Regimen · short-term

• A1C jumped from 6.5% to 9.0% — what specific factor do we think drove the regression, and what's the target A1C and timeline on the new combo?
• Glipizide was doubled to 10 mg twice daily the same day Jardiance and Actos were added. As the SGLT-2 + TZD start working, what's the taper plan for glipizide to avoid hypoglycemia (especially stacked with insulin lispro)?
• What are my "sick day rules" for Jardiance — when do I hold it (illness, dehydration, low intake) to avoid euglycemic DKA?

Pioglitazone (Actos) · cancer-risk conversation

Pioglitazone has a duration- and dose-dependent bladder cancer signal: BMJ 2016 (HR 1.63 over 14.5y), partially offset by the negative Kaiser 10y cohort which found no bladder signal but small prostate (+13%) and pancreatic (+41%) signals. AAFP notes NNT-to-harm ~20,903. France and Germany suspended the drug; FDA kept it with a label warning.

• Is there anything in my chart or family history (bladder, prostate, pancreatic cancer) that argues against pioglitazone vs an alternative TZD-sparing combo?
• What's our exit criterion for pioglitazone — a duration cap (12 / 24 months), an A1C target met, or symptom triggers?
• Should I get a baseline urinalysis given pioglitazone + SGLT-2 + my age, with periodic re-checks?
• Any baseline symptoms I should watch for: gross hematuria, unexplained urinary urgency, new-onset back/pelvic pain.
• Pioglitazone also carries a boxed warning for heart failure, plus fluid retention, bone-fracture risk, and macular edema — anything in my profile that raises any of those?

Empagliflozin (Jardiance) · non-cancer risk profile

2025 FDA label does not list cancer as a labeled risk (Jardiance label, 2025). The real signals are infection and volume.

• Genital mycotic infections and UTIs are elevated on SGLT-2s — what's the early-symptom plan and threshold for calling in?
• Rare necrotizing fasciitis of the perineum (Fournier's gangrene) — what warning signs warrant urgent care?
• Will we monitor eGFR and LDL given the modest expected changes on therapy?

Glipizide · sulfonylurea

No strong drug-specific cancer signal; class-level weak associations with liver/pancreatic cancer are usually attributed to chronic hyperinsulinemia rather than the drug itself (AHDB review). The dominant near-term risk is hypoglycemia.

• When the new combo kicks in, can we step glipizide back down or off as the SGLT-2 + TZD pick up the load?
• Should we make sure I have glucagon (GlucaGen) available and a clear low-glucose protocol given doubled dose + insulin lispro?

Metformin · keep on it

Metformin is consistently associated with lower cancer incidence and better cancer survival in diabetics (AHDB review). The 2020 NDMA recall was lot-specific, not the drug itself.

• Confirm my current metformin formulation isn't on a recalled-lot list.
• Any reason to up the metformin dose before relying on the new agents?

Decision framing

• If A1C comes back to target on this 4-drug combo, in what order do we de-escalate — glipizide first, then pioglitazone?
• What labs/imaging do you want at the 3-month and 6-month check-ins so we catch problems early?
• What's our "stop pioglitazone" trigger — specific symptom, lab abnormality, or duration?