Type 2 diabetes combines insulin resistance, falling insulin secretion, excess liver glucose output, and a weakened incretin response. Each drug class targets a different step.

Drugs without intrinsic hypoglycemia risk can still cause it when combined with insulin or a sulfonylurea — the dose of those is usually reduced.

All are used for type 2 diabetes with lifestyle therapy. Several have added indications: SGLT2 inhibitors for heart failure and chronic kidney disease (with or without diabetes); GLP-1 receptor agonists for weight management, cardiovascular risk reduction, and (semaglutide) kidney protection; tirzepatide for obesity and obstructive sleep apnea. Drug choice depends on heart, kidney, and weight goals, hypoglycemia risk, and cost — metformin remains a common first choice, and SGLT2 inhibitors or GLP-1 receptor agonists are chosen for clients with cardiovascular disease, heart failure, or CKD regardless of A1C.

Metformin — nausea, diarrhea, abdominal discomfort, metallic taste (reduced by taking with meals and by extended-release forms); vitamin B12 deficiency with long-term use (neuropathy, anemia); lactic acidosis (rare, boxed warning) — malaise, myalgia, abdominal pain, rapid breathing, somnolence, hypotension.

Sulfonylureas — hypoglycemia (prolonged with glyburide and in kidney disease or older adults), weight gain, rash, photosensitivity; US labels carry a special warning of possible increased cardiovascular mortality.

SGLT2 inhibitors

• Genital mycotic infections, urinary tract infections (rarely urosepsis or pyelonephritis)
• Volume depletion, orthostatic hypotension, acute kidney injury; an initial small eGFR dip is expected
• Euglycemic DKA — ketoacidosis with glucose below about 250 mg/dL (13.9 mmol/L); triggers: illness, surgery, fasting, low-carbohydrate diets, alcohol, insulin dose reduction
• Necrotizing fasciitis of the perineum (Fournier gangrene) — rare
• Canagliflozin: lower-limb amputation risk; bone fracture

GLP-1 receptor agonists and tirzepatide

• Nausea, vomiting, diarrhea, constipation, early satiety (usually improve with slow dose escalation)
• Boxed warning: thyroid C-cell tumors (seen in rodents)
• Acute pancreatitis, gallbladder disease (cholelithiasis, cholecystitis)
• Dehydration → acute kidney injury with severe GI losses
• Pulmonary aspiration risk during anesthesia or deep sedation (delayed gastric emptying)
• Worsening diabetic retinopathy with rapid glucose improvement (semaglutide); injection-site reactions
• On January 13, 2026, the FDA asked the makers of the weight-management products of liraglutide, semaglutide, and tirzepatide — the only GLP-1 receptor agonist labels that carried it — to remove the suicidal behavior and ideation warning after its review found no increased risk. Clients should still report new or worsening depression or suicidal thoughts.

DPP-4 inhibitors — nasopharyngitis, headache, pancreatitis, severe joint pain, bullous pemphigoid; heart failure hospitalization with saxagliptin and alogliptin.

TZDs — fluid retention and heart failure, weight gain, bone fractures, macular edema, possible bladder cancer risk (pioglitazone); slow onset (weeks).

Alpha-glucosidase inhibitors — flatulence, bloating, diarrhea.

Metformin

• Contraindicated with eGFR below 30 mL/min/1.73 m²; starting is not recommended at eGFR 30–45; reassess if eGFR falls below 45
• Contraindicated in metabolic acidosis, including DKA
• Caution: hypoxic states (acute heart failure, shock, sepsis), liver disease, heavy alcohol use
• Iodinated contrast: hold at the time of or before the procedure in clients with eGFR 30–60, liver disease, alcoholism, heart failure, or intra-arterial contrast; recheck eGFR 48 hours after and restart if kidney function is stable
• Hold for surgery with restricted intake and during vomiting or dehydration

Sulfonylureas — caution in older adults, kidney or liver disease, irregular meals; sulfonamide allergy (possible cross-sensitivity); alcohol can cause hypoglycemia (and a disulfiram-like reaction with older agents).

SGLT2 inhibitors — type 1 diabetes (not approved for glycemic control — DKA risk), history of DKA, dialysis for glycemic use; stop at least 3 days before scheduled surgery (at least 4 days for ertugliflozin); caution with diuretics (volume loss), low-carbohydrate diets, and heavy alcohol use.

GLP-1 receptor agonists and tirzepatide

• Contraindicated with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN2)
• History of pancreatitis (caution), severe gastroparesis
• Pregnancy: not recommended; semaglutide is stopped at least 2 months before a planned pregnancy
• Slowed gastric emptying changes absorption of oral drugs; tirzepatide reduces oral hormonal contraceptive effect — use a non-oral method or add a barrier method for 4 weeks after starting and after each dose increase

Pioglitazone — contraindicated in NYHA class III–IV heart failure and not recommended in symptomatic heart failure; active liver disease; active or past bladder cancer.

Alpha-glucosidase inhibitors — inflammatory bowel disease, bowel obstruction, cirrhosis.

Interactions that raise glucose: corticosteroids, thiazides, atypical antipsychotics. Beta blockers mask hypoglycemia signs. Gemfibrozil sharply raises repaglinide levels (contraindicated).

Pregnancy and lactation — insulin is preferred in pregnancy; metformin crosses the placenta and is an alternative in some clients; most other noninsulin drugs are avoided.

