Canagliflozin-current status in the treatment of type 2 diabetes mellitus with focus on clinical trial data

Table 1 Summary of clinical trials of canagliflozin

References/trial name (n = sample size)	Study population and duration of the study	Study drugs	Change in HbA1c from the baseline (in percent)	Change in FBG from baseline	Change in body weight from baseline	Other parameters (least square mean change)
Stenlöf et al[19] (n = 584)	T2DM patients on diet and exercise with inadequate glycemic control Duration of the study = 26 wk	CFZ = 100 mg/300 mg OD vs PL	-0.77% to -1.03% (CFZ 100 mg/300 mg, P < 0.001 vs PL)	-27 mg/dL to -35 mg/dL (CFZ 100 mg/300 mg, P < 0.001 vs PL)	% Body weight reduction -2.8% to -3.9% (CFZ 100 mg/300 mg, P < 0.001 vs PL)	ΔPPBG = -43 to -59 mg/dL (CFZ 100 mg/300 mg) ΔSBP = -3.3 to -5.0 mmHg (CFZ 100 mg/300 mg, P < 0.001 vs PL) ΔDBP = -1.7 to -2.1 mmHg (CFZ 100 mg/300 mg vs PL) ΔHDL = CFZ 100 mg = 11.2% (P < 0.001 vs PL) CFZ 300 mg = 10.6% (P < 0.01 vs PL) ΔLDL = 2.9% to 7.1% (CFZ 100 mg/300 mg vs PL) ΔTG = 2.5% to -2.3% (CFZ 100 mg/300 mg vs PL) HOMA-%B = 9.9% to 20.3% (CFZ 100 mg/300 mg vs PL)
CANTATA-D[20]	26-wk extension study		At the end of 26 wk	At the end of 26 wk	At the end of 26 wk	At the end of 26 wk
(n = 1284)	T2DM patients with inadequate glycemic control on protocol specified MET-IR monotherapy with HbA1c: 7.0% to 10.5%, FBG < 270 mg/dL	CFZ = 100 mg/300 mg OD + MET-IR vs PL + MET-IR for first 26 wk	-0.79% to -0.94% (CFZ 100 mg/300 mg, P < 0.001 vs PL)	-27.3 mg/dL to -37.8 mg/dL (CFZ 100 mg/300 mg, P < 0.001 vs PL)	% Body weight reduction -3.7% to -4.2% (CFZ 100 mg/300 mg, P < 0.001 vs PL)	ΔPPBG = -47.9 mg/dL to -57.1 mg/dL (CFZ 100 mg/300 mg, P < 0.001 vs PL) SITA = -49.3 mg/dL ΔSBP = -3.84 mmHg to -5.06 mmHg (CFZ 100 mg/300 mg, P < 0.001 vs PL), SITA = -1.83 mmHg ΔTG = CFZ 100 mg = 1.6%, P = 0.7 vs PL, CFZ 300 mg = -1.4%, P = 0.2 vs PL, SITA = 1.0% ΔHDL = 10.4% to 12.1% (CFZ 100 mg/300 mg, P < 0.001 vs PL), SITA = 5%
		CFZ = 100 mg/300 mg OD + MET-IR vs SITA 100 mg + MET-IR for next 26 wk	SITA = -0.82%	SITA = -20.2 mg/dL	SITA = -1.2%
			At the end of 52 wk	At the end of 52 wk	At the end of 52 wk	At the end of 52 wk
			-0.73% to -0.88% (CFZ 100 mg/300 mg)	-26.2 mg/dL to -35.2 mg/dL (CFZ 100 mg/300 mg, P < 0.001 vs SITA)	-3.8% to -4.2% (CFZ 100 mg/300 mg, P < 0.001 vs SITA)	ΔSBP = -3.53 mmHg to -4.65 mmHg (CFZ 100 mg/300 mg, P < 0.001 vs SITA) SITA = -0.66 mmHg ΔTG = CFZ 100 mg = 1.9%, P = 0.46 vs SITA CFZ 300 mg = 2.7%, P = 0.32 vs SITA SITA = -0.4% ΔHDL = 11.2% to 13.3% (CFZ 100 mg/300 mg, P < 0.001 vs SITA), SITA = 6.0%
			SITA = -0.73%	SITA = -17.7 mg/dL	SITA = -1.3%
