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


Canagliflozin (Invokana Janssen Pharmaceuticals, Inc., Titusville, NJ, USA) is the second agent of this class that has completed Phase III clinical trials and the first to be approved by the US Food and Drug Administration in March 2013.[108] Moreover, a Marketing Authorization Application has been submitted to the EMA to approve a fixed dose therapy combining canagliflozin and immediate release metformin for the treatment of type 2 diabetes.[109] The main results of the clinical trials on canagliflozin are summarized in Table 3 .

Canagliflozin is a novel thiophene derivative of C-glucosidase that has the capacity of a selective SGLT2 inhibitor (160-fold more selective for SGLT2 than for SGLT1) proposed to be taken once daily at 100 or 300 mg dose. After ingestion, it reaches maximal concentration (tmax) at 1–h post dose, bounds to plasma proteins, mainly albumin and its degradation passes through O-glucuronidation.[110] Canagliflozin has mean terminal plasma half-life of 10.6 and 13.1 h with 100 and 300 mg dose, respectively.[110] Animal studies on ZDF rats have shown that canagliflozin has strong loweringeffect on renal threshold for glucose.[77] Untreated ZDF rats experience urinary glucose excretion at blood glucose levels over 400 mg/dl and have renal threshold at ~415 mg/dl, whereas treatment with canagliflozin (1 mg/kg) depresses threshold at 94 mg/dl glucose level.[77] The same study has also demonstrated that urinary glucose excretion is negligible when blood glucose level is <90 mg/dl during the treatment with canagliflozin. Moreover, canagliflozin-treated rats significantly decreased non fasting blood glucose level, HbA1c, body weight, respiratory exchange ratio improving glycemic control and β-cell function as shown by the four-to sixfold increase of insulin/glucose ratio compared with the vehicle-treated group.[77] Nonclinical evaluation of canagliflozin includes pharmacologic and toxicologic studies on dogs and rats and assessment of carcinogenic potential in rats and mice. From life time assessment in mice and rats was concluded that canagliflozin did not increase the incidence of neoplasms or preneoplastic histologic lesions in mice. Cases of neoplasm of the renal tubules, adrenals and testicular Leydig cells reported in Sprague-Dawley rats, were caused via a nongenotoxic mode of action associated with carbohydrate malabsorption and calcium imbalance; thus, they are not expected to be present in humans.[110]

The clinical program of canagliflozin, which is provided from the briefing document of the FDA advisory committee included three Phase II studies and nine Phase III studies where 1,210 and 10,285 subjects participated, respectively.[110] In Phase III studies, canagliflozin was evaluated in subjects who were on different anti-diabetic treatments like diet and exercise (DIA3005), single oral anti-hyperglycemic agents (AHAs) (metformin in DIA3006 and DIA3009, sulfonylurea in DIA3008), dual combination of AHAs (metformin and sulfonylurea in DIA3002 and DIA3015, metformin and pioglitazone in DIA3012) or on insulin (DIA3008 insulin sub study). Moreover, the efficacy of canagliflozin was assessed in special diabetic populations such as type 2 diabetics with moderate renal impairment (DIA3004), with increased risk for CV disease (DIA3008) and older adults from 55- to 80-years old (DIA3010). Phase III studies also consisted of 52-week placebo-controlled trials (DIA3002, DIA3004, DIA3005, DIA3006 and DIA3012), 104-week placebo-control trials (DIA3010) and active comparator-controlled trials (DIA3009 with glimepiride as active comparator and DIA3015 with sitagliptin as active comparator). According to the results of these studies, canagliflozin administration resulted in a dose-dependent improvement of glycemia.[110] The basic effects of increased Urinary Glucose Excretion and decreased Renal Threshold for glucose, were verified from the majority of the clinical trials.[78–80] In placebo-controlled trials, HbA1c reductionfrom baseline, ranged from 0.3 to 0.9% in the 100 mg canagliflozin-treated groups and from 0.4 to 1.2% with canagliflozin 300 mg.[78–82]

Subjects on canagliflozin achieved glycemic goals of HbA1c <7% and HbA1c <6.5% compared with placebo.[79,81,82] In a high glycemic sub study, where the participants had HbA1c >10 and <12% at screening, the reduction from baseline of HbA1c, fasting plasma glucose (FPG) and 2-h post prandial glucose (PPG) was even larger (HbA1c reduction of −2.13 and −2.56% in canagliflozin 100 and 300 mg groups,respectively).[81] The activecomparator trials demonstrated noninferiority of canagliflozin versus glimepiride (HbA1c reduction from baseline was 0.8% for canagliflozin 100 mg, 0.9% for canagliflozin 300 mg versus 0.8% for glimepiride) and sitagliptin (HbA1c reduction from baseline was 0.95% for canagliflozin 300 mg versus 0.74% for sitagliptin).[78,79] In addition, the reduction of FPGlevels was significantly greater in canagliflozin-treated groups versus placebo.[80–82] More particular, FPG reduction ranged from −16.2 to −27.0 mg/dl in canagliflozin-treated groups, whereas the placebo and sitagliptin groups presented a 3.6 mg/dl and −12.6 mg/dl change, respectively.[79] Furthermore, canagliflozin induced asignificant 24-h mean postprandial glucose-level reduction[80] and 2-h PPG-level reduction[81] compared with placebo.

In placebo-controlled trials, canagliflozin induced a statistically significant systolic blood pressure reduction, ranged from 2.6 to 5.7 mmHg in 100 mg canagliflozin groups and from 3.5 to 7.9 mmHg in canagliflozin 300 mg groups.[81,110] Other studies have also reported an even more greater reduction of both systolic and diastolic blood pressure in canagliflozin-treated groups.[80,82]

Body weight reduction is another beneficial effectof canagliflozin reported in many clinical trials.[82,110] The percentage of body weight reduction from baseline ranged from 1.6 to 2.4% in patients treated with 100 mg of canagliflozin. A greater weight reduction was achieved in patients treated with 300 mg of canagliflozin (from 1.8 to 3.8%).[81] However, in studies where canagliflozin was added to sulfonylurea, the effect on body weight was modest or did not reach statistical significance.[110] Modest effect on body weight reduction was observed also in trials where subjects were receiving insulin.[80]

The effect of canagliflozin on lipidemic profile seems to be promising. In four out of eight trials, canagliflozin resulted in a significant increase in HDL-C. More particular, administration of 100 and 300 mg of canagliflozin resulted in 0.7 and 2.7% increase in HDL, respectively, where as an increase of 0.7% was reported in the placebo group.[81] There was also a small decrease in triglyceridesas well,[81,110] which only in one trial reached significance (DIA3012).[110] Given that dapagliflozin did not present significant effect on lipidemic profile, FDA concluded that observed changes in lipids levels were not associated to SGLT2 inhibition.[110]

Finally, canagliflozin has been reported to present a beneficial effect on b-cell function and an increase in HOMA2-%B in both 100 and 300 mgdosages compared with placebo.[79,81]