Listed in priority order.

1. Hypoglycemia — highest risk with sulfonylureas, meglitinides, and any drug combined with insulin. Below 70 mg/dL (3.9 mmol/L): 15 g fast carbohydrate, recheck in 15 minutes. For clients on acarbose, use glucose tablets or gel (sucrose breakdown is blocked).
2. Euglycemic DKA on SGLT2 inhibitors — nausea, vomiting, abdominal pain, malaise, rapid breathing with normal or mildly high glucose → check ketones and acid-base status, hold the drug, notify the prescriber.
3. Metformin and contrast/surgery — confirm eGFR; hold per protocol; recheck eGFR 48 hours after contrast when required.
4. Kidney function — eGFR at baseline and at least yearly (more often below 60) for metformin, SGLT2 inhibitors, and DPP-4 inhibitor dose adjustment (linagliptin needs none).
5. Fluid status — orthostatic BP, intake and output, and weight with SGLT2 inhibitors and GLP-1 receptor agonists; edema, weight gain, dyspnea with pioglitazone.
6. GI and pancreatitis — severe persistent abdominal pain radiating to the back, with or without vomiting → hold GLP-1 receptor agonist or DPP-4 inhibitor, check lipase.
7. Procedures — tell the anesthesia team about GLP-1 receptor agonist or tirzepatide use; follow their preoperative instructions (fasting or liquid diet changes, or holding doses).
8. Labs — A1C every 3 months until at goal, then at least twice yearly (common goal below 7%, individualized); vitamin B12 periodically on metformin; liver tests with pioglitazone.
9. Perineal and urinary symptoms — genital itching, discharge, dysuria; perineal pain, swelling, or fever (Fournier gangrene) on SGLT2 inhibitors.

• Metformin: take with meals; GI upset usually improves; report muscle pain, weakness, trouble breathing, or unusual sleepiness; limit alcohol; tell staff before any scan with contrast dye.
• Sulfonylureas: take with breakfast or the first meal; do not skip meals; carry fast-acting glucose; avoid excess alcohol.
• Meglitinides: take within 30 minutes before each meal; no meal, no dose.
• SGLT2 inhibitors: expect more urination; drink fluids; keep the genital area clean and dry; check ketones when ill even if glucose is normal; stop the drug and call during vomiting, poor intake, or dehydration; tell the surgeon — stop at least 3 days before surgery as instructed.
• GLP-1 receptor agonists/tirzepatide: eat smaller meals, stop eating when full, avoid high-fat meals; report severe abdominal pain, persistent vomiting, a neck lump, hoarseness, or trouble swallowing. Pen injections: weekly or daily on a set day; rotate sites; never share pens.
• Oral semaglutide: take on an empty stomach on waking with no more than 4 oz (120 mL) of plain water; wait at least 30 minutes before food, drinks, or other oral drugs.
• Tirzepatide: use a backup contraceptive method as instructed.
• Pioglitazone: weigh daily; report weight gain of more than about 2 kg (5 lb) in a week, swelling, shortness of breath, blood in urine, or dark urine.
• Acarbose: take with the first bite of each meal; treat lows with glucose tablets.
• All: keep lifestyle changes; monitor glucose as taught; report symptoms of low glucose.

Metformin-associated lactic acidosis — lactate above 5 mmol/L with low pH; risk rises with kidney failure, hypoxia, sepsis, alcohol, and large overdoses. Stop metformin; supportive care; hemodialysis removes metformin and corrects acidosis. Metformin alone rarely causes hypoglycemia.

Sulfonylurea overdose — severe, prolonged or recurrent hypoglycemia (may appear hours later and last days). Treat with IV dextrose, then octreotide, which blocks further insulin release; admit for observation. Even a single tablet can be dangerous for a small child.

SGLT2 inhibitor-associated DKA — treat as DKA: fluids, insulin with dextrose (because glucose is near normal), potassium replacement.

GLP-1 receptor agonist overdose — severe nausea and vomiting, dehydration, hypoglycemia with insulin or sulfonylurea; supportive care with prolonged observation (long half-lives). Dosing errors with compounded or multi-dose vial products have caused hospitalizations — verify units (mg versus mL versus "units" on syringes).

• Metformin: lowers liver glucose production; no hypoglycemia alone; GI upset; B12 deficiency; contraindicated with eGFR below 30; hold around iodinated contrast; lactic acidosis
• Sulfonylureas: hypoglycemia and weight gain; glyburide avoided in older adults; overdose → dextrose plus octreotide
• Meglitinides: skip the dose if the meal is skipped
• SGLT2 inhibitors: glucosuria → genital infections, volume loss, euglycemic DKA → check ketones when ill; stop 3 days before surgery (4 for ertugliflozin); heart and kidney benefit
• GLP-1 RA/tirzepatide: nausea, pancreatitis, gallbladder disease; contraindicated with MTC or MEN2 history; aspiration risk with anesthesia
• Oral semaglutide: empty stomach, up to 4 oz water, wait 30 minutes
• DPP-4 inhibitors: well tolerated; pancreatitis, joint pain, bullous pemphigoid
• Pioglitazone: heart failure boxed warning, edema, fractures
• Acarbose: treat hypoglycemia with glucose, not table sugar
• Insulin or sulfonylurea doses are reduced when adding other agents