Canagliflozin and cardiovascular outcomes in Type 2 diabetes

Abstract

SGLT2 inhibitors have risen to prominence in recent years as Type 2 diabetes mellitus medications with favorable effects on cardiovascular (CV) and renal outcomes. Canagliflozin is a US FDA-approved SGLT2 inhibitor that has demonstrated CV and renal outcome benefits in large scale placebo-controlled randomized trials of patients with Type 2 diabetes mellitus and elevated CV risk. Canagliflozin use may also be associated with serious and nonserious adverse effects requiring ongoing monitoring in patients initiated on this medication. This paper provides a detailed overview of canagliflozin including its pharmacologic profile, clinical efficacy and safety data, with discussion of both clinical trial results, as well as real-world evidence.

Type 2 diabetes mellitus (T2DM) is a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). In the Framingham Heart Study, it was associated with a two to threefold increase in the risk of cardiovascular (CV) disease and congestive heart failure (HF) [1]. It is estimated that approximately 12% of adults in USA have diabetes, predominantly T2DM. The 2018 American College of Cardiology/American Heart Association Multi-society guidelines for the primary prevention of ASCVD recommend an aggressive multidimensional approach in patients with T2DM for ASCVD event reduction [2]. Notably, the relationship between intensive glucose lowering and CV event reduction in T2DM has traditionally been uncertain [3]. Metformin demonstrated favorable effects on CV events in the UK Prospective Diabetes Study; on the other hand, large-scale randomized studies found no improvement in CV events with intensive glucose control [4–7]. ASCVD risk reduction in T2DM patients has thus relied strongly on risk factor control beyond glycemic control alone, including lifestyle measures, lipid control including statin therapy and hypertension management.

Recently, SGLT2 inhibitors have been demonstrated to reduce CV events in T2DM patients with elevated risk of ASCVD [8–11]. Canagliflozin is an SGLT2 inhibitor that was the first in-class medication approved by the US FDA for improved glycemic control in T2DM as an adjunct to diet and exercise, and subsequently for major CV event reduction in adults with T2DM and ASCVD [12]. Most recently, canagliflozin was approved for renal outcome benefit and reduction in heart failure (HF) hospitalizations in those with T2DM and diabetic kidney disease (DKD), representing the first medication approved for renoprotection in T2DM since renin–angiotensin blockade agents [10,13]. This review will therefore focus on the therapeutic profile of canagliflozin in detail, including pharmacologic effects, associated clinical trial and real-world evidence, areas for additional study and overall implications for diabetes care with a focus on CV outcomes.

Overview of the field

Ischemic heart disease – a predominant type of ASCVD – is the primary cause of death in T2DM patients; CV event reduction is therefore a key aspect of T2DM management [14]. In addition, T2DM is a leading cause of incident end-stage renal disease, and traditional CKD mitigation strategies in T2DM were centered largely on renin-angiotensin blockade agents [10]. Several SGLT2 inhibitors – empagliflozin, canagliflozin, and dapagliflozin – have been associated with reduction in adverse CV events in large contemporary randomized clinical trials and represent an important addition to the T2DM therapy landscape.

Our understanding of the full scope of SGLT2 inhibitor treatment effects is currently evolving. For instance, in addition to CV event reduction, canagliflozin has also been demonstrated to decrease renal events (including a renal-specific composite outcome of end-stage renal disease, doubling of serum creatinine and death from renal causes) in patients with T2DM and DKD, with benefits preserved across the spectrum of glycated hemoglobin (HgbA1c) levels, including less than 7% [15]. Recently, dapagliflozin has been shown to reduce CV deaths and heart failure events in patients with symptomatic heart failure (HF) with reduced ejection fraction, both with and without T2DM [16]. Thus, there is strong contemporary interest in understanding the full range of SGLT2 inhibitor effects in T2DM, gaining mechanistic insight into their CV reduction effects, and exploring their role for CV benefit at the population level.

