What are the cautions, adverse effects, contraindications, and monitoring recommendations for sodium‑glucose co‑transporter‑2 (SGLT‑2) inhibitors and glucagon‑like peptide‑1 (GLP‑1) receptor agonists in patients with type 2 diabetes according to the latest guidelines?

Cautions, Adverse Effects, Contraindications, and Monitoring for SGLT-2 Inhibitors and GLP-1 Receptor Agonists

SGLT-2 Inhibitors

Contraindications

• Do not initiate if eGFR <30 mL/min/1.73 m² 1
• Pregnancy or breastfeeding 1
• Type 1 diabetes (not approved for this indication) 2

Major Adverse Effects

Genital and Urinary Tract Infections (high certainty evidence)

• Genital mycotic infections occur commonly due to increased urinary glucose excretion 2, 3
• Urinary tract infections are more frequent than placebo 2
• Educate patients on perineal hygiene and early recognition of symptoms 2

Diabetic Ketoacidosis (including euglycemic DKA)

• Can occur even with near-normal glucose levels 2
• Risk factors include acute illness, reduced food intake, surgery, insulin dose reduction, and excessive alcohol 2
• Discontinue SGLT-2 inhibitors 3-4 days before major surgery 2
• Instruct patients to stop medication during acute illness and seek care if nausea, vomiting, or abdominal pain develops 2

Volume Depletion and Hypotension

• Assess volume status before initiation, especially in patients on diuretics or with low baseline blood pressure 1
• Risk is higher in elderly patients and those with impaired renal function 2
• Monitor orthostatic vital signs in at-risk patients 2

Amputation Risk (primarily lower extremity)

• Patients with foot ulcers or high amputation risk should only receive SGLT-2 inhibitors after careful shared decision making with comprehensive foot care education 4
• Perform baseline foot examination and educate on daily foot inspection 4

Acute Kidney Injury

• Transient eGFR decline of 3-5 mL/min/1.73 m² within first 4-6 weeks is expected and physiologic 1
• Do not discontinue solely for this expected decline 1
• Monitor renal function at baseline, 2-4 weeks after initiation, then periodically 2

Monitoring Requirements

Renal Function

• Baseline eGFR required; must be ≥30 mL/min/1.73 m² to initiate 1
• Recheck at 2-4 weeks, then every 3-6 months 2
• Expect initial 3-5 mL/min decline; discontinue only if acute drop >30% or symptoms of AKI 1, 2

Volume Status and Blood Pressure

• Monitor orthostatic vital signs, especially in first weeks 2
• Assess for signs of dehydration in elderly or those on diuretics 2

Foot Examination

• Baseline comprehensive foot exam in all patients 4
• Regular foot checks in those with neuropathy or prior ulcers 4

Ketone Monitoring

• Educate patients to check urine or blood ketones if feeling unwell, even with normal glucose 2
• Consider checking ketones before elective surgery 2

Key Cautions

Hypoglycemia Risk

• SGLT-2 inhibitors alone do not cause hypoglycemia 2
• When combined with sulfonylureas or insulin, reduce doses of these agents by 25-50% to prevent hypoglycemia 4, 5

Perioperative Management

• Hold 3-4 days before major surgery to reduce DKA risk 2
• Resume only after patient is eating normally 2

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GLP-1 Receptor Agonists

Contraindications

Absolute

• Personal or family history of medullary thyroid carcinoma 1
• Multiple endocrine neoplasia syndrome type 2 (MEN 2) 1
• Pregnancy or breastfeeding 1

Relative

• Severe gastroparesis (use with extreme caution) 1
• History of pancreatitis (use with caution; discontinue if pancreatitis suspected) 1

Major Adverse Effects

Gastrointestinal Symptoms (most common)

• Nausea, vomiting, and diarrhea occur in 25-45% of patients 3, 6
• Symptoms are dose-dependent and typically diminish over 4-8 weeks 1
• Start at lowest approved dose and titrate slowly over 4-8 weeks to minimize GI effects 1
• Severe gastrointestinal events may occur (low certainty evidence) 3