Guthrie et al[21]	26-wk extension study		At the end of 26 wk	At the end of 26 wk	At the end of 26 wk	At the end of 26 wk
Forst et al[22] CANTATA-MP (n = 344)	T2DM patients currently treated with PPAR gamma agent (PIO or ROSI) and MET with HbA1c: 7%-10.5% and FBG < 270 mg/dL	CFZ = 100 mg/300 mg OD + MET + PIO vs PL + MET + PIO for first 26 wk CFZ = 100 mg/300 mg OD + MET + PIO vs SITA 100 mg + MET + PIO for next 26 wk	-0.89% to -1.03% (CFZ 100 mg/300 mg, P < 0.001 vs PL)	-26.8 mg/dL to -33.2 mg/dL (CFZ 100 mg/300 mg, P < 0.001 vs PL)	-2.8% to -3.8% (CFZ 100 mg/300 mg, P < 0.001 vs PL)	ΔSBP = CFZ 100 mg = -5.30 mmHg (P = 0.005 vs PL) CFZ 300 mg = -4.70 mmHg (P = 0.016 vs PL) ΔTG = CFZ 100 mg = 3.2% (P = 0.034 vs PL) CFZ 300 mg = -1.7% (P = 0.003 vs PL) ΔHDL = CFZ 100 mg = 7.2% (P = 0.01 vs PL) CFZ 300 mg = 8.9% (P < 0.001 vs PL) HOMA-%B = 15.19% to 18.14% (CFZ 100 mg/300 mg, P < 0.01 vs PL)
			At the end of 52 wk	At the end of 52 wk	At the end of 52 wk	At the end of 52 wk
			-0.92% to -1.03% (CFZ 100 mg/300 mg)	-26.7 mg/dL to -31.5 mg/dL (CFZ 100 mg/300 mg)	-2.7% to -3.7% (CFZ 100 mg/300 mg)	ΔSBP = -3.4 to -3.7 mmHg (CFZ 100 mg/300 mg) ΔDBP = -2.5 to -2.7 mmHg (CFZ 100 mg/300 mg) ΔHDL = CFZ 100 mg = 7.0% CFZ 300 mg = 11.4% ΔLDL = 10.9% to 14.3% (CFZ 100 mg/300 mg) ΔTG = 4.7% to -0.6% (CFZ 100 mg/300 mg)
Cefalu et al[23] CANTATA-SU (n = 1450)	T2DM patients with HbA1c: 7%-9.5% on stable MET therapy ≥ 1500 mg/d, BMI = 22-45kg/m2, FBG ≤ 270mg/dL Duration of the study = 52 wk	CFZ = 100 mg/300mg OD + MET vs GLIM 6 mg/8 mg OD + MET	-0.82% to -0.93% (CFZ 100 mg/300 mg)	-1.35 mmol/L to -1.52 mmol/L (CFZ 100 mg/300 mg)	-4.2% to -4.7% (CFZ 100 mg/300 mg, P < 0.001 vs GLIM)	ΔSBP = -3.3 to -4.6 mmHg (CFZ 100 mg/300 mg) GLIM = 0.2 mmHg ΔDBP = -1.8 to -2.5 mmHg (CFZ 100 mg/300 mg) GLIM = -0.1 mmHg ΔTG = CFZ 100 mg = -3.7% CFZ 300 mg = 2.3% GLIM = 9.5% ΔHDL = CFZ 100 mg = 7.9% CFZ 300 mg = 9.0% GLIM = 0.3% ΔLDL = 9.6% to 14.1% (CFZ 100 mg/300 mg) GLIM = 5%
			GLIM = -0.81%	GLIM = -1.02 mmol/L	GLIM = 1%
Wilding et al[24]	26-wk extension study		At the end of 26 wk	At the end of 26 wk	At the end of 26 wk	At the end of 26 wk
CANTATA-MSU (n = 469)	T2DM patients currently treated with MET and SU with HbA1c: 7%-10.5% and FBG < 270 mg/dL	CFZ = 100 mg/300 mg OD + MET + SU vs PL + MET + SU	-0.85% to -1.06% (CFZ 100 mg/300 mg, P < 0.001 vs PL)	-18.2 mg/dL to -30.5 mg/dL (CFZ 100 mg/300 mg, P < 0.001 vs PL)	-2.1% to -2.6% (CFZ 100 mg/300 mg, P < 0.001 vs PL)	ΔSBP = CFZ 100 mg = -4.89 mmHg (P = 0.07 vs PL) CFZ 300 mg = -4.27 mmHg (P = 0.2 vs PL) ΔTG = CFZ 100 mg = 5.4% (P = 0.256 vs PL) CFZ 300 mg = 8.5% (P = 0.57 vs PL) ΔHDL = CFZ 100 mg = 5.7% (P = 0.153 vs PL) CFZ 300 mg = 6.5% (P = 0.056 vs PL)