Introduction to the compound

Based on several Phase III clinical trials demonstrating reduction in HgbA1c, canagliflozin was the first SGLT2 inhibitor approved by the FDA to lower blood glucose in addition to diet and exercise in patients with T2DM [17]. Subsequently, large-scale clinical trials demonstrated that canagliflozin use resulted in reduced CV and renal events in certain patients with T2DM. For example, in the CANVAS Program Analysis trial of over 10,000 patients with T2DM and either established CV disease or high CV risk, canagliflozin use resulted in reduced CV events compared with placebo [9]. The CREDENCE trial subsequently demonstrated that canagliflozin use reduced renal events compared with placebo in patients with T2DM and DKD [10]. Canagliflozin has since been approved by the FDA for use in selected patients with T2DM [12,13]. The remainder of this review outlines the clinical efficacy and safety profiles, important clinical trial and real-world evidence data and the current regulatory landscape of canagliflozin in further detail.

Pharmacology

Chemistry

Based on its chemical structure, canagliflozin is classified as a C-glucoside compound with a thiophene ring, and an organofluorine compound. It is used in its hemihydrate form as an orally available SGLT2 inhibitor. Its International Union of Pure and Applied Chemistry (IUPAC) name is (1S)-1,5-anhydro-1-(3-[5-(4-fluorophenyl)-2-thienyl]methyl-4-methylphenyl)-D-glucitol [18,19].

Pharmacodynamics & mechanisms of action

SGLT2 is a membrane protein largely expressed in the proximal tubule of the nephron, mediating approximately 90% of renal glucose reabsorption [20,21]. SGLT2 inhibitors, including canagliflozin, result in renal glucose excretion and consequent osmotic diuresis, which is thought to be responsible for their blood glucose and glycated hemoglobin lowering effects – notably representing an insulin-independent mechanism. It has been estimated that SGLT2 inhibitors increase renal glucose excretion by 60–100 g per day [22]. Canagliflozin is selective for SGLT2 compared with SGLT1, though less selective compared with other SGLT2 inhibitors [23]. SGLT1 is largely expressed in the small intestine, facilitating glucose and galactose reabsorption [21].

In addition to promoting glucose excretion, SGLT2 inhibitors may also decrease single-nephron glomerular filtration rates and intraglomerular pressures similar to renin-angiotensin system inhibiting agents, which may contribute to their renoprotective effects. They have been associated with effective natriuresis through inhibition of sodium-hydrogen exchanger-3, and synergistic natriuretic effects with loop diuretics [24]. Several additional mechanisms for renoprotection have been proposed including favorable effects on plasma uric acid level and systemic blood pressure [25]. Similarly, from a cardioprotection standpoint, there are accumulating data pointing to potential mechanisms of benefit. Several effects outlined above, including systemic blood pressure lowering, weight lowering and effective natriuresis, represent favorable outcomes on upstream mediators of cardiometabolic health. Furthermore, SGLT2i have been shown to limit vascular smooth muscle cell proliferation and migration in vitro, decrease vascular reactive oxygen species, protect endothelial function and improve arterial stiffness [26,27]. There may be pleiotropic mechanisms by which SGLT2i exert their notable cardioprotective and renoprotective effects.

Pharmacokinetics

The average bioavailability of canagliflozin is approximately 65%. Steady-state concentrations are achieved after four to five daily doses between the range of 100–300 mg [28]. Subsequently, canagliflozin undergoes O-glucuronidation to two inactive metabolites, which are renally excreted. Of note, there is minimal CYP3A4-mediated metabolism in humans [18]. In patients with estimated glomerular filtration rates of 60 ml/minute/1.73 m² or higher, canagliflozin may be dosed up to 300-mg once daily [12]. For those with eGFRs 45 to <60, it is dosed at 100-mg once daily. In the presence of urinary albumin excretion greater than 300 mg a day, the 100-mg dose may also be used with eGFR of 30 to <45 ml/min/1.73 m², in accordance with CREDENCE trial criteria [10]. Canagliflozin use is currently not recommended if eGFR <30 ml/min/1.72 m², for patients with end-stage renal dialysis, or for those on dialysis [12].

