What are the mechanisms of action and dosages of GLP-1 (Glucagon-Like Peptide-1) analogs, such as semaglutide (semaglutide) and liraglutide (liraglutide), and SGLT-2 (Sodium-Glucose Linked Transporter-2) inhibitors, such as empagliflozin (empagliflozin) and canagliflozin (canagliflozin), for a patient with type 2 diabetes and a history of pancreatitis or medullary thyroid cancer?

GLP-1 Receptor Agonists and SGLT-2 Inhibitors: Mechanisms and Dosing

GLP-1 Receptor Agonists

Mechanism of Action

GLP-1 receptor agonists work by activating GLP-1 receptors throughout the body, leading to glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, and reduced appetite. 1, 2

• Pancreatic effects: Stimulate insulin release and suppress glucagon secretion only when blood glucose is elevated, resulting in minimal hypoglycemia risk when used as monotherapy 1, 2, 3
• Gastrointestinal effects: Delay gastric emptying by inhibiting gastric peristalsis and increasing pyloric tone, mediated through vagal pathways 2, 4
• Central nervous system effects: Activate GLP-1 receptors in the hypothalamus and brainstem to suppress appetite and induce satiety 3
• Cardiovascular protection: Provide anti-inflammatory, anti-atherosclerotic effects, improved myocardial substrate utilization, and reduced ischemia injury 5
• Renal benefits: Reduce albuminuria and slow eGFR decline across all stages of chronic kidney disease 5

Individual Agents and Dosing

Semaglutide (Injectable)

• Starting dose: 0.25 mg subcutaneously once weekly for 4 weeks 1
• Titration schedule: Increase to 0.5 mg weekly for 4 weeks, then 1.0 mg weekly for 4 weeks, then 1.7 mg weekly for 4 weeks 1
• Maintenance dose: 2.4 mg subcutaneously once weekly (for obesity/cardiovascular benefit) or 1.0 mg weekly (for diabetes) 5, 1
• Weight loss efficacy: Achieves 14.9% total body weight loss at 68 weeks 5
• Cardiovascular benefit: 26% reduction in cardiovascular death, nonfatal MI, or stroke (HR 0.74,95% CI 0.58-0.95) 5

Semaglutide (Oral)

• Starting dose: 3 mg once daily for 30 days 5
• Titration: Increase to 7 mg daily, with optional escalation to 14 mg daily if needed 5
• Administration: Must be taken on empty stomach with ≤4 oz water, 30 minutes before first food/drink/medication of the day 1
• Note: Less potent than injectable formulations for weight loss but provides similar HbA1c reduction of approximately 1.4% 5

Liraglutide

• Starting dose: 0.6 mg subcutaneously once daily for at least one week 2
• Titration: Increase by 0.6 mg weekly increments 2
• Maintenance dose: 1.8 mg daily (for diabetes) or 3.0 mg daily (for obesity) 5, 2
• Weight loss efficacy: Achieves 5.24-6.1% weight loss 5
• Half-life: 13 hours, requiring daily administration 2

Dulaglutide

• Starting dose: 0.75 mg subcutaneously once weekly 5
• Maintenance dose: 1.5 mg weekly, with escalation up to 4.5 mg weekly available 5
• Administration: Pre-filled pen for once-weekly injection 4

Exenatide (Short-acting)

• Dose: 5 mcg subcutaneously twice daily initially, increasing to 10 mcg twice daily after one month 4, 3
• Administration: Within 60 minutes before morning and evening meals 3

Exenatide Extended-Release

• Dose: 2 mg subcutaneously once weekly 5
• Renal considerations: Avoid with eGFR <45 mL/min/1.73 m² 5

Critical Contraindications for GLP-1 Receptor Agonists

All GLP-1 receptor agonists are absolutely contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN2). 5, 1, 2

• This contraindication is based on animal studies showing thyroid C-cell tumors 5
• Use with caution in patients with history of pancreatitis, though causality has not been definitively established 5, 6
• Avoid in patients with severe gastroparesis or significant gastrointestinal motility disorders 4

Special Considerations for Pancreatitis History

For patients with a history of pancreatitis, GLP-1 receptor agonists should be used with extreme caution, though they are not absolutely contraindicated. 5, 6

• Monitor closely for signs of pancreatitis (persistent severe abdominal pain) 5
• Recent evidence suggests no increased pancreatic cancer risk over 7 years of follow-up (HR 0.50,95% CI 0.15-1.71) 6
• Discontinue immediately if pancreatitis is suspected 5

