2 Medications for Diabetes Beyond Insulin

Choosing a treatment

Non-insulin diabetes medicines work through different pathways and differ in their effects on glucose, weight, cardiovascular and kidney health, and risk of adverse effects. Choosing a medicine depends on treatment goals, other health conditions, preferences, and the person's ability to access and use it.

For many people with type 2 diabetes and heart failure, chronic kidney disease, or cardiovascular disease, an SGLT2 inhibitor or a GLP-1–based medicine may be recommended for health benefits even when additional glucose lowering is not needed. Some medicines in these groups have demonstrated cardiovascular or kidney benefits.

How medicine groups work

Metformin decreases liver glucose production and improves insulin sensitivity. It is a common first-line option. Gastrointestinal effects may improve with gradual dose increases and taking it with food, while long-term use can contribute to vitamin B12 deficiency. Metformin is contraindicated when eGFR is below $30\ \mathrm{mL/min/1.73\,m^2}$; kidney function and the full clinical picture should be reviewed by the prescriber.

Sulfonylureas, such as glipizide, stimulate pancreatic beta cells to release insulin. They can cause hypoglycemia and weight gain. Meglitinides, such as repaglinide, stimulate short-acting insulin release around mealtimes and can also cause hypoglycemia.

SGLT2 inhibitors, such as empagliflozin, reduce glucose reabsorption in the kidneys, increasing glucose excretion in urine. They can benefit heart and kidney outcomes. GLP-1 receptor agonists, such as semaglutide, and dual GIP/GLP-1 agonists, such as tirzepatide, enhance glucose-dependent insulin release, reduce glucagon, slow gastric emptying, and increase satiety.

DPP-4 inhibitors, such as sitagliptin, slow the breakdown of incretin hormones, supporting glucose-dependent insulin release and reducing glucagon. They are usually weight-neutral and have low hypoglycemia risk when used alone; some require dose adjustment for kidney function.

Thiazolidinediones (TZDs), such as pioglitazone, improve insulin sensitivity in muscle and fat. Alpha-glucosidase inhibitors, such as acarbose, slow digestion and absorption of carbohydrates in the intestine, mainly reducing after-meal glucose rises. Pramlintide is an amylin analogue that slows stomach emptying, reduces post-meal glucagon, and promotes fullness.

Meal timing and low blood glucose

Hypoglycemia is an important concern with medicines that stimulate insulin release. With a sulfonylurea, skipping or delaying a meal increases the risk because the medicine stimulates insulin release even when a meal is missed. Follow the prescribed meal and medication instructions, and discuss recurrent low blood glucose with the care team.

Meglitinide doses are linked to meals. Follow the specific medicine's directions about what to do when a meal is skipped; do not assume the usual meal dose should still be taken. Acarbose should be taken with the first bite of the meal as directed. If hypoglycemia occurs while taking acarbose with another glucose-lowering medicine, use glucose rather than table sugar to raise blood glucose promptly.

Pramlintide is an injectable add-on used with mealtime insulin for some people with type 1 or type 2 diabetes; it is not a substitute for insulin. It can increase hypoglycemia risk when used with insulin, so follow the prescriber's dose instructions.

Heart, kidney, and urgent safety concerns

SGLT2 inhibitors can cause genital yeast infections and volume depletion, as well as ketoacidosis. Ketoacidosis may occur with only modestly elevated glucose, so nausea, abdominal pain, or rapid breathing during an illness needs urgent medical assessment. Ask the care team about instructions for holding the medicine during prolonged fasting, serious illness, or around surgery.

TZDs such as pioglitazone can cause weight gain and fluid retention and can worsen heart failure; they should be avoided in people with heart failure. For people with type 2 diabetes and heart failure, an SGLT2 inhibitor with demonstrated benefit is recommended when appropriate for the individual, considering the medicine's specific prescribing information and individual factors.

GLP-1–based medicines and precautions

Many GLP-1 receptor agonists and dual GIP/GLP-1 agonists are injected; semaglutide is also available as a tablet. Nausea and other gastrointestinal effects are common, so gradual dose escalation is often used. Follow the prescribed escalation plan and contact the prescriber if nausea is severe or persistent.

GLP-1–based medicines are not for type 1 diabetes. They are generally not used with a DPP-4 inhibitor because the combination adds little glucose-lowering benefit.

According to semaglutide prescribing information, a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 is a contraindication. The warning is based on thyroid C-cell tumors observed in rodents; the relevance of this finding to humans is unknown.

Putting risks and goals together

Medication choice should account for kidney function, cardiovascular and heart-failure status, weight goals, hypoglycemia risk, treatment goals, preferences, and ability to access and use the medicine. The groups do not share the same benefits or risks: sulfonylureas and meglitinides can cause hypoglycemia; SGLT2 inhibitors call for ketoacidosis and illness or surgery planning; GLP-1–based medicines commonly cause gastrointestinal effects and have specific contraindications; and TZDs may worsen heart failure.