European Journal of Clinical Pharmacology

, Volume 70, Issue 10, pp 1149–1158 | Cite as

Efficacy and safety of canagliflozin in subjects with type 2 diabetes: systematic review and meta-analysis

  • Xu-Ping Yang
  • Dan Lai
  • Xiao-Yan Zhong
  • Hong-Ping Shen
  • Yi-Lan Huang
Review Article

Abstract

Purpose

To assess the efficacy and safety of the novel sodium glucose co-transporter 2 (SGLT2) inhibitor—canagliflozin for type 2 diabetes (T2DM).

Methods

A search of Medline (1946–January 2014), Embase (1950–January 2014), and The Cochrane Library for randomized controlled trials of canagliflozin compared to placebo or active comparator in T2DM was performed. Clinical Trials website and unpublished U.S. Food and Drug Administration data were also searched.

Results

Ten trials including 6,701 patients were analyzed. Compared with placebo, canagliflozin produced absolute reductions in glycated hemoglobin A1c levels when used as monotherapy (weighted mean difference (WMD) −1.08 %, 95 % confidence interval (CI) [−1.25 to −0.90], p < 0.00001) or add-on treatment (WMD −0.73 %, 95 %CI [−0.84 to −0.61], p < 0.00001). When compared with other active comparators, canagliflozin significantly reduced HbA1c by −0.21 % (WMD, 95 %CI [−0.33 to −0.08], p = 0.001). Canagliflozin led to greater body weight loss (vs. placebo, WMD −2.81 kg, 95 %CI [−3.26 to −2.37]; vs. active comparators, WMD −3.49 kg, 95 %CI [−4.86 to −2.12]). Hypoglycemia with canagliflozin was similar to placebo or sitagliptin, and was lower than glimepiride (risk ratio (RR) 0.15, 95 %CI [0.10 to 0.22]). Genital tract infections were more common with canagliflozin (vs. placebo, RR 3.76, 95 %CI [2.23 to 6.35]; vs. active comparators, RR 4.95, 95 %CI [3.25 to 7.52]). Similar incidences of urinary tract infections were noted with canagliflozin compared with control groups.

Conclusion

Canagliflozin led to improvements in reducing glycated hemoglobin A1c levels and body weight with low risk of hypoglycemia in patients with T2DM. Common adverse effects including genital tract infections and osmotic diuresis-related AEs were identified and reviewed. Risks of cardiovascular events are even less certain, and more data on long-term effects are needed.

Keywords

Canagliflozin Sodium glucose co-transporter 2 inhibitor Type 2 diabetes Systematic review 

Introduction

Type 2 diabetes (T2DM) is a chronic, progressive, and multifactorial disease. More than 340 million people worldwide are affected and other hundreds of millions are at risk of diabetes [1]. A recent position statement by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommended initial treatment with metformin as monotherapy when lifestyle intervention is inadequate, followed by additional agents (including sulfonylureas, thiazolidinediones, insulin) [2]. However, rather than reinstate or maintain long-term glucose control, many of these drugs lead to hypoglycemia or weight gain which may worsen insulin resistance [3, 4]. Thus, new antihyperglycemic agents (AHAs) that can provide long-term glycemic control with additional benefits such as minimal hypoglycemia and weight loss are needed. In this regard, sodium-glucose co-transporter 2 (SGLT2) inhibitors, which have an insulin-independent mechanism for the correction of hyperglycemia, may prove to be an appealing alternative [5, 6].

SGLT2 is mainly expressed in the early proximal renal tubule, and the kidney is responsible for the majority of glucose absorption [7, 8]. Canagliflozin is the first agent of this class to be approved by the U.S. Food and Drug Administration (FDA) in April 2013 for the treatment of T2DM [9, 10]. This new oral agent has been shown to lower the renal threshold for glucose (RTG, the glucose concentration below which minimal UGE is observed) and induce urinary glucose excretion (UGE), resulting in a decreased plasma glucose and body weight with a low intrinsic risk of hypoglycemia [5, 6, 11]. Three previous meta-analysis [12, 13, 14] had reviewed the efficacy and safety of the SGLT2 inhibitors, including canagliflozin, for treating T2DM. However, only one RCT on canagliflozin was included in Clar and Musso’s study [12, 13], Despoina’s study [14] did not evaluate the effect of canagliflozin on plasma lipids or β-cell function. To get more comprehensive profile, we conducted a systematic review and meta-analysis to summarize the benefits and harms of canagliflozin in T2DM either as monotherapy or as add-on treatment.