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SGLT-2 Inhibitors

Mechanism of Action

SGLT-2 inhibitors block glucose reabsorption in the proximal renal tubule, causing glucosuria and lowering blood glucose through a mechanism independent of insulin. 5

• Renal effects: Inhibit SGLT-2 cotransporter responsible for ~90% of urinary glucose reabsorption 5
• Glucose-dependent action: Glucosuria diminishes as blood glucose normalizes, resulting in very low hypoglycemia risk when used alone 5
• Cardiovascular benefits: Reduce heart failure hospitalization by 35% and cardiovascular death by 38% (with empagliflozin) 5
• Additional effects: Cause diuretic and natriuretic effects, weight loss (typically 2-3 kg), and systolic blood pressure reduction of 3-5 mmHg 5
• Renal protection: Slow progression of chronic kidney disease and reduce albuminuria 5

Individual Agents and Dosing

Empagliflozin

• Starting dose: 10 mg once daily 5
• Maximum dose: 25 mg once daily 5
• Cardiovascular outcomes: 14% reduction in MACE (HR 0.86,95% CI 0.74-0.99) and 38% reduction in cardiovascular death (HR 0.62,95% CI 0.49-0.77) 5
• Heart failure benefit: 35% reduction in hospitalization (HR 0.65,95% CI 0.50-0.85) 5

Canagliflozin

• Starting dose: 100 mg once daily 5
• Maximum dose: 300 mg once daily 5
• Cardiovascular outcomes: Significant reduction in MACE demonstrated in CANVAS program 5
• Amputation concern: Initial CANVAS trial showed increased amputation risk, but this was not confirmed in subsequent CREDENCE trial 5

Dapagliflozin

• Starting dose: 5 mg once daily 5
• Maximum dose: 10 mg once daily 5
• Cardiovascular benefit: Demonstrated MACE reduction in patients with type 2 diabetes and established ASCVD 5

Ertugliflozin

• Starting dose: 5 mg once daily 5
• Maximum dose: 15 mg once daily 5

Critical Safety Considerations for SGLT-2 Inhibitors

SGLT-2 inhibitors should be withheld during prolonged fasting, surgery, or critical illness due to ketoacidosis risk. 5

• Genital mycotic infections: Occur more frequently, particularly in women 5
• Volume depletion: Monitor for signs of dehydration, especially in elderly patients or those on diuretics 5
• Diabetic ketoacidosis: Can occur even with normal or mildly elevated glucose levels (euglycemic DKA) 5
• Urinary tract infections: Increased incidence compared to placebo 5
• Fournier's gangrene: Rare but serious necrotizing infection of the perineum 5

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Combination Therapy: GLP-1 Receptor Agonists + SGLT-2 Inhibitors

The combination of GLP-1 receptor agonists and SGLT-2 inhibitors provides complementary mechanisms and is strongly recommended for patients with type 2 diabetes and established cardiovascular disease or high cardiovascular risk. 5, 7

• Both drug classes independently reduce MACE and can be used together regardless of baseline HbA1c or metformin use 5
• SGLT-2 inhibitors preferentially reduce heart failure hospitalization, while GLP-1 receptor agonists preferentially reduce atherosclerotic events 5
• The combination provides additive cardiovascular protection: empagliflozin reduces heart failure hospitalization by 35% while semaglutide reduces MACE by 26% 5
• No dose adjustment needed for either class when used in combination 7

Medication Adjustments When Initiating Combination Therapy

When adding GLP-1 receptor agonists or SGLT-2 inhibitors to existing diabetes regimens, reduce or discontinue sulfonylureas and reduce insulin doses by 20% to prevent hypoglycemia. 5, 8

• Metformin can be continued without dose adjustment 8
• Discontinue DPP-4 inhibitors before starting GLP-1 receptor agonists due to overlapping mechanisms 8
• Monitor blood glucose closely during the first 2-4 weeks of combination therapy 5

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Special Population: Patients with History of Medullary Thyroid Cancer

Patients with personal or family history of medullary thyroid cancer or MEN2 syndrome cannot receive GLP-1 receptor agonists under any circumstances. 5, 1, 2

For these patients, SGLT-2 inhibitors remain an excellent option and should be prioritized. 5

• SGLT-2 inhibitors have no thyroid-related contraindications 5
• Empagliflozin or canagliflozin should be selected based on cardiovascular outcomes data 5
• Consider adding metformin if not already prescribed 5
• If additional glucose-lowering is needed, add DPP-4 inhibitors or basal insulin rather than GLP-1 receptor agonists 5