12.2 Diabetes Pharmacotherapy

The official TCO drug-class list includes endocrine agents. Domain III Planning chooses the class from comorbidities, not from a 2018 memory that metformin must come first for every adult. Domain IV Implementation is the moment you refuse a duplicate-risk stack, counsel the boxed warning, and write the sick-day hold. ADA Standards of Care 2026 treat organ protection as a core reason to prescribe, not a bonus after the A1c is already perfect.

The 2026 sequence is not metformin always first

For type 2 diabetes, start from cardiorenal risk and weight, then glycemia:

1. Does this person have established ASCVD, heart failure, or CKD (reduced eGFR and/or albuminuria)? If yes, an SGLT2 inhibitor and/or a GLP-1 receptor agonist with proven benefit belongs on the regimen from diagnosis, independent of metformin and independent of the A1c.
2. Is weight a treatment target? A GLP-1 RA or dual GIP/GLP-1 agonist with weight benefit is high-yield.
3. What is the A1c target and how far is the patient from it? Add or intensify for glycemia without stacking two drugs that share the same harm.
4. Metformin remains useful, inexpensive, weight-neutral or slightly weight-reducing, and common. It is not a mandatory universal first step that must be completed before an organ-protective agent in high-risk type 2 diabetes.

Do not fail an item by refusing empagliflozin after a recent HFrEF hospitalization until metformin is optimized. Do not refuse semaglutide after an NSTEMI because the A1c is already 6.8%.

Metformin: still a workhorse, with eGFR rules

Metformin is a biguanide that mainly reduces hepatic glucose production. Gastrointestinal upset is common; titrate, use extended-release, and take with food. Long-term use can lower vitamin B12 — check when neuropathy or anemia appears. Lactic acidosis is rare and is a renal or hypoperfusion story, not a reason to withhold the drug from a healthy kidney.

The retired sex-based creatinine cutoffs (1.4 / 1.5 mg/dL) are not current. Section 9.2 already drilled this; the endocrine exam item will hide it inside a new type 2 diagnosis.

SGLT2 inhibitors: heart, kidney, and a sick-day hold

Empagliflozin, dapagliflozin, canagliflozin, and related agents inhibit proximal-tubule glucose reabsorption. Outcome trials, not the A1c drop, are why you prescribe them in HFrEF, HFpEF, CKD with albuminuria, and ASCVD. Benefit for heart failure and CKD extends into ranges where the glycemic effect is small — that is the point of independent of A1c.

Counsel and do not skip:

• Genital mycotic infections (candida vaginitis, balanitis). Teach hygiene; treat promptly; this is not an automatic lifetime ban after one episode.
• Volume depletion and a small early eGFR dip. Hold or be cautious in a frail adult on a loop diuretic in a heat wave.
• Euglycemic DKA. Hold the SGLT2 inhibitor for sick days, prolonged fasting, and major surgery. Check ketones if the patient is nauseated even when the glucose is 160 mg/dL.
• Rare Fournier gangrene — severe genital or perineal pain and swelling go to the ED, not a watchful yeast cream.
• Foot care remains mandatory. Historical amputation signals do not cancel indicated cardiorenal therapy, but they do cancel neglect of ulcers.

Do not start two SGLT2 inhibitors. Do not promise glycemic rescue at eGFR 22 — you may still use some agents for kidney or heart protection per current labeling, but the glucose-lowering effect fades as filtered glucose falls.

GLP-1 receptor agonists and dual GIP/GLP-1 agonists

Weekly semaglutide, dulaglutide, daily liraglutide, and the dual GIP/GLP-1 agonist tirzepatide lower glucose, lower weight, and — for several GLP-1 RAs with outcome data — reduce major adverse cardiovascular events. Dual agonists currently lead on weight and A1c; cardiovascular and liver-benefit language continues to evolve in ADA 2026, including benefit signals in MASH and in some heart-failure phenotypes. For the exam, know the class actions and the counseling, not a brand-share chart.

Titrate for the gut. Nausea, vomiting, early satiety, and constipation are expected if you jump doses. Eat smaller meals, stop at fullness, and go slowly. Rapid uptitration is why people quit.

Boxed warning counseling (thyroid C-cell). Rodent C-cell tumors led to a boxed warning. Do not start if there is a personal or family history of medullary thyroid carcinoma or MEN2. Counsel patients to report a neck mass, dysphagia, or persistent hoarseness. This is counseling, not a calcitonin screening program in average-risk adults.

Retinopathy caution. A rapid A1c drop can transiently worsen preexisting diabetic retinopathy (seen with semaglutide in SUSTAIN-6). If the patient has proliferative disease or recent photocoagulation, coordinate with ophthalmology and do not crash the A1c in one month.

Other implementation facts. Gallbladder disease is increased. Do not start during active pancreatitis. Injectable teaching is Implementation. Oral semaglutide exists but has strict empty-stomach timing. Peri-procedure aspiration risk has led to hold guidance before anesthesia — follow current anesthesia and FDA language rather than inventing a universal number of days.

Insulin: when waiting is the error

Start insulin — do not add a fifth oral — when:

• The patient has type 1 or you cannot exclude it
• There are catabolic features: marked hyperglycemia with weight loss, ketonuria, or a hypertriglyceridemic crisis
• A1c is very high with symptoms (many clinicians use a threshold around 10% plus polyuria and weight loss as an insulin cue)
• Glucotoxicity is blocking any other agent from working
• Pregnancy requires it on the obstetric plan

Typical primary-care start in type 2 is basal insulin (often 10 units daily or 0.1–0.2 units/kg), with a hypoglycemia plan and follow-up in days, not months. Educate injection sites, timing, and what to do if a meal is missed. Prandial insulin comes next if fasting is controlled and post-meal readings are not. Never stop basal insulin in type 1.

Sulfonylureas, thiazolidinediones, and DPP-4 inhibitors

Sulfonylureas (glipizide, glimepiride; glyburide is the worst choice in older adults — Beers) stimulate insulin release regardless of glucose. They cause hypoglycemia and weight gain. They are inexpensive and still appear when cost is the barrier (ADA acknowledges lower-cost options). If you use one, pick a shorter-acting agent, teach the 15-15 rule, and do not combine it blindly with insulin without a dose-reduction plan.

Thiazolidinediones (pioglitazone) sensitize muscle and fat. They cause fluid retention and are contraindicated in symptomatic heart failure (avoid NYHA class III–IV). They increase fracture risk and carry a bladder-cancer caution. They have a metabolic and MASLD rationale in selected patients without heart failure. Do not add pioglitazone to a patient you just hospitalized for decompensated HF.

DPP-4 inhibitors drop A1c modestly and are well tolerated. Do not stack a DPP-4 inhibitor on a GLP-1 RA — they share the incretin pathway and you gain cost without meaningful extra benefit. Saxagliptin has a heart-failure caution.

Do not duplicate the same risk

Vignette. A 64-year-old with HFrEF, eGFR 48, UACR 180 mg/g, BMI 34, and a new A1c of 7.6% needs an SGLT2 inhibitor with HF/CKD benefit now, plus a conversation about a GLP-1 RA for weight and residual ASCVD risk. Metformin can be added if eGFR allows and GI tolerance is acceptable. Starting glyburide because it is cheap and first-line is the 2018 wrong answer.

Planning names the organ-protective class from the comorbidity. Implementation writes the mycotic, DKA-hold, GI-titration, and C-cell counseling. Evaluation is the 3-month A1c, the weight, the eGFR, and whether any lows occurred.