ICES Researchers Propose Groundbreaking Combination Treatment Algorithm for CKD in Type 2 Diabetes

The Burden of Chronic Kidney Disease in Canada

Chronic kidney disease, often abbreviated as CKD, represents a significant public health challenge across Canada. Affecting approximately one in ten Canadians, or over four million people, CKD is a progressive condition where the kidneys gradually lose their ability to filter waste from the blood effectively. This disease is particularly prevalent among older adults, with studies indicating a pooled prevalence of around 10 percent in populations over 75 years old. In Ontario alone, large-scale analyses from the Institute for Clinical Evaluative Sciences have highlighted the substantial economic and health burden, including higher rates of hospitalization and cardiovascular events.

CKD develops silently in many cases, often without symptoms until advanced stages. Risk factors include diabetes, hypertension, obesity, and cardiovascular disease, which are common in the Canadian population. The Kidney Foundation of Canada notes that CKD ranks as the country's 11th leading cause of death, underscoring the urgency for better prevention and management strategies. Recent data shows mortality rates rising alongside global trends, doubling in some regions worldwide, though Canada's prevalence sits at about 9.6 percent as of recent estimates.

Understanding CKD fully involves recognizing its stages, measured by estimated glomerular filtration rate (eGFR) and albuminuria levels. Stage 3 CKD, for instance, affects eGFR between 30-59 mL/min/1.73m², while higher stages signal more severe impairment. Early detection through routine screening, especially for at-risk groups like those with type 2 diabetes, can slow progression and improve quality of life.

Intersection of CKD and Type 2 Diabetes

Type 2 diabetes (T2D) is the leading cause of CKD in Canada, with up to 40 percent of T2D patients developing diabetic kidney disease. This comorbidity amplifies risks for end-stage kidney disease, heart failure, and stroke. Canadian guidelines from Diabetes Canada emphasize screening all T2D patients annually for kidney function via eGFR and urine albumin-to-creatinine ratio (UACR).

The pathophysiology links hyperglycemia to glomerular hyperfiltration, inflammation, and fibrosis in the kidneys. Over time, this leads to proteinuria and declining eGFR. In Canada, immigrants show a lower incidence of CKD compared to native-born individuals, attributed to a 'healthy immigrant effect,' but risks equalize with longer residency. Women, particularly older females with late-onset hypertension, face heightened CKD risk post-hypertension diagnosis.

Management traditionally focused on blood pressure control and glycemic management, but recent advances highlight organ-protective therapies targeting both kidney and heart health simultaneously—termed cardiorenal protection.

Clinical Inertia: A Key Barrier in CKD Care

Despite evidence-based guidelines, clinical inertia—the reluctance to intensify therapy despite suboptimal control—remains a major hurdle. In T2D patients with CKD, many remain on outdated regimens like metformin and RAAS inhibitors alone, missing opportunities for newer agents. Studies show only a fraction receive recommended therapies promptly, leading to faster progression.

This inertia stems from concerns over side effects, cost, polypharmacy, and lack of practical guidance. In Canadian settings, regional variations exist, with university hospitals outperforming others in SGLT2 inhibitor uptake among elderly T2D-CKD patients. Overcoming this requires simplified algorithms and education for primary care providers, who manage most cases.

Addressing inertia could significantly reduce cardiorenal events, as combination approaches show additive benefits in trials.

Guideline-Directed Medical Therapy (GDMT) Evolution

GDMT has transformed CKD-T2D care. Foundational therapies include RAAS inhibitors (ACEi/ARBs) for proteinuria reduction. Newer classes like sodium-glucose cotransporter-2 inhibitors (SGLT2i, e.g., empagliflozin, dapagliflozin) reduce CKD progression by 30-40 percent, alongside cardiovascular benefits. Glucagon-like peptide-1 receptor agonists (GLP-1RA, e.g., semaglutide) offer similar protection, especially in obese patients.

Non-steroidal mineralocorticoid receptor antagonists (nsMRAs) like finerenone further cut risks by 18 percent in trials. Canadian Cardiovascular Society and Diabetes Canada 2025 guidelines recommend SGLT2i as first-line for T2D-CKD, with GLP-1RA addition for persistent albuminuria or cardiovascular risk.

