Objective <p>We aimed to evaluate the potential metabolic benefits of pioglitazone, a PPARG agonist, and sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with familial partial lipodystrophy (FPLD).</p> Methods <p>This retrospective medical chart study included 38 adult patients with FPLD (18 treated with pioglitazone and 20 with SGLT2 inhibitors).</p> Results <p>Treatment with pioglitazone reduced HbA1c from 8.6% (6.2–9.2) to 7.0% (5.9–8.8) at month 6 (p = 0.004) and 7.0% (6.1–8.7) at month 12 (<i>p</i> = 0.107). Triglycerides decreased by 25% (6–55%) at month 6 (p = 0.001) and 16% (4–44%) at month 12 (<i>p</i> = 0.008). A modest reduction in ALT was observed at month 12 (<i>p</i>= 0.046). Treatment with SGLT2 inhibitors reduced HbA1c from 8.7% (7.9–10.2) at baseline to 8.1% (7.4–9.4) at month 6 (p = 0.003) and 7.9% (7.3–8.9) at month 12 (<i>p</i> = 0.003). Median triglyceride levels decreased by 11% (0–33%) at month 6 (p = 0.013), while changes at month 12 were not significant. No meaningful changes were observed in weight, ALT, or AST.</p> Conclusions <p>We observed modest metabolic improvements following treatment with pioglitazone and SGLT2 inhibitors in patients with FPLD.</p>