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

William T Cefalu, Lawrence A Leiter, Kun-Ho Yoon, Pablo Arias, Leo Niskanen, John Xie, Dainius A Balis, William Canovatchel, Gary Meininger

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Bottom Line

In patients with type 2 diabetes inadequately controlled on metformin, canagliflozin provided non-inferior to superior glycemic control compared to glimepiride, while simultaneously inducing weight loss and reducing the risk of hypoglycemia.

Key Findings

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

2. Canagliflozin 300 mg was statistically superior to glimepiride for HbA1c reduction (least-squares mean difference -0.12% [95% CI -0.22 to -0.02]).

3. Canagliflozin treatment resulted in significant weight loss (-3.7 kg for 100 mg and -4.0 kg for 300 mg) compared to a weight gain of +0.7 kg in the glimepiride group.

4. Documented hypoglycemia was significantly less frequent in the canagliflozin arms compared to the glimepiride arm.

5. Serious adverse events were more frequent with glimepiride (8%) compared to both canagliflozin 100 mg (5%) and 300 mg (5%).

6. Canagliflozin was associated with higher rates of genital mycotic infections in women (11-14% vs 2%) and men (7-8% vs 1%), as well as increased urinary tract infections and osmotic diuresis-related events.

Study Design

Design

Randomised Controlled Trial

Double-Blind

Sample

1,450

Patients

Duration

52 wk

Median

Setting

Multicenter, multinational

Population Adults with type 2 diabetes inadequately controlled on metformin monotherapy (HbA1c 7.0-9.5%).

Intervention Canagliflozin 100 mg or 300 mg once daily.

Comparator Glimepiride titrated up to 6 to 8 mg once daily.

Outcome Change in HbA1c from baseline at 52 weeks.

Study Limitations

• The 52-week primary endpoint duration is relatively short for evaluating long-term durability in a progressive chronic disease, although a 104-week extension was subsequently analyzed.

• Titration of glimepiride to maximal tolerated doses (up to 8 mg) may have maximized its efficacy but concurrently exaggerated the risk of hypoglycemia and weight gain compared to modern, more conservative sulfonylurea dosing strategies.

• The trial was not powered to assess major adverse cardiovascular events (MACE), which were addressed later in dedicated cardiovascular outcome trials like the CANVAS program.

Clinical Significance

CANTATA-SU fundamentally challenged the traditional use of sulfonylureas as the default second-line therapy for type 2 diabetes after metformin. By proving that an SGLT2 inhibitor (canagliflozin) can match or exceed the glycemic efficacy of a sulfonylurea while simultaneously offering weight loss and averting hypoglycemia, the trial provided crucial evidence that drove the modern paradigm shift toward prioritizing SGLT2 inhibitors in diabetes management guidelines.

Historical Context

Historically, sulfonylureas were the most commonly prescribed add-on therapy for patients failing metformin monotherapy, despite their notorious side effects of weight gain and hypoglycemia. The introduction of the SGLT2 inhibitor class offered a novel insulin-independent mechanism of action (urinary glucose excretion). CANTATA-SU was a landmark phase 3 trial that directly pitted this new class against the established sulfonylurea standard (glimepiride), demonstrating a far more favorable metabolic and safety profile that helped usher in the era of SGLT2 inhibitors.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Based on the mechanisms of action of canagliflozin and glimepiride, why does canagliflozin cause weight loss and lower hypoglycemia risk compared to glimepiride?

Key Response

Canagliflozin inhibits SGLT2 in the proximal tubule, causing glycosuria and calorie loss leading to weight loss independent of insulin, which minimizes hypoglycemia risk. Glimepiride stimulates insulin release from pancreatic beta cells, promoting fat storage and increasing hypoglycemia risk if glucose levels drop.

Resident

A patient with T2DM on metformin presents with an HbA1c of 8.2 percent. When deciding between adding an SGLT2 inhibitor like canagliflozin versus a sulfonylurea like glimepiride, which patient-specific factors and side effect profiles should guide your choice?