These agents work synergistically: SGLT2i via natriuresis and tubuloglomerular feedback, GLP-1RA via weight loss and anti-inflammation, nsMRAs via fibrosis reduction.

Breakthrough Publication from ICES and University of Toronto

Led by researchers from ICES and the University of Toronto's Division of Endocrinology and Metabolism, a pivotal review published April 13, 2026, in the Journal of Clinical Endocrinology & Metabolism synthesizes evidence for combination GDMT in CKD-T2D. Lead author Mai Mohsen, affiliated with both ICES and U of T, alongside international collaborators, proposes a practical algorithm to guide clinicians.

This work highlights how monotherapy falls short, advocating layered therapy to maximize risk reduction. The paper reviews trials like EMPA-KIDNEY, FLOW, and FIDELIO-DKD, showing 50 percent UACR reductions with combinations versus 20-30 percent monotherapy. By addressing inertia head-on, it offers a step-by-step framework tailored for high-risk patients.

Decoding the Proposed Treatment Algorithm

The algorithm starts with lifestyle optimization—diet, exercise, smoking cessation—followed by metformin if tolerated. Next, add RAASi targeting BP <130/80 mmHg and UACR <300 mg/g.

1. If albuminuria persists, initiate SGLT2i regardless of HbA1c.
2. Add GLP-1RA for BMI >27 or cardiovascular disease.
3. For hyperkalemia-tolerant patients, layer nsMRA like finerenone.
4. Monitor eGFR, electrolytes quarterly; adjust for >30 percent initial dip.

This stepwise approach prioritizes safety, with flowcharts for eGFR <45 or advanced CKD. Canadian applicability is high, aligning with public formularies covering these drugs.

Supporting Evidence from Landmark Trials

Trial data underpins the algorithm. DAPA-CKD showed dapagliflozin cut CKD progression 39 percent. Semaglutide in FLOW reduced major kidney events 24 percent. Finerenone in FIDELITY pooled analysis confirmed benefits atop SGLT2i.

Post-hoc analyses reveal combinations yield superior UACR drops—53 percent versus 29-32 percent monotherapy. Real-world ICES data supports feasibility in diverse Canadian populations.

Implications for Canadian Patients and Healthcare

Implementing this could avert thousands of dialysis starts annually, saving billions. Ontario's CKD costs exceed $2 billion yearly; optimized GDMT might halve progression rates. Primary care integration via team-based care—pharmacists, nurses, endocrinologists—is key.

Challenges include access in rural areas and Indigenous communities, where CKD prevalence is double. Equity-focused rollout, per ICES equity analyses, is essential.

Higher Education's Role in CKD Research

Canadian universities drive innovation. U Toronto's leadership via ICES exemplifies collaborative research linking population data to clinical trials. Other institutions like McMaster and UBC contribute CKD cohorts.

Training future nephrologists and endocrinologists through programs emphasizing GDMT prepares the workforce. AcademicJobs.com connects researchers to roles advancing such discoveries.

Stakeholder Perspectives and Real-World Impact

Patients report better energy and fewer complications on combinations. Nephrologists praise the algorithm's simplicity. Policymakers eye cost-savings; CADTH reviews support reimbursement.

Case example: A Toronto T2D-CKD patient on SGLT2i + GLP-1RA stabilized eGFR for years, avoiding dialysis.

Future Outlook: Trials and Innovations

Ongoing trials like CONFIDENCE test finerenone + empagliflozin. Gene therapies and xenotransplants loom. Canadian frameworks aim for national CKD strategy by 2027.

ICES plans real-world implementation studies, potentially transforming care.

Actionable Insights for Patients and Providers

• Request annual CKD screening if diabetic.
• Discuss SGLT2i/GLP-1RA eligibility.
• Monitor weight, BP, labs regularly.
• Join support groups via Kidney Foundation.

Empowerment through knowledge accelerates adoption.

Photo by George Bakos on Unsplash