The Lancet SEPTEMBER 14, 2013

Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial

Cefalu WT, Leiter LA, Yoon KH, et al.

Bottom Line

In this 52-week non-inferiority trial, canagliflozin 100 mg was non-inferior and 300 mg was superior to glimepiride in reducing HbA1c levels in patients with type 2 diabetes inadequately controlled on metformin.

Key Findings

1. At 52 weeks, canagliflozin 100 mg demonstrated non-inferiority to glimepiride for HbA1c reduction (least-squares mean difference of -0.01%, 95% CI -0.11 to 0.09).

2. Canagliflozin 300 mg showed superiority to glimepiride in HbA1c reduction (least-squares mean difference of -0.12%, 95% CI -0.22 to -0.02).

3. Canagliflozin treatment resulted in greater weight loss (3.7 kg and 4.0 kg for 100 mg and 300 mg doses, respectively) compared to a 0.7 kg weight gain in the glimepiride group.

4. Documented hypoglycemia was less frequent in the canagliflozin arms compared to the glimepiride arm, which required titration up to 6–8 mg.

5. Canagliflozin was associated with higher rates of genital mycotic infections (e.g., 11-14% in women vs 2% for glimepiride) and osmotic diuresis-related events compared to glimepiride.

Study Design

Design

RCT

Double-Blind

Sample

1,450

Patients

Duration

52 wk

Median

Setting

Multicenter, 19 countries

Population Adults aged 18-80 years with type 2 diabetes and HbA1c of 7.0-9.5% on stable metformin therapy.

Intervention Canagliflozin 100 mg or 300 mg administered once daily.

Comparator Glimepiride (up-titrated to 6-8 mg per day).

Outcome Change in HbA1c from baseline to week 52.

Study Limitations

• The study was limited to a 52-week duration, which may not capture long-term durability of glycemic control or rare long-term adverse events.

• The increased incidence of genital mycotic infections and urinary tract infections with SGLT2 inhibition remains a notable safety concern in this population.

• The trial was industry-funded, which may introduce potential biases in design and interpretation.

• The open-ended titration of glimepiride (up to 8 mg) may have contributed to a higher rate of hypoglycemia in the comparator arm, potentially accentuating the perceived safety advantage of canagliflozin.

Clinical Significance

The results established canagliflozin as an effective oral second-line therapy for type 2 diabetes in patients failing metformin, offering the distinct clinical advantages of weight reduction and a lower risk of hypoglycemia compared to traditional sulfonylurea therapy.

Historical Context

Published shortly after the initial approval of the SGLT2 inhibitor class, this trial was pivotal in positioning canagliflozin as a competitive alternative to sulfonylureas in the treatment algorithm for type 2 diabetes by demonstrating both glycemic efficacy and favorable secondary outcomes like weight loss.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How do the mechanisms of action for canagliflozin and glimepiride differ in their effect on insulin secretion and glucose excretion, and how does this explain the difference in hypoglycemia risk observed in the CANTATA-SU trial?

Key Response

Canagliflozin is an SGLT2 inhibitor that promotes glucose excretion in the urine by blocking reabsorption in the proximal tubule, a process that is insulin-independent and glucose-dependent (efficacy diminishes as blood sugar normalizes). In contrast, glimepiride is a sulfonylurea that stimulates insulin secretion from pancreatic beta cells regardless of ambient glucose levels. This fundamental difference explains why canagliflozin has a significantly lower risk of hypoglycemia compared to the 'secretagogue' effect of glimepiride.

Resident

In a patient with type 2 diabetes inadequately controlled on metformin, what clinical factors beyond HbA1c reduction—as highlighted by the secondary endpoints of CANTATA-SU—would favor the selection of canagliflozin over glimepiride?

Key Response

While both agents reduce HbA1c, CANTATA-SU demonstrated that canagliflozin leads to significant weight loss and lower blood pressure, whereas glimepiride is associated with weight gain. For residents managing patients with the metabolic syndrome, the 'weight-neutral or weight-loss' profile of SGLT2 inhibitors provides a clear clinical advantage over the weight gain typically seen with sulfonylureas, aiding in the management of comorbid hypertension and obesity.

Fellow

The CANTATA-SU trial showed a diverging HbA1c curve between canagliflozin and glimepiride toward the 52-week mark. How does this relate to the concept of 'beta-cell exhaustion' and the durability of glycemic control between SGLT2 inhibitors and sulfonylureas?

