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

CentralAdiposity

Dyslipidemia

Abnormal Glucose

Metabolism

PeripheralLipoatrophy

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;13:1000-2.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 42.0 42.8 0.53

Male gender (%) 15 (60) 12 (52.2) 0.59

CD4 count, cells/mm3 370 420 0.61

HIV RNA, log 10 copies/mL

2.94 2.26 0.09

Current PI use (%) 13 (52) 12 (52) 0.99

BMI, kg/m2 27.3 28.9 0.23

Fasting glucose, (mg/dL) 94.0 97.2 0.73

Fasting insulin, µU/mL 15.7 14.4 0.09

Glucose AUC (120 min), (mmol/L)

8.32 8.70 0.81

Visceral adipose tissue (VAT), cm2

176 172 0.91

Appendicular fat mass, kg

9.84 12.26 0.29

Baseline Characteristics

Change in VAT at week 24

140

145

150

155

160

165

170

175

180

metformin

week 0week 24

placebo

Mea

n V

AT

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 24Adjusted For Age, Height, and Baseline VAT

Metformin

n=18

Placebo

n=18

P value

Appendicular Fat Mass, g

-686 161 0.03

Mean Change in Appendicular Fat Mass at wk 24

Metformin

n=18

Placebo

n=18

P value

Appendicular fat mass, g

-614 95 .12

Change in Appendicular Fat Mass at wk 24Adjusted for Age, Height, Baseline

Appendicular Fat Mass

Metformin

n=20

Placebo

n=19

P value

HDL, mg/dL -0.5 -0.7 .95

LDL, mg/dL 3.9 -6.2 .65

TG, mg/dL -13.0 9.9 .68

Change in Lipid Profile at wk 24Adjusting 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/m2)

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