Clinical efficacy

Glycemic control

While glycemic control is not the focus of this review, it is helpful to note that canagliflozin initially demonstrated glycemic control efficacy in T2DM as monotherapy as well as add-on therapy in Phase II and Phase III clinical trials that examined intermediate end points including glucose control and body weight reduction [17,21,29–34]. For example, in the CANTATA-SU trial of 1452 patients, canagliflozin demonstrated greater hemoglobin A1c reduction compared with glimepiride as add-on therapy to metformin. Canagliflozin demonstrated improved glycemic trial compared with placebo when added to metformin and pioglitazone in a trial of 342 patients [31,32]. In addition, canagliflozin monotherapy demonstrated body weight and systolic BP reduction compared with placebo in the CANTATA-M study over a 52-week follow-up period [33].

Cardiovascular outcomes

The CANVAS Program analysis was a large Phase III trial that consisted of two similarly designed, multicenter, double-blind, randomized clinical trials (CANVAS and CANVAS-R) [9]. A total of 10,142 patients were randomized in 1:1:1 fashion to canagliflozin 300 mg daily, canagliflozin 100 mg daily or matching placebo, with a primary composite outcome consisting of death from CV causes, nonfatal MI and nonfatal stroke. After a median follow-up period of 126.1 weeks, canagliflozin use resulted in glycated hemoglobin change of -0.58% (95% CI: -0.61 to -0.56), systolic blood pressure change of -3.93 mmHg (95% CI: -4.3 to -3.56) and body weight change of -1.6 kg (95% CI: -1.7 to -1.51). The canagliflozin group had fewer primary outcome events compared with placebo (hazard ratio [HR] 0.86; 95% CI: 0.75–0.97) (Table 1). Canagliflozin also had a lower incidence of selected exploratory secondary outcomes – including hospitalization for HF (HR: 0.67; 95% CI: 0.52–0.87) and a composite renal end point including 40% reduction in eGFR, renal replacement therapy or renal death (HR: 0.60; 95% CI: 0.47–0.77) – though these findings were not considered statistically significant on the basis of the prespecified hypothesis testing sequence.

Table 1. . Summary of selected cardiovascular and renal efficacy outcomes from the CANVAS program analysis.

Outcome	Hazard ratio (95% CI) for canagliflozin vs placebo
Death from CV causes, nonfatal myocardial infarction or nonfatal stroke (primary outcome)	0.86 (0.75–0.97)
Death from CV causes	0.87 (0.72–1.06)
Death from any cause	0.87 (0.74–1.01)
Nonfatal myocardial infarction	0.85 (0.69–1.05)
Nonfatal stroke	0.90 (0.71–1.15)
Hospitalization for heart failure	0.67 (0.52–0.87)
40% reduction in estimated glomerular filtration rate, renal-replacement therapy or renal death	0.60 (0.47–0.77)
Progression of albuminuria	0.73 (0.67–0.79)

CV: Cardiovascular.

Recently, the CREDENCE trial randomly assigned 4401 patients with T2DM and chronic kidney disease to canagliflozin 100 mg daily or matching placebo to examine renal outcomes [10]. The primary outcome was a composite of end-stage kidney disease, doubling of the serum creatinine level, or death from renal or CV causes (Table 2). After a median follow-up period of 2.62 years, the canagliflozin group experienced a lower frequency of the primary composite outcome compared with the placebo group (HR: 0.70; 95% CI: 0.59–0.82). Hospitalization for HF (HR: 0.611; 95% CI: 0.47–0.80), and risk of CV death, nonfatal MI and nonfatal stroke (0.80; 95% CI: 0.67–0.95) were less frequent in the canagliflozin group.

Table 2. . Summary of selected cardiovascular and renal efficacy outcomes from the CREDENCE trial.

