What are the considerations for using SGLT3 (Sodium-Glucose Linked Transporter 3) inhibitors in patients with abnormal glycosylation or certain cancers, given their age, gender, medical history, and current health status?

SGLT2 Inhibitors: Clinical Applications and Considerations

Primary Indications and Evidence-Based Use

SGLT2 inhibitors (sodium-glucose cotransporter-2 inhibitors) are first-line agents for patients with type 2 diabetes who have established cardiovascular disease, heart failure, or chronic kidney disease, regardless of baseline glycemic control. 1, 2

Cardiovascular Disease and Heart Failure

• For patients with heart failure and reduced ejection fraction (HFrEF), SGLT2 inhibitors reduce cardiovascular death and heart failure hospitalizations (HR 0.74,95% CI 0.65-0.85 for dapagliflozin), with benefits extending to patients regardless of diabetes status 1

• In heart failure with preserved ejection fraction (HFpEF, LVEF >40%), empagliflozin reduces the composite outcome of cardiovascular death or hospitalization for heart failure 1

• SGLT2 inhibitors are recommended for patients with type 2 diabetes and heart failure for management of hyperglycemia as part of guideline-directed medical therapy 1

• Cardiovascular outcomes trials demonstrate SGLT2 inhibitors reduce 3-point MACE (cardiovascular death, MI, stroke) with hazard ratios of 0.86-0.93 across multiple agents 2

Chronic Kidney Disease

• In patients with type 2 diabetes and CKD, SGLT2 inhibitors reduce worsening nephropathy (HR 0.53-0.71), including progression to end-stage renal disease 2

• The CREDENCE trial demonstrated canagliflozin reduced the composite renal outcome (ESRD, doubling of creatinine, or death from renal/cardiovascular causes) by 30% (HR 0.70) 2

• For patients with eGFR 30-44 mL/min/1.73 m², SGLT2 inhibitors remain beneficial for cardiorenal protection, though metformin dose should be reduced to 1000 mg daily 3

Type 2 Diabetes Management

• SGLT2 inhibitors are preferred first-line agents for patients ≥18 years with type 2 diabetes and established ASCVD, heart failure, CKD, or high cardiovascular risk 1, 2

• The 2025 ADA Standards recommend starting SGLT2 inhibitors or GLP-1 receptor agonists with proven cardiovascular benefit based on patient-specific comorbidities 1

• In youth with type 2 diabetes aged 10-17 years, empagliflozin (10-25 mg) significantly reduces A1C by 0.84% compared to placebo (P = 0.012) without severe hypoglycemia 1

Critical Safety Considerations

Diabetic Ketoacidosis Risk

• SGLT2 inhibitors increase susceptibility to diabetic ketoacidosis, including atypical euglycemic presentations, particularly with insulin pump malfunctions, significant insulin dose reductions, or prolonged fasting/carbohydrate restriction 1

• The mechanism involves increased ketone production through reduced insulin levels, increased glucagon leading to lipolysis, and decreased renal clearance of ketones 1

• Assess underlying susceptibility before initiating SGLT2 inhibitors and provide education on ketoacidosis prevention strategies and monitoring 1

• SGLT2 inhibitors are contraindicated in type 1 diabetes outside of carefully monitored settings due to ketoacidosis risk 1

Medication Interactions and Dose Adjustments

• When initiating SGLT2 inhibitors in patients on metformin, reduce metformin dose by 20% to prevent hypoglycemia 2

• In patients with eGFR 30-44 mL/min/1.73 m², metformin should be withheld until eGFR >40 mL/min/1.73 m² to reduce lactic acidosis risk 3

• For contrast procedures in CKD patients, administer IV fluid at 1 mL/kg/h for 6-12 hours before the procedure and minimize contrast volume (<30 mL if possible) 3

Special Populations

Older Adults (≥65 Years)

• Obinutuzumab/chlorambucil, ibrutinib, or ofatumumab/chlorambucil are preferred for frail patients ≥65 years with significant comorbidities in the context of chronic lymphocytic leukemia, though this relates to cancer treatment rather than SGLT2 inhibitor use 1

