What are the classes of drugs used to treat diabetes, their respective medications, and benefits?

Diabetes Medication Classes: Drugs and Benefits

For type 2 diabetes, SGLT2 inhibitors and GLP-1 receptor agonists are the preferred second-line agents after metformin because they reduce all-cause mortality and major cardiovascular events, unlike other classes. 1

First-Line Therapy

Biguanides

Medications:

• Metformin 1

Benefits:

• Reduces cardiovascular mortality compared to sulfonylureas 1, 2
• Weight neutral or modest weight loss 1, 2
• No hypoglycemia risk when used alone 1
• Reduces hepatic glucose production 1
• Inexpensive and long-established safety profile 1

Second-Line and Add-On Therapies

SGLT2 Inhibitors (Gliflozins)

Medications:

• Canagliflozin 1, 3
• Dapagliflozin 1
• Empagliflozin 1

Benefits:

• Reduce all-cause mortality compared to usual care, insulin, and DPP-4 inhibitors 1
• Reduce major cardiovascular events (MACE) compared to DPP-4 inhibitors and sulfonylureas 1
• Reduce heart failure hospitalization 1
• Reduce chronic kidney disease progression 1
• Reduce severe hypoglycemia compared to sulfonylureas and insulin 1
• Weight loss (mechanism: urinary glucose excretion) 1
• Reduce serious adverse events compared to usual care 1

Common Pitfall: Genital mycotic infections are increased with this class 2. Monitor renal function as efficacy decreases with declining kidney function 3.

GLP-1 Receptor Agonists

Medications:

• Injectable: Exenatide, liraglutide, semaglutide, dulaglutide, albiglutide, lixisenatide 1
• Oral: Oral semaglutide 4

Benefits:

• Reduce all-cause mortality compared to usual care, insulin, and DPP-4 inhibitors 1
• Reduce major cardiovascular events (MACE) 1
• Reduce stroke compared to usual care 1
• Reduce severe hypoglycemia compared to sulfonylureas and insulin 1
• Significant weight loss, most pronounced with injectable formulations 1, 4
• Glucose-dependent insulin secretion minimizes hypoglycemia risk 5

Common Pitfall: Nausea and vomiting are limiting side effects, particularly early in treatment 1. Injectable formulations have superior glucose-lowering efficacy and weight loss compared to oral formulations 4. When combined with insulin or sulfonylureas, hypoglycemia risk increases significantly 5.

DPP-4 Inhibitors (Gliptins)

Medications:

• Sitagliptin 1, 6
• Saxagliptin 1, 6
• Linagliptin 1
• Alogliptin 1

Benefits:

• Weight neutral 1, 2
• No hypoglycemia when used alone 1
• Enhance circulating GLP-1 and GIP concentrations 1
• Well-tolerated with minimal side effects 1

Important Limitation: Do NOT reduce all-cause mortality or MACE compared to usual care 1. Cardiovascular outcome trials showed neutrality only 1, 7. Smaller HbA1c reduction compared to other classes 1.

Sulfonylureas

Medications:

• Glimepiride 1
• Glyburide 1
• Glipizide 1

Benefits:

• Effective glucose control through stimulation of insulin release 1
• Inexpensive 1

Major Drawbacks:

• Increased severe hypoglycemia compared to SGLT2 inhibitors and GLP-1 agonists 1
• Weight gain 1, 2
• Higher secondary failure rate due to beta-cell exhaustion 1
• Increased cardiovascular mortality compared to metformin 1, 2

Thiazolidinediones (TZDs/Glitazones)

Medications:

• Pioglitazone 1
• Rosiglitazone (limited availability) 1

Benefits:

• Improve insulin sensitivity in skeletal muscle 1
• No hypoglycemia risk 1
• More durable effectiveness than sulfonylureas 1
• Pioglitazone showed modest cardiovascular benefit in patients with established macrovascular disease 1

Major Drawbacks:

• Weight gain 1, 2
• Fluid retention leading to edema and heart failure exacerbation 1
• Increased bone fracture risk 1
• Pioglitazone associated with possible bladder cancer risk 1

Meglitinides (Glinides)

Medications:

• Repaglinide 1
• Nateglinide 1

Benefits:

• Stimulate insulin release with shorter duration than sulfonylureas 1
• May have less hypoglycemia than sulfonylureas 1
• Useful for patients with irregular meal schedules or sulfa allergies 1

Drawback: Require more frequent dosing 1

Insulin

Medications:

• Basal: NPH, glargine, detemir, degludec 1
• Rapid-acting: Regular, lispro, aspart, glulisine 1

Benefits:

• Most effective for severe hyperglycemia (glucose >300-350 mg/dL or HbA1c >10-12%) 1
• No maximum dose limitation 1
• Essential for type 1 diabetes and eventually needed for many type 2 patients 1

Major Drawbacks:

• Highest hypoglycemia risk of all classes 1
• Weight gain 1, 2
• Increases serious adverse events compared to usual care 1
• Does NOT reduce all-cause mortality compared to usual care 1

Dual GLP-1/GIP Agonists

Medications:

• Tirzepatide 1

Benefits:

• Potent glucose lowering 1
• Significant weight loss 1

Important Limitation: Does NOT reduce all-cause mortality compared to usual care 1. Insufficient long-term data on cardiovascular outcomes 1.

Treatment Algorithm Based on Patient Profile

For patients with established cardiovascular disease or high cardiovascular risk:

• Add SGLT2 inhibitor or GLP-1 receptor agonist to metformin 1, 8

For patients with heart failure or at risk for heart failure:

• Prioritize SGLT2 inhibitor over GLP-1 receptor agonist 7, 9

For patients with chronic kidney disease (albuminuric):

• Prioritize SGLT2 inhibitor 1, 7, 9

For patients requiring significant weight loss:

• Prioritize GLP-1 receptor agonist (especially injectable semaglutide or liraglutide) 4, 5

For patients at low cardiovascular risk without comorbidities:

• Consider DPP-4 inhibitor, sulfonylurea, or thiazolidinedione as add-on to metformin, with selection based on cost, side effect profile, and patient preference 1, 8

Critical Caveat: Avoid sulfonylureas and insulin when SGLT2 inhibitors or GLP-1 receptor agonists are available, as they increase hypoglycemia and do not provide mortality or cardiovascular benefits 1, 9.