Methods

Data sources and search strategy

We searched Medline, Pubmed, Embase, and the Cochrane Collaboration Library from inception to January 2014, without restriction of language. FDA data and Clinical Trials (http://www.clinicaltrials.gov) were also searched. Our search strategy used the following terms: “sodium-glucose cotransporter 2 inhibitor”, “SGLT2 inhibitor”, “canagliflozin”, “Invokana”, “JNJ 28431754”, “T2DM”, and “Type 2 diabetes”. These terms were adjusted to comply with the relevant rules in each database.

Study selection

Titles and abstracts of all retrieved citations were screened by two independent reviewers (X.P.Y and X.Y.Z) to identify potentially relevant studies. Full texts were retrieved for relevant citations. Any resulting discrepancies were resolved by discussion, with involvement of a third reviewer when necessary.

Inclusion criteria

Randomized controlled trials (RCTs) of canagliflozin for the treatment of T2DM according to the WHO diagnostic criteria were included if they met the following criteria. (1) Patients: inclusive of any ethnic origin and aged over 18; (2) interventions: any use of canagliflozin in dual or triple therapy or monotherapy, duration of the intervention was at least 12 weeks; (3) comparison intervention: placebo or active comparators with or without background therapy; (4) report at least one of the following outcomes: (a) HbA1c, (b) fasting plasma glucose (FPG), (c) body weight, (d) HOMA2-%β, (e) blood pressure, (f) plasma lipids, and (g) AEs.

Non-randomized trials, case reports, editorials, letters to the editors, and studies with no comparison group were excluded.

Data extraction

Data were abstracted independently by two reviewers (X.P.Y and X.Y.Z), and any discrepancies were resolved by consensus. As canagliflozin 300 mg/day is likely to be the highest dose used in clinical practice, we mainly focused on the data for patients randomly assigned to canagliflozin 300 mg/day. From each study, we extracted study characteristics, baseline characteristics, and prespecified outcomes of efficacy and safety.

Risk of bias

Two reviewers (X.P.Y and X.Y.Z) independently applied the Cochrane Risk of Bias tool to assessed the risk of bias of randomized trials [15], including random sequence generation, allocation concealment, blinding, incomplete data regarding outcome, selective reporting, and other items (ie., groups comparable at baseline, funder, and incomplete information in the text).

Data synthesis and analysis

All outcomes were pooled using RevMan5.2 software [16]. For continuous and dichotomous data, differences were calculated using WMD and RR, respectively. All results were estimated from each study with 95 % confidence interval (CI). Heterogeneity was assessed using the chi-square test and the I2 statistics, if I2 < 50 %, the fixed-effect model with Mantel-Haenszel method was used; otherwise, the random-effect model was adopted. If our primary outcome data (ie., standard deviation (SD) and variance measures) were missing or incomplete, we e-mailed the corresponding authors or the sponsors. When necessary, the value of SD was calculated from CI or SE as described in the Cochrane Handbook.

Results

Forty-two articles that met our inclusion criteria were identified after being reviewed by two independent reviewers (X.P.Y and X.Y.Z), a total of 10 RCTs (n = 6701 ) [17, 18, 19, 20, 21, 22, 23, 24, 25, 26] met final inclusion criteria for meta-analysis (Fig. 1).
Fig. 1

Flow chart of study selection process

Study characteristics

The characteristics and results of the included studies were shown in Table 1. All included trials were double-blind RCTs, two were phase II [18, 20] and eight phase III [17, 19, 21, 22, 23, 24, 25, 26]. Trial durations ranged from 12 to 52 weeks, all trials had longer-term extension periods (ranged from 12 to 78 weeks). Mean baseline HbA1c levels across the study populations ranged from 7.7 to 8.2 %; mean baseline FPG levels ranged from 8.5 to 9.6 mmol/L. Participants in most trials were mainly middle-aged and overweight adults who had T2DM for more than 4 years. Mean baseline weight levels in most trials ranged from 85.4 to 93.8 kg, and mean age ranged from 52.9 to 68.6 years but were typically between 55 and 57 years.
Table 1