Schernthaner et al[25] CANTATA-D2 (n = 755)	T2DM patients currently treated with MET and SU with HbA1c: 7%-10.5% and FBG < 300 mg/dL Duration of the study = 52 wk	CFZ = 300 mg OD + MET + SU vs SITA = 100 mg OD + MET + SU	CFZ 300 mg = -1.03% (P < 0.001 vs SITA) SITA = -0.66%	CFZ 300 mg = -29.9 mg/dL (P < 0.001 vs SITA) SITA = -5.85 mg/dL	CFZ 300 mg = -2.5% (P < 0.001 vs SITA) SITA = 0.3%	ΔSBP = CFZ 300 mg = -5.06 mmHg (P < 0.001 vs SITA) SITA = 0.85 mmHg ΔTG = CFZ 300 mg = 9.6% (P = 0.554 vs SITA) SITA = 11.9% ΔHDL = CFZ 300 mg = 7.6% (P < 0.001 vs SITA) SITA = 0.6%
Devineni et al[26] (n = 29)	T2DM patients not optimally controlled on insulin and up to one oral AHA with BMI: 25-45 kg/m2, FBG: 3.3-5.5 mmol/L, HbA1c: 7%-10.5% and serum creatinine: < 132.6 mmol/L for males and < 123.8 mmol/L for women Duration of the study = 28 d	CFZ 100 mg OD/300 mg bid + Insulin + upto one AHA vs PL + insulin + upto one AHA	-0.73% to -0.92% (CFZ 100 mg/300 mg)	-2.11 mmol/L to -2.35 mmol/L (CFZ 100 mg/300 mg)	-0.73 kg to -1.19 kg (CFZ 100 mg/300 mg)	ΔUGE = 71.9 g/d to 129.2 g/d
Rosenstock et al[27] (n = 451)	T2DM patients under stable MET monotherapy (≥ 1500 mg/d) with HbA1c: 7%-10%, BMI: 24-45 kg/m2, serum creatinine: < 1.5mg/dL for males and < 1.4 mg/dL for females Duration of the study = 12 wk	CFZ = 50/100/200/300 mg OD or 300 mg bid + MET vs PL + MET vs SITA 100 mg OD + MET	CFZ 50 mg = -0.79% 100 mg = -0.76% 200 mg = -0.70% 300 mg = -0.92% 300 mg bid = -0.95% SITA = -0.74%	CFZ 50 mg = -16.2 mg/dL 100 mg = -25.2 mg/dL 200 mg = -27.0 mg/dL 300 mg = -25.2 mg/dL 300 mg bid = -3.4 mg/dL SITA = -12.6 mg/dL	CFZ 50 mg = -2.3% 100 mg = -2.60% 200 mg = -2.70% 300 mg = -3.40% 300 mg bid = -3.4% SITA = -0.60%	ΔSBP = -3.3 to -5 mmHg (CFZ 100 mg/300 mg) SITA = -0.8 mmHg ΔDBP = -1.7 to -2.1 mmHg (CFZ 100 mg/300 mg) SITA = -0.6 mmHg ΔTG = CFZ 100 mg = 2.5% CFZ 300 mg = -2.3% ΔHDL = CFZ 100 mg = 11.2% CFZ 300 mg = 10.6% ΔLDL = 2.9% to 7.1% (CFZ 100 mg/300 mg) HOMA-%B = CFZ 50-300 mg OD = 6% to 18% CFZ 300 mg bid = 16% SITA = 10%
ClinicalTrials. gov identifier: NCT01064414[28] (n = 272)	26-wk extension study		At the end of 26 wk	At the end of 26 wk
	T2DM patients with or without AHA, on regular diet and exercise with moderate renal impairment	CFZ = 100 mg/300 mg OD with or without AHA vs PL with or without AHA	-0.33% to -0.44% (CFZ 100 mg, P = 0.01 vs PL, CFZ 300 mg, P < 0.001 vs PL)	CFZ 100 mg = -14.9 mg/dL, P = 0.02 CFZ 300 mg = -11.7 mg/dL, P = 0.06	Information was not available	Information was not available