• SGLT2 inhibitors demonstrated consistent cardiovascular benefits across age groups in major trials, including patients ≥65 years 1

Cancer Patients

• In patients with cancer therapy-related cardiomyopathy (EF <50%), SGLT2 inhibitors for management of hyperglycemia in those with heart failure and type 2 diabetes is reasonable 1

• For asymptomatic patients with cancer therapy-related cardiomyopathy, ARB, ACEi, and beta blockers are reasonable to prevent progression to heart failure 1

• Multidisciplinary discussion about risk-benefit ratio of cancer therapy continuation is recommended when cardiomyopathy develops 1

Racial and Ethnic Considerations

• In the EMPA-REG trial, empagliflozin showed particularly strong cardiovascular benefit in Asian populations (HR 0.68,95% CI 0.48-0.95) and Hispanic/LatinX populations (HR 0.63,95% CI 0.44-0.90) 1

• The CANVAS trial demonstrated benefit in Hispanic/LatinX patients (HR 0.84,95% CI 0.53-1.33), though confidence intervals were wider due to smaller sample size 1

Abnormal Glycosylation and Cancer Context

Glycosylation Alterations in Cancer

• Altered glycosylation is a hallmark of cancer, with tumor cells exhibiting abnormal glycan structures that contribute to tumor invasion, metastasis, and immune evasion 4, 5

• High-mannose core structures of N-linked glycans become exposed in cancer cells due to abnormal glycosylation pathways, serving as potential therapeutic targets 6

• There is no evidence that SGLT2 inhibitors directly affect glycosylation pathways or tumor-associated carbohydrate antigens 4, 5, 7

Clinical Implications

• SGLT2 inhibitors do not require dose adjustment or avoidance in patients with abnormal glycosylation or congenital disorders of glycosylation, as their mechanism of action (inhibiting glucose reabsorption in the proximal tubule) is independent of cellular glycosylation pathways 8

• In cancer patients with diabetes, SGLT2 inhibitors provide cardiovascular and renal protection without interfering with glycosylation-targeted cancer therapies 1, 2

• For patients with congenital disorders of glycosylation who develop type 2 diabetes, standard SGLT2 inhibitor dosing applies, with attention to the same safety considerations as the general population 8

Practical Implementation Algorithm

1. Verify indication: Type 2 diabetes with ASCVD, heart failure (any EF), CKD (eGFR ≥30), or high cardiovascular risk 1, 2

2. Assess contraindications: Type 1 diabetes (relative), eGFR <30 mL/min/1.73 m² (agent-specific), recurrent ketoacidosis history 1

3. Select agent: Dapagliflozin 10 mg, empagliflozin 10-25 mg, or canagliflozin 100-300 mg daily based on cardiovascular outcomes trial data 2

4. Adjust concomitant medications: Reduce metformin by 20%, consider insulin dose reduction by 10-20% to prevent hypoglycemia 2

5. Patient education: Ketoacidosis symptoms (nausea, vomiting, abdominal pain with normal or mildly elevated glucose), sick day management, adequate hydration 1

6. Monitor: Renal function at baseline and periodically, volume status in elderly or those on diuretics, genital mycotic infections 1, 2

Common Pitfalls to Avoid

• Do not withhold SGLT2 inhibitors in patients with well-controlled diabetes (A1C <7%) – cardiorenal benefits are independent of glycemic control 1, 2

• Do not prioritize sulfonylureas over SGLT2 inhibitors for glucose control – sulfonylureas lack cardiovascular benefit and increase hypoglycemia risk, especially in CKD 2

• Do not assume SGLT2 inhibitors are contraindicated in cancer patients – they provide cardiovascular protection during and after cancer therapy 1

• Do not forget to counsel on ketoacidosis risk during illness, fasting, or low-carbohydrate diets – this is the most serious adverse effect requiring immediate medical attention 1

• Do not discontinue SGLT2 inhibitors perioperatively without clear indication – temporary discontinuation may be considered for major surgery with prolonged fasting, but resume as soon as oral intake is established 1