Outcome	Hazard ratio (95% CI) for canagliflozin vs placebo
End-stage kidney disease, doubling of serum creatinine level, or renal or CV death (primary outcome)	0.70 (0.59–0.82)
Doubling of serum creatinine level	0.60 (0.48–0.76)
End-stage kidney disease	0.68 (0.54–0.86)
CV death	0.78 (0.61–1.00)
CV death or hospitalization for HF	0.69 (0.57–0.83)
CV death, nonfatal myocardial infarction or nonfatal stroke	0.80 (0.67–0.95)
Hospitalization for HF	0.61 (0.47–0.80)
End-stage kidney disease, doubling of serum creatinine level or renal death	0.66 (0.53–0.81)
Death from any cause	0.83 (0.68–1.02)

CV: Cardiovascular; HF: Heart failure.

There are accumulating data suggesting that SGLT2 inhibitor benefits may be independent of glycemic status. An analysis of CREDENCE data showed that renal and CV outcome benefits of canagliflozin in patients with T2DM and CKD were preserved independent of baseline hemoglobin A1c, including less than 7% [15]. In the contemporary DAPA-HF trial, dapaglifozin resulted in favorable cardiovascular outcomes in patients with heart failure with reduced ejection fraction (HFrEF), both with and without diabetes [16]. At the time of this review, based on available trial data, canagliflozin may be the preferred agent in patients with T2DM and CKD independent of baseline hemoglobin A1c. Dapagliflozin may be the agent of choice for patients with heart failure with reduced ejection fraction and no diabetes at baseline. Ongoing and future analyses will allow definitive determination of whether dapagliflozin benefits with HFrEF or canagliflozin benefits with T2DM and CKD are class-wide or agent-specific effects. Based on the body of RCT evidence currently available regarding cardiovascular efficacy, SGLT2 inhibitors should likely be considered a first-line agent for patients with diabetes on par with traditional agents such as metformin. In certain clinical situations, they should be used preferentially over metformin based on clinical trial data – such as canagliflozin for renoprotection and HF hospitalization reduction in patients with T2DM and CKD; or dapagliflozin as add-on therapy for HFrEF with or without diabetes.

Real-world evidence

Robust contemporary real-world data have demonstrated CV outcome benefit from SGLT2 inhibitor use, including canagliflozin. The Comparative Effectiveness of Cardiovascular Outcomes (CVD-REAL) study included a total of 309,056 propensity-score matched patients from Denmark, Norway, Sweden and USA who were starting an SGLT2 inhibitor versus other glucose-lowering drugs. Canagliflozin accounted for 53, 42 and 45% of the total SGLT2 inhibitor exposure time for the outcomes of hospitalization for HF, all-cause death and the composite of hospitalization for HF and all-cause death, respectively. Compared with other glucose-lowering drugs, SGLT2 inhibitors as a class were associated with a lower risk of hospitalization for HF (pooled HR: 0.61; 95% CI: 0.51–0.73), all-cause death (pooled HR: 0.49; 95% CI: 0.41–0.57) and the composite of hospitalization for HF or death (pooled HR: 0.54; 95% CI: 0.48–0.60) [35]. The follow-up CVD-REAL 2 study included 235,064 patients from Asia–Pacific, the Middle East and North America, and found that SGLT2 inhibitor initiation – compared with other glucose-lowering drugs – was associated with a lower risk of a range of CV outcomes including MI (HR: 0.81; 95% CI: 0.74–0.88), stroke (HR: 0.68; 95% CI: 0.55–0.84), hospitalization for HF (HR: 0.64; 95% CI: 0.74–0.88) and death (HR: 0.51; 95% CI: 0.37–0.70) [36]. More recently, the CVD-REAL-3 study of 65,321 patients from Israel, Italy, Japan, Taiwan and the UK found lower rates of renal function decline in the SGLT2-inhibitor group compared with other glucose-lowering drugs [37].