Key Response

Sulfonylureas often show a 'secondary failure' where initial glycemic gains are lost as beta-cell function continues to decline, partly due to the strain of forced insulin secretion. SGLT2 inhibitors provide 'glucose-lowering' without taxing the beta cells (and potentially reducing glucotoxicity), which may lead to more durable glycemic control over time. The 52-week data in CANTATA-SU showed canagliflozin 300 mg was superior, suggesting better sustainability of effect compared to the waning efficacy often seen with glimepiride.

Attending

Considering the results of CANTATA-SU alongside later cardiovascular outcome trials (CVOTs), how has the value proposition of 'metformin + sulfonylurea' shifted for the modern practitioner when cost is not the primary barrier?

Key Response

CANTATA-SU established that canagliflozin 300mg is not just non-inferior but superior to glimepiride in glycemic control with better safety (less hypoglycemia/weight gain). When integrated with later data (like CANVAS) showing CV and renal protection, the 'standard' second-line add-on of a sulfonylurea is increasingly difficult to justify clinically. This trial was a pivotal step in moving the treatment paradigm from 'glucose-centric' to 'organ-protective and safety-centric' management.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The trial employed a fixed-dose regimen for canagliflozin but allowed titration for glimepiride (up to 6 or 8 mg). How does this asymmetric dosing design affect the interpretation of the non-inferiority margin and the subsequent claim of superiority for the 300 mg canagliflozin dose?

Key Response

Titrating the comparator (glimepiride) to 'maximum tolerated dose' creates a rigorous 'active-control' benchmark. However, because glimepiride titration is limited by hypoglycemia, the 'superiority' of canagliflozin 300 mg reflects not just potency but a wider therapeutic index. Methodologically, the PhD must consider if the 0.3% non-inferiority margin is sufficiently stringent given that a fixed-dose SGLT2i was being compared against an optimized, patient-specific dose of a potent agent.

Journal Editor

What are the implications of the differential dropout rates between the treatment arms—specifically the higher discontinuation rate in the glimepiride group due to lack of efficacy—on the trial's Intention-to-Treat (ITT) versus Per-Protocol analysis?

Key Response

In non-inferiority trials, an ITT analysis can be 'anti-conservative' (biasing results toward non-inferiority by diluting treatment differences). If more patients in the glimepiride arm dropped out due to treatment failure or hypoglycemia, the last-observation-carried-forward (LOCF) method or other imputation strategies could mask the true extent of canagliflozin's superiority. A tough reviewer would demand a sensitivity analysis to ensure that the superiority of the 300mg dose holds up under various missing-data assumptions.

Guideline Committee

Based on the 52-week CANTATA-SU data, should the preference for SGLT2 inhibitors over Sulfonylureas be upgraded in clinical guidelines for patients without established ASCVD or CKD, and how does this impact the 'Grade of Recommendation'?

Key Response

Current ADA Standards of Care prioritize SGLT2 inhibitors (Level A) primarily for patients with CKD/HF/ASCVD. However, CANTATA-SU provides high-quality (Level A) evidence that even for general glycemic management, SGLT2 inhibitors offer superior efficacy (at 300mg), better weight profiles, and significantly lower hypoglycemia risk compared to the previous standard (Sulfonylureas). The committee must weigh these clinical benefits against the higher cost of SGLT2 inhibitors to determine if they should be the 'preferred' second-line agent for all patients.

Clinical Landscape

Noteworthy Related Trials

1998

UKPDS 33

n = 3,867 · Lancet

Tested

Intensive blood-glucose control with sulfonylureas or insulin

Population

Newly diagnosed T2DM patients

Comparator

Conventional therapy

Endpoint

Diabetes-related endpoints

Key result: Intensive glucose control with sulfonylureas significantly reduced the risk of microvascular complications in patients with type 2 diabetes.

2015

EMPA-REG OUTCOME Trial

n = 7,020 · NEJM

Tested

Empagliflozin

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Empagliflozin significantly reduced the risk of cardiovascular death and hospitalization for heart failure.

2017

CANVAS Program

n = 10,142 · NEJM

Tested

Canagliflozin

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Canagliflozin demonstrated a reduction in the risk of cardiovascular events and heart failure hospitalizations.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis