A Randomized Placebo- Controlled Trial of Metformin for the Treatment of HIV Lipodystrophy Rakhi Kohli MD MS, Christine Wanke MD, Sherwood Gorbach MD, Abby Shevitz MD MPH Division of Geographic Medicine and Infectious Disease Tufts-New England Medical Center Boston, MA

Central Adiposity Dyslipidemia Abnormal Glucose Metabolism Peripheral Lipoatrophy HIV-Associated Lipodystrophy

Metformin Biguanide insulin-sensitizing agent Decreases hepatic glucose output Stimulates glucose uptake by peripheral tissues

Metformin in Treatment of HIV Lipodystrophy Prior studies focused on HIV+ persons with central adiposity and severe insulin resistance (>20 µU/mL) Metformin  insulin AUC, weight, triglycerides, and visceral adipose tissue (VAT) Limited by short duration and low dose Saint-Marc et al. AIDS 1999;13: Hadigan et al. JAMA 2000;284:472-7.

Metformin in Treatment of HIV Lipodystrophy Efficacy of metformin in HIV+ persons with central adiposity and without marked insulin resistance not well studied

Objective To investigate the effect of metformin vs. placebo in HIV+ persons with central adiposity and fasting insulin <18 µU/mL: –Primary endpoints: –Visceral adipose tissue (single slice abd CT) –Appendicular fat mass (DEXA) –Secondary endpoints: –Serum HDL, LDL, triglycerides –Glucose and insulin AUC from 2 hr 75 g OGTT

Methods Participants included HIV+ men and women with self-reported increase in abdominal girth and abnormal waist-hip ratio (≥0.95 in men and ≥0.85 in women) Randomly assigned in double blind fashion to receive metformin 1500 mg or placebo daily for 24 weeks

Methods Persons with history of diabetes or previously undiagnosed diabetes excluded At baseline and 24 wks following measures obtained: –Single slice CT scan at level of L4 pedicle –DEXA –Lipid profile –2 hr 75 gm OGTT

Metformin n=25 Placebo n=23 P value Age, y Male gender (%)15 (60)12 (52.2)0.59 CD4 count, cells/mm HIV RNA, log 10 copies/mL Current PI use (%)13 (52)12 (52)0.99 BMI, kg/m Fasting glucose, (mg/dL) Fasting insulin, µU/mL Glucose AUC (120 min), (mmol/L) Visceral adipose tissue (VAT), cm Appendicular fat mass, kg Baseline Characteristics

Change in VAT at week 24 placebo Mean VAT cm 2 P=.17

Metformin n=17 Placebo n=19 P value VAT-10.1 %-3.2 %0.58 Percentage Change in VAT at wk 24 Adjusted For Age, Height, and Baseline VAT

Metformin n=18 Placebo n=18 P value Appendicular Fat Mass, g Mean Change in Appendicular Fat Mass at wk 24

Metformin n=18 Placebo n=18 P value Appendicular fat mass, g Change in Appendicular Fat Mass at wk 24 Adjusted for Age, Height, Baseline Appendicular Fat Mass

Metformin n=20 Placebo n=19 P value HDL, mg/dL LDL, mg/dL TG, mg/dL Change in Lipid Profile at wk 24 Adjusting for Age, Height, and Baseline Values

Change in Glucose Metabolism and BMI at wk 24 Metformin vs. placebo did not significantly improve glucose or insulin AUC at week 24 Metformin group did not experience significant change in fasting glucose or insulin at week 24 Metformin group experienced significant reduction in BMI at week 24 (from a mean of 27.3 to 25.7 kg/m 2 )

Summary Metformin did not significantly improve fat redistribution or dyslipidemia in HIV+ persons with central adiposity and fasting insulin < 18 µU/mL Metformin associated with unexpected trend in reduction in appendicular fat mass Metformin did not significantly improve insulin AUC at week 24 compared to placebo

Conclusions Data suggests that metformin should be used with caution in HIV lipodystrophy Reserved for persons with marked insulin resistance and adequate subcutaneous fat