Characteristics of randomized controlled trials

Study, Year (reference)

Participants

Interventions

HbA1c

(%)

FPG

(mmol/l)

Body weight

(kg)

T2DM duration (years)

Background

therapy

Duration

(extension)

Stenlof et al. 2013 [17]

N: 584

Age (years): 55.4 ± 10.6

BMI (kg/m2): 31.6 ± 6.2

CANA 300 mg

PBO

8.0 ± 1.0

8.0 ± 1.0

9.6 ± 2.4

9.3 ± 2.1

86.9 ± 20.5

87.6 ± 19.5

4.3 ± 4.7

4.2 ± 4.1

Monotherapy

26 w (26w)

Rosenstock et al. 2012 [18]

N: 451

Age (years): 52.9 ± 8.1

BMI (kg/m2): 31.5 ± 4.9

CANA 300 mg

SITA 100 mg

PBO

7.7 ± 1.0

7.7 ± 0.9

7.8 ± 0.8

8.7 ± 1.9

8.7 ± 1.9

9.1 ± 2.1

87.3 ± 15.9

87.2± 18.0

85.9 ± 19.5

5.9 ± 5.2

5.6 ± 4.7

6.4 ± 5.0

Add on to MET

12 w (2w)

Bode et al. 2013 [19]

N: 714

Age (years): 63.6 ± 6.2

BMI (kg/m2): 31.6 ± 4.6

CANA 300 mg

PBO

7.7 ± 0.8

7.8 ± 0.8

8.5 ± 2.0

8.7 ± 2.2

88.8 ± 17.1

91.1 ± 17.5

11.3 ± 7.2

11.4 ± 7.3

Add on to one or more AHA including INSb

26 w (78w)

Inagaki et al. 2013 [20]

N: 383

Age (years): 57.4 ± 10.6

BMI (kg/m2): 25.7 ± 4.2

CANA 300 mg

PBO

8.2 ± 0.8

8.0 ± 0.8

9.4 ± 1.9

9.5 ± 1.8

71.3 ± 12.2

72.6 ± 15.4

NR

Monotherapy

12 w (2w)

Wilding et al. 2013 [21]

N: 469

Age (years): 56.8 ± 9.3

BMI (kg/m2): 33.1 ± 6.5

CANA 300 mg

PBO

8.1 ± 0.9

8.1 ± 0.9

9.3 ± 2.1

9.4 ± 2.2

93.5 ± 22.0

91.2 ± 22.6

9.4 ± 6.4

10.3 ± 6.7

Add on to MET + SUs

26 w (26w)

NCT01106690 2013 [22]

N: 342

Age (years): 55.4 ± 9.42

CANA 300 mg

PBO

NRa

NRa

NR

NR

Add on to MET + PIO

26 w (26w)

Yale et al. 2013 [23]

N: 269

Age (years): 68.5 ± 8.3

BMI (kg/m2): 33.0 ± 6.2

CANA 300 mg

PBO

8.0 ± 0.8

8.0 ± 0.9

8.8 ± 3.2

8.9 ± 2.4

90.2 ± 18.1

92.8 ± 17.4

17.0 ± 7.8

16.4 ± 10.1

Add on to one or more AHA including INSb

26 w (26w)

Lavalle-González et al. 2013 [24]

N: 1,284

Age (years): 55.4 ± 9.4

BMI (kg/m2):31.8 ± 6.2

CANA 300 mg

SITA 100 mg

PBO

7.9 ± 0.9

7.9 ± 0.9

8.0 ± 0.9

9.6 ± 2.5

9.4 ± 2.3

9.1 ± 2.1

85.4 ± 20.9

87.7 ± 21.6

86.6 ± 22.4

7.1 ± 5.4

6.8 ± 5.2

6.8 ± 5.3

Add on to MET

26 w (26w)

