Prescribing cascades don’t usually start with “bad” medications. In fact, they often begin with some of our most effective therapies. Metformin, SGLT2 inhibitors, and GLP-1 receptor agonists all have strong outcome data in type 2 diabetes. But when adverse effects are misinterpreted as new medical conditions, patients can quickly accumulate unnecessary medications, testing, and harm. Recognizing these cascades and diabetes polypharmacy early is a key skill for any clinician.

Metformin

Metformin remains a useful therapy for type 2 diabetes, but gastrointestinal intolerance is common, especially early in therapy or with dose escalation.

Common adverse effects include diarrhea, abdominal cramping, bloating, and nausea. When these symptoms are not linked back to metformin, patients are often started on antidiarrheals, antispasmodics, or even proton pump inhibitors, leading to diabetes polypharmacy and the prescribing cascade. Over time, a short-term side effect turns into long-term therapy for a problem that never needed another drug. New-onset diarrhea or GI upset shortly after starting or increasing metformin should trigger a dose reduction, switch to extended-release, change in therapy, or slower titration before adding symptom-treating medications (excellent board exam nugget).

SGLT-2 Inhibitors

In addition to their blood sugar-lowering effects, SGLT2 inhibitors (i.e. empagliflozin) offer cardiovascular and heart failure benefits, as well as renal protection. However, their mechanism of action makes genitourinary adverse effects predictable.

Patients may develop genital mycotic infections, urinary frequency, dysuria, or volume depletion. These symptoms are sometimes treated with repeated antifungals or antibiotics for presumed UTIs, or bladder medications when polyuria is misinterpreted. Recurrent yeast infections or UTIs after starting an SGLT2 inhibitor should prompt reassessment of dose, hydration, hygiene counseling, or drug continuation rather than reflexive prescribing.

GLP-1 Agonists

GLP-1 receptor agonists are increasingly used for both diabetes and weight management, but nausea and vomiting are common complaints. These adverse effects can lead to prescriptions for antiemetics or acid-suppressing therapy. Significant GI symptoms requiring the use of new medications should always trigger a review of GLP-1 dosing, titration speed, and ongoing appropriateness—especially in older adults where diabetes polypharmacy may be more likely.

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