Additionally, in an analysis of four large US databases, canagliflozin was associated with decreased risk of heart failure hospitalizations in the on-treatment analysis (HR: 0.39; 95% CI: 0.26–0.60) compared with non-SGLT2 inhibitor therapy. No statistically significant difference was observed for efficacy when comparing other with SGLT2-inhibitors or for limb amputations between canagliflozin versus non SLGT2 inhibitor therapy [38]. In a Department of Defense Military Health System cohort analysis of 15,395 propensity-matched new users of canagliflozin versus non SGLT2-inhibitor anti-hyperglycemic therapy (except for metformin) with T2DM cardiovascular disease, canagliflozin was associated with decreased risk of a composite outcome of all-cause mortality and hospitalization for heart failure (HR: 0.61; 95% CI: 0.53–0.71). Few amputations were observed overall, and no statistically significant increase was seen in the canagliflozin group (HR: 1.44; 95% CI: 0.82–2.52) [39].

From a cost standpoint, in secondary analysis of two databases – Truven and Optum – the per-patient-per-month cost for heart failure hospitalizations was $21.31 lower and $30.43 lower respectively for patients taking canagliflozin versus a non SGLT-2 inhibitor glucose lowering medication [3].

Safety & tolerability

The CANVAS Program and the observational EASEL study found an increased risk of below the knee amputations with canagliflozin compared with placebo and non-SGLT2 inhibitor glucose-lowering therapy, respectively (Table 3) [9,39]. Amputations were mainly minor, and risk for amputation was associated with expected risk factors including prior history of amputation, peripheral vascular disease, and neuropathy [40]. Conversely, a real-world study that included 73,024 new canagliflozin users from the Truven MarketScan database found no evidence of increased below-the-knee amputation with canagliflozin use compared with non-SGLT2 inhibitor agents [41]. Analysis of 4 large claims databases including 142,800 new canagliflozin users demonstrated no increased risk of below-the-knee amputations compared with non SGLT2 inhibitor agents [38]. Reassuringly, increased amputation risk with canagliflozin was not observed in the CREDENCE trial, despite a potentially higher risk population for amputations (Table 4) [10]. Of note, the placebo group in the CREDENCE trial demonstrated a higher rate of amputations compared with the placebo group from the CANVAS Program Analysis (11.2 per 1000 patient-years vs 3.4 per 1000 patient-years). Overall, while risk of amputations may not be as high in patients without additional risk factors, patients should be counseled and monitored while on canagliflozin – and canagliflozin use should likely be avoided in patients with additional risk factors such as existing foot ulceration, neuropathy or peripheral arterial disease. The FDA has included a black box warning for an increased risk of lower limb amputations as part of its labeling for canagliflozin.

Table 3. . Summary of selected safety outcomes from the CANVAS Program Analysis comprising of CANVAS and CANVAS-R trials.

Outcome	Events per 1000 patient-years		p-value
	Canagliflozin	Placebo
All serious adverse events	104.3	120.0	0.04
Diabetic ketoacidosis	0.6	0.3	0.14
Amputation	6.3	3.4	<0.001
All fractures	15.4	11.9	0.02
Low-trauma fractures	11.6	9.2	0.06
Male genital infections	34.9	10.8	<0.001
Osmotic diuresis (CANVAS only)	34.5	13.3	<0.001
Volume depletion (CANVAS only)	26	18.5	0.009
Acute kidney injury (CANVAS only)	3.0	4.1	0.33
Urinary tract infection (CANVAS only)	40.0	37.0	0.38
Female mycotic genital infection (CANVAS only)	68.8	17.5	<0.001

Table 4. . Summary of selected safety outcomes from CREDENCE.

