Diabetes: Choosing Second-Line Drugs and Alternatives to Metformin

If metformin alone doesn’t reach your A1c goal, you don’t have to guess the next step. Pick a drug based on the person — their heart and kidney health, weight goals, risk of low blood sugar, budget, and whether they prefer a pill or injection. Below are clear options and practical tips to help you and your clinician decide quickly.

Pick a class based on the person

SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) lower glucose, often help with weight loss, and protect the heart and kidneys in many patients. Watch for genital yeast infections, dehydration, and a small risk of diabetic ketoacidosis in insulin-deficient people. Always check kidney function before starting.

GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide) offer strong glucose lowering and consistent weight loss. They reduce some cardiovascular risks in higher-risk patients. Expect nausea early on; start low and titrate slowly. These are injectables (except oral semaglutide) and can be more expensive.

DPP-4 inhibitors (sitagliptin, linagliptin) are weight-neutral, well tolerated, and have low hypoglycemia risk. Their glucose-lowering effect is modest, so they suit patients needing smaller A1c drops or who can’t tolerate stronger agents.

Sulfonylureas (glimepiride, glipizide) and meglitinides are powerful glucose-lowering pills but raise hypoglycemia risk and can cause weight gain. Use cautiously in older adults and people with irregular eating patterns.

Thiazolidinediones (pioglitazone) improve insulin sensitivity and give durable control, but they can cause fluid retention, weight gain, and are less ideal for people with heart failure. Consider bone fracture risk in older women.

Insulin remains the go-to when A1c is very high or symptoms are present. Short-term insulin can quickly control glucose and then be stepped down when things improve.

Practical starting tips

1) Check labs: get an eGFR and liver tests before starting or changing meds. Some drugs need dose changes or shouldn’t be started at low kidney function. 2) Match therapy to goals: prioritize GLP-1 or SGLT2 if weight loss or cardiovascular/renal protection matters. 3) Minimize hypoglycemia: avoid sulfonylureas in older adults or replace with agents that have low hypoglycemia risk. 4) Start low and titrate: with GLP-1s, nausea is often dose-related. 5) Teach side-effect prevention: for SGLT2s discuss genital hygiene and signs of dehydration; for insulin and sulfonylureas review hypoglycemia symptoms and dosing around meals.

Finally, cost and access matter. If a patient can’t afford a GLP-1 or SGLT2, DPP-4 inhibitors or careful use of older agents may be reasonable while arranging support programs or trials for coverage. Talk through preferences: injections, weight goals, and daily routines will shape the best choice. Regular follow-up and A1c checks every 3 months after any change will show if the plan is working or needs adjustment.