Key Response

SGLT2 inhibitors are preferred in patients where weight loss or avoiding hypoglycemia is critical, or those with ASCVD, heart failure, or CKD. However, they carry risks of genital mycotic infections and euglycemic DKA. Sulfonylureas are generally reserved for when cost is a primary barrier, as they cause weight gain and hypoglycemia.

Fellow

The CANTATA-SU trial demonstrated superior glycemic control with canagliflozin. From an endocrinology perspective, how might the compensatory physiological responses to SGLT2 inhibition alter the long-term durability of this glycemic efficacy compared to sulfonylurea-induced beta-cell exhaustion?

Key Response

SGLT2 inhibition lowers blood glucose, which paradoxically stimulates glucagon release and increases endogenous hepatic glucose production, partially offsetting the glucose-lowering effect. However, sulfonylureas directly stress beta cells, often leading to progressive beta-cell failure and loss of glycemic durability over time, whereas SGLT2 inhibitors preserve beta-cell function by reducing glucotoxicity.

Attending

While CANTATA-SU established the efficacy of canagliflozin over glimepiride as a second-line agent, how do we reconcile the drug cost and access barriers in real-world practice when counseling patients who might otherwise default to affordable but less optimal sulfonylureas?

Key Response

Shared decision-making must balance the clinical superiority of SGLT2 inhibitors against their high out-of-pocket costs. Physicians must be adept at navigating insurance formularies and knowing when a sulfonylurea is the only viable option to prevent acute hyperglycemia, prioritizing medication adherence over a theoretically optimal but unaffordable regimen.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The CANTATA-SU trial utilized a non-inferiority design that transitioned to superiority testing. What are the statistical and methodological challenges of establishing the non-inferiority margin in a trial comparing a novel mechanism to an established active comparator, and how does hierarchical testing control the family-wise error rate?

Key Response

Choosing a non-inferiority margin requires historical data to ensure the active comparator's effect is preserved. A closed testing procedure is used to first test for non-inferiority, and if met, test for superiority without inflating the Type I error rate. A critical challenge is ensuring assay sensitivity and avoiding biocreep.

Journal Editor

Given the distinct side effect profiles of canagliflozin, such as genital infections, and glimepiride, such as hypoglycemia, how might functional unblinding have compromised the double-blind design of the CANTATA-SU trial, and what impact would this have on subjective endpoints?

Key Response

Patients and investigators could likely guess their treatment assignment due to characteristic adverse events. While objective endpoints like HbA1c are less susceptible to this bias, subjective reporting of adverse events, dietary compliance, or quality of life measures could be significantly skewed by functional unblinding, a key limitation peer reviewers must scrutinize.

Guideline Committee

How does the evidence from CANTATA-SU support the shift in ADA and EASD consensus guidelines to prioritize SGLT2 inhibitors over sulfonylureas as second-line agents after metformin?

Key Response

CANTATA-SU provided foundational evidence that SGLT2 inhibitors offer superior durability, weight benefits, and reduced hypoglycemia compared to sulfonylureas. Combined with subsequent cardiovascular outcome trials, this directly informs current ADA/EASD guidelines, which strongly recommend SGLT2 inhibitors over sulfonylureas to minimize weight gain and hypoglycemia, and to provide cardiorenal protection despite higher costs.

Clinical Landscape

Noteworthy Related Trials

2015

EMPA-REG OUTCOME

n = 7,020 · NEJM

Tested

Empagliflozin 10mg or 25mg daily

Population

T2DM patients with established CV disease

Comparator

Placebo

Endpoint

3-point MACE

Key result: Empagliflozin was the first SGLT2 inhibitor to show a significant reduction in cardiovascular mortality and hospitalization for heart failure.

2017

CANVAS Program

n = 10,142 · NEJM

Tested

Canagliflozin 100mg or 300mg daily

Population

T2DM patients with high CV risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Canagliflozin significantly reduced the risk of the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared to placebo.

2019

CAROLINA Trial

n = 6,033 · JAMA

Tested

Linagliptin 5mg daily

Population

T2DM patients with elevated CV risk

Comparator

Glimepiride 1-4mg daily

Endpoint

3-point MACE

Key result: Linagliptin was non-inferior to glimepiride regarding cardiovascular outcomes, though glimepiride caused significantly more hypoglycemia and weight gain.

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