Schernthaner et al. 2013 [25]

N: 755

Age (years): 56.7 ± 9.5

BMI (kg/m2): 31.6 ± 6.9

CANA 300 mg

SITA 100 mg

8.1 ± 0.9

8.1 ± 0.9

9.4 ± 2.6

9.2 ± 2.5

87.4 ± 23.2

89.1 ± 23.2

9.4 ± 6.1

9.7 ± 6.3

Add on to MET + SUs

52 w (4w)

Cefalu et al. 2013 [26]

N:1,450

Age (years): 56.2 ± 9.2

BMI (kg/m2): 31.0 ± 5.4

CANA 300 mg

GlIM 6–8 mg

7.8 ± 0.8

7.8 ± 0.8

9.1 ± 2.0

9.2 ± 2.1

86.6 ± 19.5

86.5 ± 19.8

6.7 ± 5.5

6.6± 5.0

Add on to MET

52 w (52w)

CANA canagliflozin, PBO placebo, BMI body mass index, MET metformin, INS insulin, SUs sulfonylureas, PIO pioglitazone, GlIM glimepiride, SITA sitagliptin, NR not report

aNCT01106690: this study have not been published. Inclusion criteria: patients in the study must have a HbA1c between 7 and 10.5 % and a FPG < 15 mmol/L

bPatients in the same group were on several different background therapies (ie., metformin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors as well as insulin, alone or in combination) in both Yale and Bode’s trials

Canagliflozin was administered orally, dose of 300 mg once daily was assessed in all trials. Background glucose-lowering drugs included metformin [18, 24, 26] or other combination therapy [19, 21, 22, 23, 25]. Except for the study by Schernthaner and Cefalu [25, 26], all studies included a placebo group. Four studies included an active comparator: glimepiride (dose 6–8 mg) in the study by Cefalu [26] and sitagliptin (100 mg) in three canagliflozin studies [18, 24, 25].

Risk of bias

All studies were randomized controlled trials and had a low risk for bias for the various items assessed (Supplementary Table 1). However, random sequence generation and allocation concealment were unclear in two RCTs [18, 22]. All studies were double blind, and all were funded by industry.

Glycemic levels

Figure 2 shows the effects of canagliflozin versus placebo on HbA1c. Compared with placebo, canagliflozin produced absolute reductions in HbA1c when used as monotherapy (WMD −1.08 %, 95 %CI [−1.25 to −0.90], p < 0.00001) or add-on treatment (WMD −0.73 %, 95 %CI [−0.84 to −0.61], p < 0.00001). A greater proportion of subjects treated with canagliflozin compared with placebo achieved the target of HbA1c <7 % (RR 2.41, 95 %CI 1.96 to 2.96, p < 0.00001) (Supplementary Fig. 1).
Fig. 2

Meta-analysis for HbA1c change from baseline, canagliflozin versus placebo

Compared with active comparator, canagliflozin significantly reduced HbA1c by −0.21 % (WMD, 95 %CI [−0.33 to −0.08], p = 0.001) (Fig. 3). When compared with each active hypoglycemic agents, HbA1c was also reduced with canagliflozin compared with sitagliptin (WMD −0.24 %, 95 %CI [−0.40 to −0.09], p = 0.002) and glimepiride (WMD −0.12 %, 0.95 %CI [−0.23 to −0.01], p = 0.03) (Fig. 3).
Fig. 3

Meta-analysis for HbA1c change from baseline, canagliflozin versus active comparator

Significant improvements from baseline in FPG levels were also observed with canagliflozin (Supplementary Fig. 2 and Fig. 3). Compared with placebo or active comparator, canagliflozin provided a significant greater reduction in FPG (vs. placebo, WMD −33.50 mg/dl, 95 %CI [−39.22 to −27.78], p < 0.00001; vs. active comparators, WMD −15.86 mg/dl, 95 %CI [−23.17 to −8.56], p < 0.00001).

Body weight

Treatment with canagliflozin was associated with a significant reduction in body weight. Compared with placebo, body weight was reduced by −2.81 kg (WMD, 95 %CI [−3.26 to −2.37], p < 0.00001) (Supplementary Fig. 4). Similarly, canagliflozin had a superior effect on body weight reduction compared with active comparator (WMD −3.49 kg, 95 %CI [−4.86 to −2.12], p < 0.00001) (Supplementary Fig. 5), with WMD vs. sitagliptin of −2.84 kg (95 %CI [−3.21 to −2.48], p < 0.00001). When compared canagliflozin with glimepiride, weight loss occurred much greater with canagliflozin (WMD −5.40 kg, 95 %CI [−5.95 to −4.85], p < 0.00001) (Supplementary Fig. 5).

HOMA2-%β

Canagliflozin was associated with a greater significant improvement in HOMA2-%β, the pooled WMD with canagliflozin vs. placebo for HOMA2-%β was 15.07 (WMD, 95 %CI [7.14 to 23.00], p = 0.0002) and vs. active comparator 11.33 (WMD, 95 %CI [5.31 to 17.34], p = 0.0002), respectively (Table 2).
Table 2

Meta-analyses for efficacy and safety outcomes

Outcome

Interventions

Studies, n

Participants analyzed, n

Effect estimate (95 %CI)

pa

I2 (%)

canagliflozin

comparator

Mean change in HbA1c (%) from baseline

canagliflozin vs placebo

8

1271

1090

−0.81 [−0.96, −0.67]

<0.00001

79

canagliflozin vs active agents

4

1268

1254

−0.21 [−0.33, −0.08]

0.001

65

canagliflozin vs sitagliptin

3

794

781

−0.24 [−0.40, −0.09]

0.002

63

canagliflozin vs glimepiride

1

474

473

−0.12 [−0.23, −0.01]

0.03

Mean change in FPG (mg/dl) from baseline

canagliflozin vs placebo

8

1269

1085

−33.50 [−39.22, −27.78]

<0.00001

70

canagliflozin vs active agents

4

1268

1256

−15.86 [−23.17, −8.56]

<0.00001

81

canagliflozin vs sitagliptin

3

794

783

−19.09 [−24.87, −13.32]

<0.00001

51

canagliflozin vs glimepiride

1

474

473

−9.00 [−12.99, −5.01]

<0.00001

Mean change in body weight (kg) from baseline

canagliflozin vs placebo

7

1186

1006

−2.81 [−3.26, −2.37]

<0.00001

62

canagliflozin vs active agents

4

1277

1274

−3.49 [−4.86, −2.12]

<0.00001

95

canagliflozin vs sitagliptin

3

797

796

−2.84 [−3.21, −2.48]

<0.00001

0

canagliflozin vs glimepiride

1

480

478

−5.40 [−5.95, −4.85]

<0.00001

Mean change in HOMA2-%β (%) from baseline

canagliflozin vs placebo

4

361

344

15.07 [7.14,23.00]

0.0002

87

canagliflozin vs active agents

2

398

433

11.33 [5.31, 17.34]

0.0002

0

Mean change in SBP (mmHg) from baseline

canagliflozin vs placebo

7

918

917

−5.05 [−6.81,−3.28]

<0.00001

56

canagliflozin vs active agents

4

1279

1267

−4.34 [−5.31, −3.36]

<0.00001

0

canagliflozin vs sitagliptin

3

799

787

−4.09 [−5.29, −2.90]

<0.00001

0

canagliflozin vs glimepiride

1

480

480

−4.80 [−6.46, −3.14]

<0.00001

Mean change in DBP (mmHg) from baseline

canagliflozin vs placebo

5

652

654

−2.43 [−3.29, −1.57]

<0.00001

0

canagliflozin vs active agents

4

1279

1267

−2.17 [−2.79, −1.54]

<0.00001

0

canagliflozin vs sitagliptin

3

799

787

−2.06 [−2.82, −1.30]

<0.00001

17

canagliflozin vs glimepiride

1

480

480

−2.40 [−3.51, −1.29]

<0.0001

Hypoglycaemia

canagliflozin vs placebo

3

336

332

1.13 [0.40, 3.20]

0.81

0

canagliflozin vs active agents

4

1288

1289

0.33 [0.25, 0.43]

<0.00001

94

canagliflozin vs sitagliptin

3

808

809

1.29 [0.82, 2.03]

0.28

30

canagliflozin vs glimepiride

1

480

480

0.15 [0.10, 0.22]

<0.00001

UTIs

canagliflozin vs placebo

8

1298

1113

1.19 [0.82, 1.73]

0.36

0

canagliflozin vs active agents

4

1294

1290

1.18 [0.84, 1.64]

0.34

0

canagliflozin vs sitagliptin

3

809

809

1.05 [0.68, 1.61]

0.83

0

canagliflozin vs glimepiride

1

485

482

1.40 [0.82, 2.38]

0.21

Genital mycotic infections

canagliflozin vs placebo

8

740

598

3.76 [2.23, 6.35]

<0.00001

0

canagliflozin vs active agents

4

1257

1253

4.95 [3.25, 7.52]

<0.00001

0

canagliflozin vs sitagliptin

3

772

771

4.20 [2.51, 7.03]

<0.00001

1

canagliflozin vs glimepiride

1

485

482

6.52 [3.14, 13.52]

<0.00001

0

ap<0.05, there was a statistical significance between two groups

Blood pressure

Compared with placebo, treatment with canagliflozin produced a significant higher reduction in systolic blood pressure (SBP) (WMD −5.05, 95 %CI [−6.81 to −3.28], p < 0.00001) (Supplementary Fig. 6 and Table 2) and diastolic blood pressure (DBP) (WMD −2.43, 95 %CI [−3.29 to −1.57], p < 0.0001) (Supplementary Fig. 8 and Table 2).

When compared with other antidiabetic agents, canagliflozin provided higher reduction in SBP by −4.34 mmHg (WMD, 95 %CI [−5.31 to −3.36], p < 0.00001) (Supplementary Fig. 7 and Table 2). For DBP, significant higher reductions were also seen in canagliflozin group (WMD −2.17, 95 %CI [−2.79 to −1.54], p < 0.00001) (Supplementary Fig. 9 and Table 2).

Plasma lipids

Compared with placebo, treatment with canagliflozin was associated with a significant increase in LDL-C levels (WMD 0.16, 95 %CI [0.08 to 0.24], p < 0.0001) (Supplementary Fig. 10) and HDL-C levels (WMD 3.15, 95 %CI [2.21 to 4.18], p < 0.00001), a decrease in triglycerides levels (WMD −10.84, 95 %CI [−17.07 to −4.62], p = 0.0006); no significant difference was seen with canagliflozin in LDL-C/HDL-C ratio compared to placebo (WMD −0.00, 95 %CI [−0.07 to 0.07], p = 0.95) (Supplementary Table 2).

No significant differences were seen in plasma lipids levels between canagliflozin and sitagliptin in our meta-analysis (all p > 0.05) (Supplementary Table 2). Canagliflozin relative to glimepiride was associated with an increase in LDL-C (WMD 0.20, 95 %CI [0.09 to 0.31], p = 0.0004) (Supplementary Fig. 11) and HDL-C levels (WMD 0.11, 95 %CI [0.08 to 0.14], p < 0.00001); a similar decreases in triglycerides levels (WMD −0.09, 95 %CI [ −0.23 to 0.05], p = 0.2), with smaller increases in LDL-C/HDL-C ratio (WMD −0.03, 95 %CI [−0.11 to 0.05], p = 0.48) across groups (Supplementary Table 2).

Overall AEs

Hypoglycemia

Incidence of hypoglycemia was low in most treatment groups, no severe hypoglycemic events reported in most studies. The risk of hypoglycemia with canagliflozin 300 mg was similar with that of placebo when used as monotherapy or an add-on treatment to metformin (RR 1.13, 95 %CI [0.40 to 3.20], p = 0.81) (Fig. 4). However, incidence of hypoglycemia was higher with canagliflozin than with placebo among patients receiving a sulfonylurea or insulin as background therapy or allocation treatment (RR 1.49, 95 %CI [1.14 to 1.95], p = 0.004) (Fig. 4).
Fig. 4

