SGLT2 Inhibitors

SGLT2 inhibitors (SGLT2i) are oral glucose-lowering agents that block sodium-glucose cotransporter-2 in the renal proximal tubule, causing urinary glucose excretion regardless of insulin. Their primary clinical significance in the tirzepatide context is not glycaemic control — where they are modest — but rather their dedicated powered cardiovascular and kidney outcomes trials, which give them a distinct and evidence-based role in T2D management that tirzepatide cannot currently replicate. KDIGO 2022 recommends SGLT2i with Grade 1A evidence as second-line therapy (after metformin) in T2D+CKD, ahead of GLP-1 RAs.

Key agents: empagliflozin (Jardiance, Boehringer/Lilly), dapagliflozin (Farxiga/Forxiga, AstraZeneca), canagliflozin (Invokana, J&J).

Ontology SGLT2 Inhibitors [relates] Tirzepatide SGLT2 Inhibitors [relates] KDIGO 2022 CKD Diabetes Guideline SGLT2 Inhibitors [relates] Dedicated CKD Outcome Trial

Kidney Outcomes Trials

CREDENCE (Canagliflozin, NEJM 2019)

• Population: T2D+CKD (eGFR 30–90), n=4,401, median follow-up 2.62 years (stopped early for efficacy)
• Primary endpoint (ESRD, doubling creatinine, renal/CV death): HR 0.70 (95% CI 0.59–0.82) — 30% relative reduction
• Event rates: 43.2 vs 61.2 per 1000 patient-years
• CV secondary: MACE HR 0.80 (P=0.01); HF hospitalisation HR 0.61 (P<0.001)
• ESRD alone: HR 0.68 (95% CI 0.54–0.86)
• First dedicated kidney outcomes trial for any antidiabetic drug in T2D+CKD

DAPA-CKD (Dapagliflozin, NEJM 2020)

• Population: CKD eGFR 25–75 (mean 43.1), n=4,304, median 2.4 years; importantly 32% did not have T2D — establishing kidney protection independent of glucose lowering
• Primary endpoint (≥50% eGFR decline, ESRD, renal/CV death): HR 0.61 (95% CI 0.51–0.72) — 39% reduction; strongest effect of the three trials
• Kidney-specific endpoint alone: HR 0.56
• CV death/HF hospitalisation: HR 0.71
• Benefit consistent in T2D and non-T2D subgroups — confirms haemodynamic/non-glycaemic mechanism

EMPA-KIDNEY (Empagliflozin, NEJM 2023)

• Population: CKD eGFR 20–90, n=6,609, median 2.0 years (stopped early); 54% without diabetes; 35% had baseline eGFR <30
• Primary endpoint (kidney progression or CV death): HR 0.72 (95% CI 0.64–0.82) — 28% reduction; event rates 13.1% vs 16.9%
• Largest of the three; confirms benefit extends to eGFR 20–30 range (where CREDENCE excluded patients)
• All-cause hospitalisation significantly lower

Ontology SGLT2 Inhibitors [evidence_from] Dedicated CKD Outcome Trial SGLT2 Inhibitors [relates] Tirzepatide in Advanced CKD

Cardiovascular Outcomes Trial

EMPA-REG OUTCOME (Empagliflozin, NEJM 2015)

• Population: T2D+established ASCVD, n=7,020, mean age 63, median 3.1 years; mean baseline eGFR 74 (26% had eGFR 30–60)
• 3-point MACE: HR 0.86 (95% CI 0.74–0.99, P=0.04) — placebo-controlled superiority
• CV death: HR 0.62 (P<0.001) — 38% reduction (3.7% vs 5.9%)
• HF hospitalisation: HR 0.65 (P=0.002) — 35% reduction (2.7% vs 4.1%)
• All-cause mortality: 32% relative reduction (5.7% vs 8.3%)
• First placebo-controlled MACE superiority result for any antidiabetic drug; established SGLT2i as cardioprotective

Companion trials: CANVAS (canagliflozin, HR 0.86 MACE, 2017), DECLARE-TIMI 58 (dapagliflozin, HR 0.93 MACE non-inferior, 2019, established HF benefit even without established ASCVD).

Ontology SGLT2 Inhibitors [relates] Cardiovascular Risk SGLT2 Inhibitors [relates] Heart Failure Outcomes

The eGFR Threshold: A Critical Nuance

SGLT2i have a counter-intuitive eGFR profile that clinicians must understand:

Clinical implication: SGLT2i should not be discontinued when eGFR drops below 45 in a patient using them for kidney or cardiovascular protection (not for glucose lowering). KDIGO 2022 and ADA/EASD 2022 consensus both support continuation to eGFR ≥20. This is the opposite of the historical approach of stopping “renal drugs” at low eGFR.

The mechanism at low eGFR is haemodynamic and metabolic — not glycosuric: SGLT2i reduce intraglomerular pressure (beneficial eGFR “dip” at initiation, analogous to RAAS agents), reduce tubular oxygen demand, and modulate mitochondrial energetics in the myocardium.

SGLT2i vs Tirzepatide: Complementary, Not Competing

The KDIGO 2022 algorithm explicitly positions SGLT2i before GLP-1 RAs for T2D+CKD. When SGLT2i are used, tirzepatide is the preferred intensification agent — the two drugs have minimal pharmacodynamic overlap and are expected to be additive. ADA/EASD 2022 consensus supports combination use.

Ontology SGLT2 Inhibitors [relates] ADA Standards of Care 2023-2024 SGLT2 Inhibitors [relates] ADA EASD 2022 Consensus Report

Connections

• KDIGO 2022 CKD Diabetes Guideline — recommended_by (Grade 1A, 2nd line T2D+CKD)
• Dedicated CKD Outcome Trial — evidence_gap tirzepatide; evidence_confirmed SGLT2i
• Tirzepatide in Advanced CKD — relates (SGLT2i have eGFR 20–30 data; tirzepatide has eGFR <30 excluded)
• Cardiovascular Risk — relates (EMPA-REG is placebo-controlled MACE superiority)
• Heart Failure Outcomes — relates (HF hospitalisation benefit confirmed)
• ADA Standards of Care 2023-2024 — recommended_by
• ADA EASD 2022 Consensus Report — recommended_by

Sources

• CREDENCE — canagliflozin CKD (NEJM 2019)
• DAPA-CKD — dapagliflozin CKD (NEJM 2020)
• EMPA-KIDNEY — empagliflozin CKD (NEJM 2023)
• EMPA-REG OUTCOME — empagliflozin CV (NEJM 2015)