What drug classes are used to treat diabetes mellitus, particularly type 2?

Drug Classes for Diabetes Treatment

The primary drug classes for treating type 2 diabetes include biguanides (metformin), sulfonylureas, thiazolidinediones (TZDs), meglitinides (glinides), alpha-glucosidase inhibitors, DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 receptor agonists, and insulin. 1, 2

First-Line Therapy: Biguanides

• Metformin is the preferred initial pharmacologic agent for most adults with type 2 diabetes when lifestyle modifications alone are insufficient. 1
• Metformin works primarily by reducing hepatic glucose production while enhancing insulin sensitivity in liver and muscle tissue. 2, 3
• This agent is effective, safe, inexpensive, weight-neutral, and carries low hypoglycemia risk. 1
• Critical contraindications include advanced renal insufficiency and alcoholism due to rare but serious risk of lactic acidosis. 2

Second-Line Options: Insulin Secretagogues

Sulfonylureas

• Sulfonylureas stimulate insulin release by closing ATP-sensitive potassium channels on pancreatic β-cells. 2
• Available agents in China include gliburide, glimepiride, gliclazide, glipizide, and gliquidone. 4
• These agents demonstrate high glucose-lowering efficacy with expected HbA1c reduction of 1.0-1.5%. 2
• Major limitations include significant hypoglycemia risk (particularly in elderly patients) and modest weight gain. 4, 2
• Patients with mild renal insufficiency should use gliquidone. 4

Meglitinides (Glinides)

• Meglitinides are shorter-acting nonsulfonylurea insulin secretagogues that reduce postprandial blood glucose by stimulating early-phase insulin secretion. 4
• Available agents include repaglinide, nateglinide, and mitiglinide, which can lower HbA1c by 0.5% to 1.5%. 4
• These agents must be taken immediately before meals and carry lower hypoglycemia risk compared to sulfonylureas. 4, 2
• Glinides can be used in patients with renal insufficiency. 4

Insulin Sensitizers

Thiazolidinediones (TZDs)

• TZDs are peroxisome proliferator-activated receptor γ activators that improve insulin sensitivity in skeletal muscle and reduce hepatic glucose production. 2
• Available agents in China are rosiglitazone and pioglitazone, which decrease HbA1c by 0.7% to 1.0%. 4
• TZDs do not cause hypoglycemia when used alone but may increase this risk when combined with insulin or insulin secretagogues. 4
• Significant contraindications include heart failure (NYHA class II and above), active liver disease, transaminase elevations exceeding 2.5 times the upper limit of normal, and severe osteoporosis. 4
• Major side effects include weight gain, edema, increased fracture risk, and heart failure. 4, 2

Incretin-Based Therapies

DPP-4 Inhibitors

• DPP-4 inhibitors enhance circulating concentrations of active GLP-1 and GIP, regulating insulin and glucagon secretion in a glucose-dependent manner. 2, 3
• Available agents in China include sitagliptin, saxagliptin, vildagliptin, linagliptin, and alogliptin, which reduce HbA1c by 0.4% to 0.9%. 4
• These agents are weight-neutral with low hypoglycemia risk when used alone. 1, 2
• When combined with sulfonylureas, hypoglycemia risk increases by 50% compared to sulfonylurea alone. 2

GLP-1 Receptor Agonists

• GLP-1 receptor agonists are recommended early in patients with established cardiovascular disease or at high cardiovascular risk. 1
• These agents provide 12%-26% risk reduction for atherosclerotic cardiovascular disease over 2 to 5 years. 5
• High-potency GLP-1RA medications result in weight loss exceeding 5% in most individuals, with some achieving greater than 10% weight loss. 5
• Common side effects include gastrointestinal symptoms. 1

SGLT-2 Inhibitors

• SGLT-2 inhibitors are recommended early in patients with established cardiovascular disease, heart failure, or chronic kidney disease. 1
• These agents block renal glucose reabsorption, causing glucosuria and lowering blood glucose independent of insulin action. 2, 3
• SGLT-2 inhibitors provide 18%-25% risk reduction for heart failure and 24%-39% risk reduction for kidney disease over 2 to 5 years. 5
• These agents provide modest weight loss and blood pressure reduction. 1, 2
• Critical safety concerns include increased risk of genital mycotic infections, urinary tract infections, acute kidney injury, dehydration, and orthostatic hypotension. 2

Alpha-Glucosidase Inhibitors

• Alpha-glucosidase inhibitors slow carbohydrate absorption in the upper small intestine by inhibiting carbohydrate hydrolysis. 4, 2, 3
• Available agents in China include acarbose, voglibose, and miglitol. 4
• Acarbose 300 mg/day demonstrated similar hypoglycemic effect to metformin 1500 mg/day in newly diagnosed Chinese patients. 4
• These agents demonstrate lower glucose-lowering efficacy with expected HbA1c reduction of 0.5-1.0%. 2
• Main side effect is flatulence due to unabsorbed carbohydrates reaching the colon; starting with a small dose and gradually increasing reduces adverse effects. 4, 2
• When patients using alpha-glucosidase inhibitors manifest hypoglycemia, glucose or honey should be used as treatments; dietary sucrose and starchy foods have poor ability to correct hypoglycemia. 4

Insulin Therapy

• Insulin should be initiated regardless of background therapy when HbA1c >10% or blood glucose ≥300 mg/dL, especially if symptomatic. 1
• Approximately one-third of patients with type 2 diabetes require insulin treatment during their lifetime. 5
• Insulin is associated with the highest risk of hypoglycemia and weight gain among all medication classes. 1

Clinical Selection Algorithm

• When metformin monotherapy fails to achieve glycemic targets, prioritize SGLT-2 inhibitors or GLP-1 receptor agonists if the patient has cardiovascular disease, heart failure, chronic kidney disease, or high cardiovascular risk. 1, 5
• When HbA1c is ≥1.5% above target, initiate dual-combination therapy or more potent agents rather than sequential monotherapy. 1
• Add sulfonylureas for high glucose-lowering efficacy when hypoglycemia risk is acceptable and cost is a concern. 2
• Choose DPP-4 inhibitors when weight neutrality and low hypoglycemia risk are priorities. 2
• Consider TZDs for durability of effect, but weigh carefully against fluid retention and fracture risks. 2
• Reserve alpha-glucosidase inhibitors primarily for postprandial glucose control. 2

Critical Pitfalls to Avoid

• Never use metformin in patients with advanced renal insufficiency or alcoholism due to lactic acidosis risk. 2
• Avoid sulfonylureas in elderly patients or those at high hypoglycemia risk; choose shorter-acting agents if necessary. 2
• Do not overlook fluid retention risks with TZDs in patients with heart failure predisposition. 2
• Remember to adjust DPP-4 inhibitor doses based on renal function (except linagliptin). 2
• When combining agents, recognize that sulfonylureas increase hypoglycemia risk even with drugs that don't typically cause hypoglycemia alone. 2