependency(14.9% in canagliflozin 300 mg, 12.9% in canagliflozin 100 mg and 3.2% in placebo group).[110] In placebo-controlled studies, the overall incidence of genital mycotic infections was higher in women than men. Treatment with canagliflozin increased the incidence of these infections, compared with placebo, in male subjects too (3.7% with canagliflozin 300 mg, 4.2% with canagliflozin 100 mg and 0.6% with placebo).[110] UTI is another adverse event associated to the glucosuric effect of canagliflozin.[79,82,111] In placebo-controlled trials, dysuria, frequency, urgency and suprapubic pain constituted >90% of the symptoms of UTIs. Women were far more susceptible to these events (87% of the cases are women) compared with men.[110] The incidence of these events was slightly higher in the canagliflozin 100 mg group (5.9%) compared with canagliflozin 300 mg group (4.3%) or placebo (4.0%).[110]

The assessment of cardiovascular events related to canagliflozin has been demonstrated in a meta-analysis of one Phase II, seven Phase III and one Phase III, clinical trials, dedicated to cardiovascular safety referred as CANVAS (study of a population with higher background of CV risk).[110,111] This meta-analysis, which is included in the NDA application package of canagliflozin, analyses only the Major Adverse Cardiovascular Events Plus (MACE-plus). According to the results of this meta-analysis, there was an imbalance in MACE-plus during the first 30 days of CANVAS.[110,111] There were 13 MACE-plus events in the canagliflozin arms versus 1 in the placebo group and the estimated hazard ratio was 6.50 (95% CI 0.85–49.66). Due to the small number of events, a wide confidence interval of hazard ratio was observed; thus, a significant increase in risk cannot be concluded.[110,111] After Day 30, in CANVAS study, there were reported 95 events in canagliflozin arms versus 52 in the placebo and the hazard ratio was 0.89 (95% CI 0.64–1.25). The estimated hazard ratio for all trials excluding CANVAS was 0.65 (95% CI 0.35–1.21), and the MACE-plus risk was not significantly increased either in the first 30 days or overall.[110,111] The total estimated hazard ratio for the MACE-plus risk of canagliflozin versus all comparators for all the trials of the meta-analysis including CANVAS was 0.91 (95% CI 0.68–1.22).[110,111] Consequently, according to the authors, these results were not indicative for increased MACE-plus risk with canagliflozin treatment. The reported imbalance in the first 30 days of CANVAS may be attributed to chance or maybe there is indeed an early increased risk of MACE-plus among subjects with high background of cardiovascular risk, which is eliminated along with the administration of canagliflozin.[110,111]

Finally, canagliflozin was reported to induce changes in serum electrolytes as a result of osmotic diuresis. Although magnesium exhibits a 7.3% elevation with canagliflozin 100 mg from baseline and8.8% with canagliflozin 300 mg, compared with−1% with placebo, there were no adverse events related to the elevated magnesium levels.[82,110] Potassium levels were significantly increased from baseline as well (2.6 and 3.3% with canagliflozin 100 and 300 mg, respectively compared with 2% for placebo). The adverse events related to high potassium levels were overall low and were more commonly observed in subjects with moderate renal impairment and in those whose medication was precipitated hyperkalemia. In these subjects, hyperkalemia events were more serious and some of them led to discontinuation.[110]

Regarding the safety of canagliflozin administration in subjects with renal impairment, it is reported that increasing severity of renal function increased the mean elimination t½ of canagliflozin (14.2 h in subjects with normal renal function who received 200 mg canagliflozin compared with 22.8, 17.5 and 23.9 h with mild, moderate and severe renal impairment, respectively).[110] Additionally, increased renal dysfunction decreased the glucosuric effect of the drug as well as the 24 h urinary glucose excretion inducing less reduction in renal threshold for glucose excretion (RTG was 76 and 72 mg/dl in subjects with normal and mild renal function compared to 86 mg/dl and 96 mg/dl in subjects with moderate or severe renal impairment).[82,110] Finally, it was determined that the drug may not be recommended in subjects with severe or end-stage renal disease, a 100 mg dose is proposed for moderate renal disease subjects and standard doses in mild renal impairment and normal subjects.[82,110]