CMAJ study: combining GLP-1 drugs with SGLT2 inhibitors shows stronger heart failure protection than either alone

This article is for informational purposes only and is not medical advice. Consult your Canadian healthcare provider about your situation.

A network meta-analysis published July 13, 2026 in the Canadian Medical Association Journal (CMAJ), pooling data from 12 large randomized controlled trials and 99,683 adults with type 2 diabetes, found that taking a GLP-1 receptor agonist (GLP-1RA) together with an SGLT2 inhibitor (SGLT2i) was associated with a lower risk of heart failure hospitalization than taking either drug class alone. The combination did not, however, produce a statistically significant reduction in heart attacks, strokes, or kidney failure compared with monotherapy, and the authors rated the certainty of all combination-versus-monotherapy comparisons as very low.

For Canadians living with type 2 diabetes, both drug classes are already Health Canada-approved and in clinical use. SGLT2 inhibitors available in Canada include empagliflozin (Jardiance), dapagliflozin (Forxiga), and canagliflozin (Invokana). GLP-1 receptor agonists include semaglutide (sold in Canada as Ozempic for diabetes and Wegovy for weight management), liraglutide (Victoza), and dulaglutide (Trulicity). Prescribing both together is already permitted under Health Canada's approvals, and Canadian endocrinologists and cardiologists do prescribe the combination for patients with high cardiovascular or kidney risk. Whether provincial drug plans cover both drugs simultaneously varies: Ontario's OHIP-funded Ontario Drug Benefit (ODB) program, Quebec's RAMQ, British Columbia's PharmaCare, and Alberta's AHCIP each have their own formulary criteria, and patients may face coverage gaps or prior-authorization requirements for one or both agents.

What this means in Canada

Health Canada has approved each of these drug classes separately for type 2 diabetes management, and several agents carry additional indications for heart failure or chronic kidney disease. The CMAJ study does not change those individual approvals, but it adds to a growing body of evidence that the combination may offer incremental benefit for heart failure specifically. The Society of Obstetricians and Gynaecologists of Canada (SOGC) does not issue guidance on diabetes pharmacotherapy; the relevant Canadian bodies are Diabetes Canada, which publishes clinical practice guidelines, and the Canadian Cardiovascular Society (CCS). As of this article's publication date, neither Diabetes Canada nor the CCS has issued a specific position statement on combination SGLT2i plus GLP-1RA therapy in direct response to this CMAJ paper. Diabetes Canada's 2023 clinical practice guidelines already recommend considering both drug classes in patients with established cardiovascular disease or high cardiovascular risk, though not necessarily in combination as a default strategy.

On cost: in Ontario, dapagliflozin and empagliflozin are listed on the ODB formulary with limited-use criteria tied to heart failure or chronic kidney disease diagnoses. Semaglutide (Ozempic) is listed on several provincial formularies for type 2 diabetes but often requires prior authorization. Patients prescribed both agents may find that one or both require special authorization, and out-of-pocket costs for uninsured patients can run CAD $150 to $300 or more per month per drug. The federal government's Canadian Drug Agency (CDA, formerly CADTH) has previously assessed cost-effectiveness of these agents individually; a combined-therapy assessment has not yet been published.

What changed

Previous meta-analyses, including the 2024 SMART-C collaboration published in Lancet Diabetes & Endocrinology and a 2024 Circulation analysis, examined whether SGLT2i or GLP-1RA benefits held up when patients were already on the other drug class. Both found that each drug class retained its individual benefits regardless of background therapy, but neither was designed to directly compare the combination against monotherapy in a network framework.

This CMAJ analysis takes a different approach. Using network meta-analysis, the authors compared four treatment arms simultaneously: combination therapy, SGLT2i alone, GLP-1RA alone, and placebo. The 12 included trials, published between 2015 and 2025, covered major outcome studies including EMPA-REG OUTCOME, DECLARE-TIMI 58, CREDENCE, LEADER, and the FLOW trial of semaglutide in chronic kidney disease.

