leptin replacement therapy improves insulin resistance in highly active antiretroviral therapy...
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Leptin Replacement Therapy Improves Insulin Resistance in Highly Active Antiretroviral Therapy (HAART)Induced Lipodystrophy and Metabolic Syndrome in HIV+ Patients
Jennifer H. Lee1, Jean L. Chan1, Robyn Murphy2, Alex M. DePaoli2, Christos S. Mantzoros1
1Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 2Amgen Inc., Thousand Oaks, CA
1 contains effects for treatment, period, and treatment-by-period interaction2 contains effects for treatment, period, treatment-by-period interaction, and change in visceral fat mass.
Mean (SE) Range
Age (yrs) 45.8 (2.0) 39 - 53
Sex (male) 7 N/A
BMI (kg/m2) 21.8 (0.8) 19.4 – 24.8
Fasting insulin (IU/ml) 11.5 (2.7) 1.7 – 19.5
Fasting glucose (mg/dl) 81.1 (6.7) 60-108
HbA1c (%) 5.1 (0.3) 4.2 – 6.9
Leptin (ng/ml) 1.34 (0.2) 0.89 – 2.59
Triglyceride (mg/dl) 530 (53.8) 305 - 669
CD4 count (cells/ l) 454 (94) 80 - 820
HIV viral load (copies/ml) 24,524 (13,693) <50 – 80,500
BackgroundHighly active antiretroviral therapy (HAART) for HIV
infection may cause a metabolic syndrome characterized by insulin resistance, hyperlipidemia and lipodystrophy. A previously published uncontrolled study showed that leptin replacement therapy dramatically improves the metabolic syndrome associated with congenital or acquired non-HIV lipoatrophy.
We conducted a double-blinded, randomized, placebo-controlled, cross-over study to test the hypothesis that leptin replacement to physiologic levels would improve the metabolic abnormalities associated with HAART-induced HIV lipoatrophy.
Methods7 HIV-1-infected lipoatrophic and leptin-deficient
adults on HAART were randomized to receive recombinant-methionyl human leptin at a physiologic dose or placebo for 2 months. After a one-month washout period, the subjects were crossed-over to the alternate therapy for 2 additional months.
We determined the effect of leptin therapy on insulin resistance (Boost challenge test and insulin suppression test), lipid and apolipoprotein levels, lipoprotein particle size, hormone levels (insulin, TNF-α, IL-6, CRP, adiponectin), glycemia, free fatty acids, body composition (anthropometry, BIA, DEXA, abdominal CT scan), HIV viral load, lymphocyte subsets, blood pressure.
Repeated-measures ANOVA and linear models with independent factors controlling for treatment, period, treatment-by-period interaction, and visceral fat mass were used.
Baseline Characteristics
HOMA-IR declines with leptin therapy
0
1
2
3
4
5
6
7
HO
MA
-IR
Pre-therapy
Post-therapy
Leptin Placebo
P<0.03 P=0.22
Rpt-measuresANOVA
Baseline insulin declines with leptin therapy
0
5
10
15
20
25
30
Ins
ulin
(u
IU/m
l)
Pre-therapy
Post-therapy
Absolute Changes in Insulin Sensitivity, Body Composition & LipidsMain Model1 (LSM ± SE) VFat Model2 (LSM ± SE)
Leptin Placebo p-value Leptin Placebo p-value
Insulin Sensitivity
Fasting Insulin -4.90 ± 3.77 5.69 ± 4.22 0.103 -4.89 ± 2.86 6.78 ± 3.22 0.035
Fasting Glucose 1.50 ± 2.45 3.25 ± 2.74 0.648 1.50 ± 2.64 3.24 ± 2.98 0.679
HOMA-B -83.04 ± 43.49 44.98 ± 48.62 0.091 -82.96 ± 31.25 58.07 ± 35.26 0.024
HOMA-IR -1.03 ± 0.82 1.31 ± 0.92 0.099 -1.03 ± 0.62 1.54 ± 0.71 0.035
Body Composition
Weight (kg) -1.30 ± 0.81 2.20 ± 0.90 0.024
Fat mass (gm) -598.30 ± 98.91 257.08 ± 110.59 <0.001
Visceral Fat (gm) -12.50 ± 18.72 -5.00 ± 20.93 0.797
Liver Fat (mL) 0.06 ± 0.69 -0.16 ± 0.77 0.839
Liver Volume (mL) -174.50 ± 101.1 -5.42 ± 113.03 0.302
Lipids Cholesterol (mg/dL) 24.08 ± 9.30 -15.67 ± 10.40 0.025
Triglycerides (mg/dL) 100.92 ± 104.24 71.13 ± 116.54 0.854
HDL (mg/dL) 3.78 ± 2.19 -3.52 ± 2.45 0.062
LDL (md/dL) 4.03 ± 14.36 -11.98 ± 16.06 0.482
SummaryBaseline insulin levels decline significantly after 2 months of leptin therapy compared to placebo
HOMA also decreases significantly on leptin therapy.
Leptin therapy causes a decrease in fat mass and weight.
There were no significant changes in triglyceride levels, liver fat or visceral fat content.
ConclusionLeptin replacement therapy mildly improves insulin resistance in HIV-1-infected adults with HAART-induced lipoatrophy and metabolic syndrome.
Leptin
P=0.04
Placebo
P=0.24
Rpt-measuresANOVA