Outcome	Events per 1000 patient-years		Hazard ratio (95% CI) for canagliflozin vs placebo
	Canagliflozin	Placebo
Any adverse event	351.4	379.3	0.87 (0.82–0.93)
Any serious adverse event	145.2	164.4	0.87 (0.79–0.97)
Serious adverse event related to trial drug	12.2	8.6	1.45 (0.98–2.14)
Amputation	12.3	11.2	1.11 (0.79–1.56)
Fracture	11.8	12.1	0.98 (0.70–1.37)
Acute kidney injury	16.9	20.0	0.85 (0.64–1.13)
Diabetic ketoacidosis	2.2	0.2	10.80 (1.39–83.65)

Of note, some data suggest that amputation risk may be related to an SGLT2 inhibitor class effect. In an analysis of the WHO global database of individual case safety reports (VigiBase), there were 79 reports of lower limb amputations among 31,495 reports associated with SGLT2 inhibitors. Empagliflozin and canagliflozin were associated with an elevated risk of lower limp amputations, and dapagliflozin with toe amputations [42].

The CREDENCE trial showed an increased risk of diabetic ketoacidosis (DKA) with canagliflozin as compared with placebo, with low overall rates (2.2 vs 0.2 per 1000 patient-years) [10]. CANVAS, on the other hand, did not demonstrate an increased risk of DKA with canagliflozin compared with placebo [9].

Other commonly reported adverse events in Phase II clinical trials of canagliflozin were genital mycotic infections (GMIs), urinary tract infections, osmotic diuresis, and volume depletion [21]. In the CANVAS Program Analysis, the canagliflozin group had more female GMIs (68.8 vs 17.5 events per 1000 patient-years, p < 0.001) and male GMIs (34.9 vs 10.8 events per 1000 patient-years, p < 0.001) compared with placebo. There was no increased risk of urinary tract infections with canagliflozin use in CANVAS. Osmotic diuresis (34.5 vs 13.1 per 1000 patient years, p < 0.001) and volume depletion (26 vs 18.5 per 1000 patient-years, p = 0.009) events occurred more frequently in the canagliflozin group compared with placebo in CANVAS. Prior retrospective study suggested an increased risk of acute renal failure with canagliflozin use [43]. However, there was no increased risk of acute kidney injury with canagliflozin use in both the CANVAS and CREDENCE trials [9,10].

Fractures have been previously reported with canagliflozin use [44]. In the CANVAS trial, patients taking canagliflozin had a higher frequency of fractures compared with placebo (15.4 vs 11.9 events per 1000 patient-years, p = 0.02), with evidence of heterogeneity between CANVAS and CANVAS-R in terms of fracture risk with canagliflozin versus placebo [9]. The implications of this safety outcome heterogeneity between the two trials in the CANVAS Program Analysis are unclear. Conversely, in the CREDENCE trial, canagliflozin use was not associated with an increased risk of fractures [10].

Regulatory affairs

In USA, based on data from Phase III trials demonstrating glycemic efficacy and interim data from CANVAS, the FDA approved canagliflozin in 2013 as an adjunct to diet and exercise to improve glycemic control in adults with T2DM (Tables 5 & 6). Following the completion of the CANVAS Program Analysis, canagliflozin was additionally approved to reduce the risk of major adverse CV events in adults with T2DM and established CV disease [12]. In 2019, based on CREDENCE trial data, canagliflozin was approved to decrease the risk of end-stage kidney disease, worsening kidney function, CV death and hospitalization for HF in patients with T2DM and albuminuric kidney disease [13].

Table 5. . FDA-approved indications for canagliflozin.

Year of label expansion	Indication
2013	Adjunct to diet and exercise to improve glycemic control in adults with T2DM
2018	To reduce risk of major adverse CV events in adults with T2DM and established CV disease
2019	To reduce risk of end-stage kidney disease, worsening kidney function, CV death and hospitalization for heart failure in patients with T2DM and albuminuric kidney disease

CV: Cardiovascular; T2DM: Type 2 diabetes mellitus.

Table 6.  . SGLT2 inhibitors approved by the US FDA for use in patients with Type 2 diabetes mellitus as of February 2020.