Meta-analysis for incidence of hypoglycemia, canagliflozin versus placebo

When compared canagliflozin with sitagliptin, there was no significant difference in all types of hypoglycemia between two groups (RR 1.29, 95 %CI [ 0.82 to 2.03], p = 0.28) (Fig. 5). In the RCT comparing canagliflozin to glimepiride [26], the hypoglycemic rates were significantly lower with canagliflozin 100 mg (6 %) and 300 mg (5 %) than with glimepiride (34 %) (p < 0.0001 for both). The frequency of severe hypoglycemia was also lower with canagliflozin (<1 % for both doses) than with glimepiride (3 %). The pooled RR of hypoglycemia of canagliflozin relative to glimepiride was 0.15 (95 %CI [0.10 to 0.22], p < 0.00001) (Fig. 5).
Fig. 5

Meta-analysis for incidence of hypoglycemia, canagliflozin versus active comparator

Urinary tract infections and genital tract infections

Overall, there was no significant difference in the rate of urinary tract infections (UTIs) when compared canagliflozin with placebo or other antidiabetic agents, the pooled RRs were 1.19(95 %CI [0.82 to 1.73], p = 0.36) and 1.18 (95 %CI [0.84 to 1.64], p = 0.34), respectively (Table 2). However, a significant increase, with a non-dose-dependent manner, was seen in canagliflozin group in the incidence of genital tract infections (vs. placebo, RR 3.76, 95 %CI [2.23 to 6.35], p < 0.00001; vs. active comparators, RR 4.95, 95 %CI [3.25 to 7.52], p < 0.00001) (Table 2).

The overall incidence of genital mycotic infections with canagliflozin was higher in female than in male. In all cases, the reported UTIs and genital tract infections were not severe and could be resolved with simple treatment.

Other adverse events

Compared with placebo or active comparator, the incidence of any AE, serious AEs or discontinuation due to AEs did not differ between the two groups (all p > 0.05) (Supplementary Table 3). However, the risks of osmotic diuresis-related AEs (ie., pollakiuria and diarrhea) were slightly higher with canagliflozin (vs. placebo, RR 3.93, 95 %CI [2.25 to 6.86], p < 0.00001; vs. active comparators, RR 2.57, 95 %CI [1.26 to 5.25], p = 0.009). Volume-related AEs (ie., postural dizziness, orthostatic hypotension) were similar among patients treated with canagliflozin and those receiving placebo or active comparator (all p > 0.05) (Supplementary Table 3).

Discussion

In this systematic review, we mainly evaluated the efficacy and safety of canagliflozin in patients with T2DM. Compared with placebo, canagliflozin significantly lowered HbA1c levels, which were consistent with the results reported in previous meta-analyses [14]. Canagliflozin also showed statistical superiority to other antidiabetic agents in HbA1c-lowering effect. Of the studies that reported sitagliptin or glimepiride, both two drugs had clinical glucose-lowering ability in patients with T2DM [2], our results indicated that canagliflozin provided meaningful clinical value in this patient population. Canagliflozin provided significantly greater reductions in FPG compared with all comparators when used as monotherapy or add-on therapy.

In addition to improved glycemic efficacy, treatment with canagliflozin was also associated with significant decreases in body weight. Many patients with T2DM are overweight or obese [27], while antidiabetic agents like sulfonylureas lead to increases in body weight which may enhance the risk of cardiovascular events [28, 29]. In our results, canagliflozin significantly lowered body weight compared with all comparators. The most likely mechanism of weight loss is the caloric losses related to renal glucose wasting [30]. Reductions in body weight with canagliflozin were clinically useful, particularly in the setting of obese patients among whom available oral AHAs are limited.

In this meta-analysis, canagliflozin provided significant and clinically meaningful improvements in β-cell function in terms of HOMA2-%β, and weight loss may contribute to this observation [31]. Canagliflozin was also associated with greater reductions in systolic and diastolic BP relative to all comparators. The mechanism by which canagliflozin reduces blood pressure is thought to be related to the osmotic diuretic effect associated with the increased RTG [32]. In terms of plasma lipids, canagliflozin therapy vs. placebo was associated with a significant increase in HDL-C, a decrease in triglycerides as well as an increase in LDL-C levels. Mechanism of the increased LDL-C with canagliflozin might be related to the increased excretion of glucose, as well as moderate hemoconcentration due to the osmotic diuretic effect [33]. Long-term impacts of increased LDL-C levels remained to be determined with additional planned analyses of plasma lipids.

Prior studies have shown that the RTG is decreased to 80 to 90 mg/dL with canagliflozin treatment [17, 34], which is above the usual threshold for hypoglycemia (<72 mg/dL) [35]. Thus, the incidence of hypoglycemia with canagliflozin is expected to be low. In our meta-analysis, risk of hypoglycemia with canagliflozin was similar to that of placebo when used as monotherapy or an allocation to metformin. However, canagliflozin led to higher incidences of hypoglycemia compared with placebo among patients on background therapy with a sulfonylurea or insulin. In this analysis, canagliflozin relative to glimepiride led to lower risk of hypoglycemia. The ADA guidelines emphasize that prevention of hypoglycemia should be considered when selecting a drug [27]. As a precaution, reduction of the dose of an insulin or sulfonylurea if adding a SGLT2 inhibitor might be appropriate.

Adverse events were evaluated in all RCTs included in this systematic reviews. Treatment with canagliflozin was well tolerated in most trials; most AEs of canagliflozin were transient, mild to moderate in intensity, and led to few discontinuations. Serious AEs incidences were similar across treatment groups. The AEs associated with SGLT2 inhibition, including genital mycotic infections, a small increase in UTIs (with no statistical significance) and AEs-related osmotic diuresis, were also seen in our results and consistent with previous meta-analysis [12, 14]. Canagliflozin relative to placebo increased the incidence of renal-related AEs in subjects with moderate renal impairment [36]; patients with mild to moderate renal insufficiency should monitor kidney function and adjust the dosage.

The glucose reduction, weight loss, blood pressure decrease, and effects on plasma lipid levels with canagliflozin, could each influence the incidence of cardiovascular events [37]. The CANVAS study [38] was started primarily to capture major adverse cardiac events with canagliflozin as add-on to normal care in 4,400 patients for more than 4 years; the effects of canagliflozin on cardiovascular risk are to be anticipated within the next few years.

Limitations of studies reviewed

This study had several potential limitations. First, durations of studies included in this meta-analysis were mostly 26 weeks, study period is insufficient, and longer duration of observation is needed to understand the long-term benefits and risks of canagliflozin. Second, only one glimepiride-controlled RCT and three sitagliptin-controlled RCTs were included in this study, more trials with active agents will help to judge the relative therapeutic effect of canagliflozin. Third, we did not assess the cancer risk or liver toxicity of canagliflozin; however, data on blander and breast cancer and liver toxicity could be retrieved from FDA reports [36]. Finally, because of considerable heterogeneity in our primary outcomes, to examine the contribution of participants’ baseline characteristics (ie., baseline HbA1c, duration of treatment) with sensitivity analyses or meta-regression is needed.

Conclusion

Treatment with canagliflozin provided clinically and statistically significant reductions in HbA1c levels in patients with T2DM. These effects were associated with significant improvements in FPG levels, body weight as well as β-cell function. However, due to the higher rates of genital infections, increase in LDL-C levels and unclear cardiovascular risks, careful patient selection, and ongoing monitoring will be important.

Notes

Conflict of interest

The authors have nothing to disclose

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Xu-Ping Yang
    • 1
  • Dan Lai
    • 2
  • Xiao-Yan Zhong
    • 4
  • Hong-Ping Shen
    • 1
  • Yi-Lan Huang
    • 3
  1. 1.Department of PharmacyThe TCM Hospital Affiliated to Luzhou Medical CollegeLuzhouPeople’s Republic of China
  2. 2.Department of ENTThe Affiliated Hospital of Luzhou Medical CollegeLuzhouPeople’s Republic of China
  3. 3.Department of PharmacyThe Affiliated Hospital of Luzhou Medical CollegeLuzhouPeople’s Republic of China
  4. 4.College of PharmacyLuzhou Medical CollegeLuzhouPeople’s Republic of China

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