OD: Once daily; FBG: Fasting blood glucose; PL: Placebo; CFZ: Canagliflozin; ΔSBP: Change in systolic blood pressure from baseline; ΔDBP: Change in diastolic blood pressure from baseline; ΔHDL: Change in blood HDL level from baseline; ΔLDL: Change in blood LDL level from baseline; ΔTG: Change in blood triglycerides level from baseline; ΔPPBG: Change in postprandial blood glucose from baseline; MET: Metformin; SU: Sulphonylurea; SITA: Sitagliptin; PIO: Pioglitazone; ROSI: Rosiglitazone; AHA: Antihyperglycemic agent; IR: Immediate release; GLIM: Glimepride; HOMA-%B: Homeostasis Model Assessment estimating steady state beta cell function in percentage; LDL: Low-density lipoprotein; T2DM: Type 2 diabetes mellitus; PPAR: Peroxisome proliferator activated receptor.

Table 2 Summary of adverse events observed in the canagliflozin clinical trials

S. No	ClinicalTrials.gov identifier	Adverse events	Ref.
1	NCT01081834	Increased incidence of AEs in CFZ groups Serious AEs and AE related discontinuations similar in all groups Increased incidence of UTI, genital mycotic infections and osmotic diuresis related AEs in CFZ groups Moderate increase in BUN, serum creatinine and decrease in serum uric acid	Stenlöf et al[19]
2	NCT01106677	AEs similar across all groups Higher incidence of pollakiuria in CFZ groups -5.71% with 100 mg CFZ and 2.72% with 300 mg CFZ vs 0.55% of PL	[20]
3	NCT01106690	Vulvovaginal mycotic infections: 2.65% to 5.26% vs 0% of placebo Pollakiuria: 6.14% to 9.42% vs 0.87% of placebo Increased rate of hypoglycemic event with CFZ 300 mg (5.26% vs 1.74% of PL)	Guthrie et al[21]
4	NCT00968812	Osmotic diuresis related AEs in 3% of CFZ groups as compared to < 1% in placebo groups Genital infections and increase in LDL cholesterol more in CFZ groups	Cefalu et al[23]
5	NCT01106625	Superficial genital mycotic infection: 16.0% to 21.0% vs 5% in women and 3.4% to 6.6% vs 1.3% in men More subjects treated with CFZ had ≥ 1 hypoglycemic episodes	Wilding et al[24]
6	NCT01137812	Genital mycotic infections: 9.2% of CFZ 300 mg vs 0.5% of SITA Osmotic diuresis related AEs: 2.4% of CFZ 300 mg vs 1.3% of SITA Higher incidence of increased TG in CFZ groups	Schernthaner et al[25]
7	Not available	Similar rate of AEs and discontinuations across all groups No serious AEs	Devineni et al[26]
8	NCT00642278	Non dose dependent increase in incidence of genital infections (3%-8% vs 2% of SITA) and UTI (3%-9% vs 2% of SITA) in CFZ groups Low incidence of hypoglycemia Small increase in LDL cholesterol in CFZ groups	Rosenstock et al[27]
9	NCT01064414	AEs similar across all groups Increased incidence of hypoglycemic events in CFZ groups -14.44% with 100 mg CFZ and 11.24% with 300 mg CFZ vs 4.44% of PL	[28]

AEs: Adverse events; CFZ: Canagliflozin; UTI: Urinary tract infections; SITA: Sitagliptin; LDL: Low-density lipoprotein; PL: Placebo; TG: Triglycerides; BUN: Blood urea nitrogen.