Generic name	Year(s) of initial FDA approval
Canagliflozin	2013
Empagliflozin	2014
Dapagliflozin	2014
Ertugliflozin	2017
Dapagliflozin/metformin extended release	2014
Canagliflozin/metformin and canagliflozin/metformin extended release	2014 and 2016 (extended release)
Empagliflozin/linagliptin	2015
Empagliflozin/metformin and empagliflozin/metformin extended release	2015 and 2016 (extended release)
Empagliflozin/linagliptin/metformin	2020

In Europe, canagliflozin was initially approved in 2013 by the European Medicines Agency (EMA) as an adjunct to diet and exercise in adults with T2DM, either as monotherapy if metformin is not appropriate or as add-on therapy [45]. The label was subsequently expanded in 2018 to include prevention of major CV events (CV death, nonfatal MI, and nonfatal stroke) in adults with T2DM and either a history of CV disease or at-least 2 CV risk factors [46].

Conclusion

Canagliflozin is an SGLT2 inhibitor that acts upon the proximal tubule in the kidneys to promote urinary glucose excretion. Phase III clinical trials have demonstrated its glycemic efficacy, blood pressure and weight reduction effects. Importantly, canagliflozin has proven CV outcome benefit in adults with T2DM with established CV disease or elevated risk for CV disease, along with renal and CV outcome benefit in patients with diabetic kidney disease. Canagliflozin may be associated with adverse events in selected patients and requires ongoing monitoring and patient counseling. Canagliflozin is currently approved by the US FDA for glycemic control in patients with T2DM, reduction of major adverse CV events in adults with T2DM and established CV disease, and reduction in adverse renal events and hospitalization for HF in adults with diabetic kidney disease.

Executive summary.

• Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular (CV) disease and chronic kidney disease.

• Canagliflozin is a SGLT2 inhibitor that has an emerging, potentially important role in the management of T2DM, including for CV and renal outcome benefit.

Pharmacology

• The SGLT2 receptor primarily acts to promote glucose reabsorption in the proximal tubule of the kidney

• Canagliflozin thus facilitates urinary glucose excretion, which is thought to be responsible for its glycemic efficacy.

• Canagliflozin may be dosed at either 100 mg or 300 mg once daily based on renal function and indication and is not recommended for patients with end-stage renal disease, dialysis dependence, or an estimated glomerular filtration rate less than 30 mg/min/1.73 m².

CV efficacy

• Contemporary large-scale placebo-controlled randomized trials have demonstrated CV and renal outcome benefit with canagliflozin use in patients with T2DM and established or elevated risk for CV disease, and in patients with T2DM and albuminuric kidney disease.

• In the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program Analysis of 10,142 patients with T2DM and established CV disease or elevated risk for CV disease, the canagliflozin group experienced a lower incidence of a composite outcome of CV death, nonfatal myocardial infarction (MI) and nonfatal stroke.

• In the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial of 4401 patients with T2DM and diabetic kidney disease, the canagliflozin group experienced a lower incidence of adverse renal events (composite of end-stage kidney disease, twofold increase in serum creatinine level, or death from CV or renal causes), and of hospitalization from heart failure.

Safety

• Canagliflozin increased the risk of lower limb amputation in the CANVAS Program Analysis, but not in the CREDENCE trial.

• The FDA label for canagliflozin carries a black box warning for limb amputation risk.

• Canagliflozin increases genital mycotic infections, osmotic diuresis and volume depletion based on clinical trial data.

Regulatory status

• Canagliflozin is approved by the US FDA for:

  • 1.Glycemic control as an adjunct to diet and exercise in adults with T2DM.
  • 2.Reduction of major adverse CV events in adults with T2DM and established CV disease or elevated CV disease risk.
  • 3.Reduction of adverse renal events and hospitalization for heart failure in patients with T2DM and albuminuric kidney disease.

• In Europe, canagliflozin is currently approved by the EMA for glycemic control and reduction of adverse CV events similar to indications 1 and 2 outlined above.