The headline finding: combination therapy was associated with a 28% lower risk of heart failure hospitalization compared with SGLT2i alone (risk ratio 0.72, 95% CI 0.52 to 0.99) and a 38% lower risk compared with GLP-1RA alone (risk ratio 0.62, 95% CI 0.45 to 0.86). Those numbers look meaningful, but the authors graded the evidence as very low certainty for all combination-versus-monotherapy comparisons, meaning the true effect could be substantially different. No significant difference appeared for the composite of cardiovascular death, heart attack, and stroke, nor for the composite of major kidney events.

The analysis also found that GLP-1RA alone was associated with a modestly lower risk of major cardiovascular events than SGLT2i alone (risk ratio 0.91, 95% CI 0.83 to 0.99), while SGLT2i alone appeared to outperform GLP-1RA alone on kidney outcomes. Neither finding is new, but the network framework puts them side by side in a way that prior pairwise analyses could not.

What Canadian patients should know

If you have type 2 diabetes and are already on one of these drug classes, this study does not mean you should ask to be switched or automatically added to the other. The very low certainty rating matters: it reflects the fact that no trial in this analysis directly randomized patients to combination versus monotherapy. The combination group was constructed from patients who happened to be on one drug at baseline when they were enrolled in a trial of the other. That is a methodologically weaker design than a head-to-head trial, and the authors are explicit about this limitation.

For patients with type 2 diabetes who also have heart failure or are at high risk of it, the heart failure hospitalization finding is worth discussing with a cardiologist or endocrinologist. Both drug classes are already recommended in that setting by major guidelines, so the conversation may already be happening.

Provincial coverage differences are real. A patient in British Columbia may face different formulary criteria than one in Quebec or Manitoba. Patients who are uninsured or underinsured can ask their prescriber about patient support programs offered by manufacturers, though those programs vary and are subject to change. Canadian telehealth platforms such as Maple and Telus Health can facilitate prescription renewals and specialist referrals, but formulary coverage decisions rest with provincial drug plans regardless of how the prescription is written.

Science & Humans (scienceandhumans.com), a Canadian platform focused on metabolic and hormonal health, is one of several services where Canadians can access virtual consultations about diabetes medications, though coverage and formulary access still depend on provincial plans.

Limitations and open questions

The authors are direct about what this study cannot answer. All comparisons involving combination therapy relied on indirect or subgroup data, not on patients who were prospectively randomized to receive both drugs together from the start. Patients in the combination group were likely already tolerating one drug before being enrolled in a trial of the second, which may make them a healthier or more adherent subgroup than the general population.

The certainty of evidence for every combination-versus-monotherapy comparison was rated very low by the GRADE framework, meaning the estimates are highly uncertain. The confidence intervals for heart failure hospitalization, while statistically significant, are wide enough that the true benefit could be modest.

No trial in this analysis directly compared combination therapy with monotherapy as its primary design. The authors call explicitly for randomized controlled trials built around that question. Until those trials exist, the combination-versus-monotherapy comparison remains an inference from indirect data.

Health Canada has not issued specific guidance on combination SGLT2i plus GLP-1RA prescribing beyond the individual drug approvals. The Canadian Drug Agency has not yet published a combined-therapy health technology assessment. Diabetes Canada's guidelines acknowledge both drug classes but do not yet specify a combination-first strategy for most patients.

What the study does confirm, with somewhat stronger evidence, is that both drug classes individually outperform placebo for cardiovascular and kidney outcomes in type 2 diabetes. That finding is consistent with years of prior trial data and is already reflected in Canadian clinical guidelines.

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This article is for informational purposes only and is not medical advice. Consult your Canadian healthcare provider about your situation.

Editorial note

Hormone Journal articles are written by our editorial team and reviewed against published clinical guidelines, with a focus on Canadian patient access. We do not promote specific clinics or providers.