Pancreatitis

• Rare but serious adverse effect 1
• Instruct patients to report severe, persistent abdominal pain 1
• Discontinue immediately if pancreatitis is suspected 1

Hypoglycemia

• GLP-1 agonists alone do not cause hypoglycemia 3
• When combined with insulin, sulfonylureas, or glinides, reduce doses of these agents to prevent hypoglycemia 1, 5

Injection Site Reactions

• Local reactions (redness, itching) are common with injectable formulations 3
• Rotate injection sites to minimize reactions 3

Monitoring Requirements

Glycemic Control

• Self-monitoring of blood glucose may be unnecessary when GLP-1 agonist is combined with metformin alone 4
• Monitor HbA1c every 3 months until stable, then every 6 months 4

Gastrointestinal Tolerance

• Assess nausea, vomiting, and diarrhea at each visit during titration 1
• If intolerable, slow titration or consider alternative agent 1

Renal Function

• Liraglutide: Use with caution if eGFR 15-29 mL/min/1.73 m²; not recommended if eGFR <15 1
• Dulaglutide: Not recommended if eGFR <30 1
• Semaglutide (injectable): No dose adjustment required for renal impairment 1

Pancreatitis Surveillance

• Educate patients on symptoms (severe abdominal pain radiating to back) 1
• Check lipase if symptoms develop 1

Thyroid Monitoring

• Routine calcitonin monitoring is not recommended 1
• Educate patients on symptoms of thyroid tumors (neck mass, dysphagia, dyspnea) 1

Key Cautions

Titration Strategy

• Begin at lowest approved dose (liraglutide 0.6 mg daily, dulaglutide 0.75 mg weekly, semaglutide 0.25 mg weekly) 1
• Increase dose every 4-8 weeks based on GI tolerance 1
• Do not advance dose if patient has persistent nausea or vomiting 1

Oral Semaglutide Administration

• Take on empty stomach with ≤4 oz water 1
• Wait ≥30 minutes before eating, drinking, or taking other medications 1
• Absorption is significantly reduced if taken with food 1

Hypoglycemia Prevention

• When adding GLP-1 agonist to sulfonylurea: reduce sulfonylurea dose by 50% 5
• When adding to basal insulin: reduce insulin dose by 10-20% 5

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Combination Therapy Considerations

SGLT-2 Inhibitor + GLP-1 Agonist

• Concurrent use is appropriate for additive cardiovascular and renal benefits 1, 7
• Do not avoid combination when both are indicated 1
• Monitor for volume depletion more closely when combining with GLP-1 agonist (due to potential reduced oral intake from nausea) 7

With Metformin

• Continue metformin as foundational therapy 1
• No dose adjustment of metformin needed when adding SGLT-2 inhibitor or GLP-1 agonist 5

With Insulin or Sulfonylureas

• Reduce insulin dose by 10-20% when adding SGLT-2 inhibitor or GLP-1 agonist 4, 5
• Reduce sulfonylurea dose by 50% when adding SGLT-2 inhibitor or GLP-1 agonist 4, 5
• Intensify glucose monitoring during first 2-4 weeks 5

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Common Pitfalls to Avoid

SGLT-2 Inhibitors

• Do not delay initiation based on HbA1c level; cardiovascular and renal benefits are independent of glycemic control 4, 1
• Do not discontinue for expected initial eGFR decline of 3-5 mL/min 1
• Do not forget to hold before major surgery 2
• Do not overlook foot examination in high-risk patients 4

GLP-1 Receptor Agonists

• Do not advance dose too quickly; slow titration prevents GI intolerance 1
• Do not postpone initiation until HbA1c rises; cardiovascular benefit occurs at any HbA1c 4, 1
• Do not use short-acting agents (exenatide twice daily, lixisenatide) for cardiovascular protection; they lack MACE reduction data 1
• Do not forget to reduce concomitant insulin or sulfonylurea doses 4, 5