What is the most appropriate medication to initiate for a 60-year-old female patient with type 2 diabetes mellitus (T2DM), dyslipidemia, hypertension, obesity, and a body mass index (BMI) of 35 kg/m2, who is motivated to lose weight and has a hemoglobin A1c (HbA1c) of 8.6%?

Semaglutide is the Most Appropriate Medication for This Patient

For this 60-year-old female patient with uncontrolled type 2 diabetes, obesity, and multiple metabolic comorbidities who is motivated to lose weight, semaglutide 0.25 mg subcutaneously weekly is the most appropriate medication to initiate.

Rationale for Selecting Semaglutide

Patient-Specific Factors

• Current clinical status: HbA1c 8.6% (inadequately controlled on metformin)
• BMI: 35 kg/m² (obesity)
• Comorbidities: Dyslipidemia, hypertension, obesity, type 2 diabetes
• Patient goal: Weight loss
• Current medications: Metformin 1000 mg ER BID, hydrochlorothiazide 25 mg daily, atorvastatin 40 mg daily
• Renal function: Normal (eGFR 75 mL/min/1.73 m²)

Comparative Analysis of Options

1. Semaglutide 0.25 mg subcutaneously weekly

   • Provides superior glycemic control with HbA1c reductions of 1.4-1.8% 1
   • Significant weight loss benefit (5.4-14.9% of body weight) 2
   • Cardiovascular benefits shown in LEADER trial 3
   • Starting dose of 0.25 mg weekly with gradual titration minimizes GI side effects 2

2. Empagliflozin 10 mg orally once daily

   • Moderate glycemic control (HbA1c reduction ~0.6-0.7%) 4
   • Modest weight loss (2-3% of body weight) 4
   • Cardiovascular benefits in EMPA-REG trial 3
   • Risk of euglycemic diabetic ketoacidosis 3

3. Pioglitazone 15 mg orally once daily

   • Associated with weight gain 3
   • Fluid retention and increased risk of heart failure 3
   • Not recommended for patients seeking weight loss

4. Alogliptin 25 mg orally once daily

   • Weight neutral 3
   • Modest HbA1c reduction (~0.5-0.8%)
   • FDA warning about increased risk of heart failure 3
   • No significant weight loss benefit

Treatment Algorithm

1. Initiate semaglutide 0.25 mg subcutaneously weekly

   • Follow recommended titration schedule:
     • Weeks 1-4: 0.25 mg weekly
     • Weeks 5-8: 0.5 mg weekly
     • Gradually increase to maintenance dose of 2.4 mg weekly as tolerated 2

2. Monitor for efficacy and side effects

   • Assess response at 12 weeks
   • Target ≥5% weight loss from initial body weight 2
   • Continue treatment indefinitely in responders to prevent weight regain

3. Management of side effects

   • Anticipate gastrointestinal side effects (nausea, vomiting, diarrhea)
   • Slow titration can minimize these effects
   • Consider antiemetics if needed for severe symptoms

Supporting Evidence

The American Diabetes Association Standards of Care (2025) recommends GLP-1 receptor agonists for patients with type 2 diabetes and obesity, particularly when weight management is a key treatment goal 3. For patients with obesity and T2DM, "glucose-lowering agents that also promote weight loss, for example, glucagon-like peptide-1 receptor agonists and sodium–glucose cotransporter-2 inhibitors" should be considered 3.

Semaglutide has demonstrated superior efficacy compared to other GLP-1 RAs, with mean weight loss of 14.9-16.0% at 68 weeks for the 2.4 mg dose 2. The SUSTAIN FORTE trial showed that semaglutide achieved HbA1c reductions of 2.1-2.2 percentage points and weight loss of 6.4-6.9 kg 5.

Important Considerations and Caveats

• Contraindications: Personal or family history of medullary thyroid cancer, multiple endocrine neoplasia syndrome type 2, pregnancy, and caution in patients with history of pancreatitis or gallbladder disease 2

• Common side effects: Gastrointestinal symptoms (nausea, vomiting, diarrhea) occur in up to 74.2% of patients, with approximately 7% discontinuing treatment due to adverse effects 2

• Cost considerations: While semaglutide is more expensive than some alternatives, its superior efficacy in both glycemic control and weight loss makes it cost-effective for patients with obesity and diabetes 2

• Monitoring requirements: Assess efficacy at 12 weeks; discontinue if 5% weight loss is not achieved 2

Semaglutide is clearly the superior choice for this patient given her clinical profile, uncontrolled diabetes, obesity, and desire for weight loss. The medication addresses both her glycemic control needs and weight management goals while providing potential cardiovascular benefits.