What are the typical medications for managing Diabetes Mellitus (DM)?

Typical Medications for Managing Diabetes Mellitus

Metformin is the preferred first-line pharmacologic agent for most adults with type 2 diabetes when lifestyle modifications alone are insufficient, followed by a structured approach to treatment intensification based on patient-specific cardiovascular and renal risk factors. 1

First-Line Therapy

• Metformin should be initiated as the foundation of therapy for nearly all patients with type 2 diabetes, as recommended by the American Diabetes Association 2, 1
• Metformin is effective, safe, inexpensive, weight-neutral, and carries minimal hypoglycemia risk 1
• The medication works by reducing hepatic glucose production, decreasing insulin resistance, and improving peripheral insulin sensitivity 2
• Metformin can lower HbA1c by approximately 1.5% when used as monotherapy 2

Second-Line and Treatment Intensification Options

When metformin monotherapy fails to achieve glycemic targets after 3 months, the following medication classes should be considered based on patient characteristics:

For Patients with Cardiovascular Disease, Heart Failure, or Chronic Kidney Disease

• SGLT-2 inhibitors or GLP-1 receptor agonists with proven cardiovascular benefit should be prioritized early in patients with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease 2, 1
• SGLT-2 inhibitors reduce all-cause mortality, major adverse cardiovascular events (MACE), chronic kidney disease progression, and heart failure hospitalizations compared to usual care 2
• GLP-1 receptor agonists reduce all-cause mortality, MACE, and stroke compared to usual care 2
• Both SGLT-2 inhibitors and GLP-1 receptor agonists demonstrate lower rates of severe hypoglycemia compared to insulin or sulfonylureas 2

Traditional Second-Line Agents

Sulfonylureas:

• Stimulate insulin secretion from pancreatic beta cells 1
• Associated with high risk of hypoglycemia (24% vs. 2% with SGLT-2 inhibitors) and weight gain 1, 3
• Recommended by WHO as second-line therapy in resource-limited settings due to cost considerations 2

DPP-4 Inhibitors:

• Weight-neutral with low hypoglycemia risk 1
• Reduce HbA1c by approximately 0.6-0.8% 1
• Do not reduce all-cause mortality compared to usual care 2
• May be added when insulin is unsuitable in resource-limited settings 2

Thiazolidinediones (TZDs):

• Improve insulin sensitivity 1
• Associated with weight gain, edema, heart failure risk, and bone fractures 1
• Should be used cautiously and withdrawn when more complicated insulin regimens are initiated 2

SGLT-2 Inhibitors:

• Provide modest weight loss 1
• May be continued with insulin to improve glucose control and reduce total daily insulin dose 2
• Potential side effects include hypotension, elevated LDL cholesterol, volume depletion, and genital mycotic infections 2

GLP-1 Receptor Agonists:

• Associated with weight loss and cardiovascular benefits 1
• Common side effects include gastrointestinal symptoms (nausea, vomiting, diarrhea) 1
• Usually withdrawn when more complicated insulin regimens (beyond basal insulin) are used 2

Insulin Therapy

Indications for Insulin:

• Insulin should be initiated immediately when HbA1c ≥10% or blood glucose ≥300 mg/dL, especially if symptomatic or catabolic features are present 2, 1, 4
• Consider insulin when HbA1c is ≥9% 2
• For severe hyperglycemia (blood glucose 300-350 mg/dL or HbA1c 10-12%), basal insulin plus mealtime insulin is the preferred initial regimen 2, 4

Basal Insulin:

• Initiate at 10 units or 0.1-0.2 units/kg body weight 2, 4
• Continue metformin and possibly one additional noninsulin agent when starting basal insulin 2, 4
• Options include NPH, glargine, detemir, or degludec 2

Bolus/Prandial Insulin:

• Rapid-acting insulin analogues (lispro, aspart, or glulisine) are preferred for covering postprandial glucose excursions 2
• Administered 1-3 times daily immediately before meals 2

Human vs. Analog Insulin:

• Human insulin (regular and NPH) is recommended as the standard insulin for both type 1 and type 2 diabetes in resource-limited settings 2
• Long-acting insulin analogues (glargine, detemir) should be considered only for patients with frequent severe hypoglycemia on human insulin 2
• The modest benefits of insulin analogues do not justify universal use given the substantial price difference 2

Pediatric Considerations

• Metformin remains first-line therapy for youth with type 2 diabetes 2, 1
• GLP-1 receptor agonists are approved for children ≥10 years old 1
• SGLT-2 inhibitors (specifically empagliflozin) are recently approved for pediatric use 1
• Insulin is recommended for severe hyperglycemia, ketoacidosis, or when HbA1c ≥8.5% 1

Treatment Intensification Algorithm

When HbA1c remains ≥1.5% above target:

• Initiate dual-combination therapy or more potent agents rather than sequential monotherapy 1
• Do not delay treatment intensification—add a second agent immediately if monotherapy at maximum tolerated dose fails after 3 months 4, 3

Combination Therapy Considerations:

• Sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists are usually withdrawn when more complicated insulin regimens (beyond basal insulin) are used 2
• Thiazolidinediones or SGLT-2 inhibitors may be continued with insulin to improve glucose control and reduce total daily insulin dose 2
• Metformin should be continued as the foundation unless contraindicated 4, 3

Critical Clinical Pitfalls to Avoid

• Never delay insulin therapy in patients with severe hyperglycemia (HbA1c ≥10% or glucose ≥300 mg/dL), as this represents significant insulin deficiency requiring immediate intervention 2, 4, 3
• Metformin should be discontinued in patients presenting with acute conditions associated with lactic acidosis, such as cardiogenic or distributive shock 2
• Avoid sulfonylureas in patients where hypoglycemia is a major concern, particularly elderly patients or those with irregular meal patterns 3
• Selection of add-on therapy must prioritize presence of cardiovascular disease, heart failure, or chronic kidney disease, as SGLT-2 inhibitors and GLP-1 receptor agonists provide proven mortality and cardiovascular benefits in these populations 2, 1
• Reassess glycemic control every 3 months and intensify therapy promptly if targets are not met 4, 3