The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No.

11, e4327–e4339
https://doi.org/10.1210/clinem/dgab499
Clinical Research Article

Clinical Research Article

Leptin Attenuates Cardiac Hypertrophy in

Patients With Generalized Lipodystrophy

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My-Le Nguyen,1 Vandana Sachdev,1 Thomas R. Burklow,2 Wen Li,1
Megan Startzell,3 Sungyoung Auh,3 and Rebecca J. Brown3
1
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA;
2
NIH Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA; and 3National Institute of
Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
ORCiD number: 0000-0002-2589-7382 (R. J. Brown).

Abbreviations: BP, blood pressure; GLD, generalized lipodystrophy; HOMA-IR, homeostasis model assessment of insulin
resistance; LV, left ventricular; PLD, partial lipodystrophy; RV, right ventricular.
Received: 7 May 2021; Editorial Decision: 1 July 2021; First Published Online: 5 July 2021; Corrected and Typeset:
30 July 2021.

Abstract
Context: Lipodystrophy syndromes are rare disorders of deficient adipose tissue,
low leptin, and severe metabolic disease, affecting all adipose depots (generalized
lipodystrophy, GLD) or only some (partial lipodystrophy, PLD). Left ventricular (LV)
hypertrophy is common (especially in GLD); mechanisms may include hyperglycemia,
dyslipidemia, or hyperinsulinemia.
Objective: Determine effects of recombinant leptin (metreleptin) on cardiac structure
and function in lipodystrophy.
Methods: Open-label treatment study of 38 subjects (18 GLD, 20 PLD) at the National
Institutes of Health before and after 1 (N = 27), and 3 to 5 years (N = 23) of metreleptin.
Outcomes were echocardiograms, blood pressure (BP), triglycerides, A1c, and
homeostasis model assessment of insulin resistance.
Results: In GLD, metreleptin lowered triglycerides (median [interquartile range] 740
[403-1239], 138 [88-196], 211 [136-558] mg/dL at baseline, 1 year, 3-5 years, P < .0001), A1c
(9.5 ± 3.0, 6.5 ± 1.6, 6.5 ± 1.9%, P < .001), and HOMA-IR (34.1 [15.2-43.5], 8.7 [2.4-16.0],
8.9 [2.1-16.4], P < .001). Only HOMA-IR improved in PLD (P < .01). Systolic BP decreased
in GLD but not PLD. Metreleptin improved cardiac parameters in patients with GLD,
including reduced posterior wall thickness (9.8 ± 1.7, 9.1 ± 1.3, 8.3 ± 1.7 mm, P < .01),
and LV mass (140.7 ± 45.9, 128.7 ± 37.9, 110.9 ± 29.1 g, P < .01), and increased septal e′
velocity (8.6 ± 1.7, 10.0 ± 2.1, 10.7 ± 2.4 cm/s, P < .01). Changes remained significant after
adjustment for BP. In GLD, multivariate models suggested that reduced posterior wall
thickness and LV mass index correlated with reduced triglycerides and increased septal

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e4328  The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11

e′ velocity correlated with reduced A1c. No changes in echocardiographic parameters

were seen in PLD.
Conclusion: Metreleptin attenuated cardiac hypertrophy and improved septal e′
velocity in GLD, which may be mediated by reduced lipotoxicity and glucose toxicity.
The applicability of these findings to leptin-sufficient populations remains to be
determined.
Key Words: Leptin, lipodystrophy, cardiomyopathy, left ventricular hypertrophy

Lipodystrophy syndromes are a rare group of heter- function in patients with lipodystrophy are not known.

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ogenous disorders whose common feature is a selective
deficiency of adipose tissue, which may lead to low
levels of adipokines such as leptin (1). The distribution
of missing fat in lipodystrophy syndromes may involve
nearly the entire body (generalized lipodystrophy, associ-
ated with very low leptin) or only selected adipose depots
(partial lipodystrophy, associated with variable leptin,
ranging from low to normal or even high) (2). The com-
bination of hyperphagia from leptin deficiency and low
adipose tissue storage capacity leads to ectopic lipid de-
position in muscle and liver, resulting in severe metabolic
disease with insulin resistance, diabetes, dyslipidemia, and
nonalcoholic fatty liver disease (1).
A variety of cardiac manifestations have been observed
in patients with lipodystrophy, including hypertension,
cardiac conduction system abnormalities, cardiac auto-
nomic dysregulation, coronary artery disease, and hyper-
trophic cardiomyopathy (1, 3-8). Left ventricular (LV)
hypertrophy is the major cardiac abnormality in patients
with generalized lipodystrophy, present in approximately
half of patients (5). Other associated cardiac abnormal-
ities in patients with generalized lipodystrophy include
diastolic dysfunction (5, 9-11) and dilated cardiomyop-
athy (5, 12). The mechanisms leading to LV hypertrophy
and cardiomyopathy in generalized lipodystrophy are not
clear, and may include hypertension, glucose toxicity from
inadequately controlled diabetes, ectopic lipid deposition
leading to lipotoxicity, or excess insulin action via insulin-
like growth factor-1 receptors (13-15).
Administration of recombinant human methionyl
leptin (metreleptin) to patients with lipodystrophy has
been shown to reduce hyperphagia and improve meta-
bolic complications of lipodystrophy, including insulin
resistance, hyperglycemia, and hypertriglyceridemia.
More dramatic benefits have been observed in patients
with generalized lipodystrophy and very low leptin con-
centrations, vs those with partial lipodystrophy who have
higher leptin concen­trations (2, 16-21). This is consistent
with leptin biology being most relevant in the transi-
tion from leptin deficiency to sufficiency. The effects of
metreleptin administration on cardiac structure and
We hypothesized that metreleptin would improve cardiac
structure and function in patients with lipodystrophy, that
these effects would be more pronounced in patients with
severe leptin deficiency due to generalized lipodystrophy,
and that improvements in cardiac parameters would be
associated with reductions in glucose, triglycerides, and/
or insulin.
Materials and Methods
Eligibility Assessment
Patients with lipodystrophy participated in prospective,
open-label, interventional studies of metreleptin
(NCT00005905, NCT00025883, or NCT01778556) at
the National Institutes of Health (NIH) Clinical Center,
Bethesda, MD, between 2000 and 2019. Studies were ap-
proved by the Institutional Review Board of the National
Institute of Diabetes and Digestive and Kidney Diseases.
All subjects or their legal guardians provided written con-
sent, and minors provided assent, prior to participation.
All studies had comparable eligibility criteria and
metreleptin treatment. Eligibility criteria for the clinical
trials included a clinical diagnosis of non-HIV–associated
lipodystrophy, age 6 months or older, leptin level <12 ng/
mL in females and <8 ng/mL in males, and ≥1 metabolic
abnormality, including diabetes per 2007 American Diabetes
Association criteria, fasting hyperinsulinemia (>30 µU/mL),
or hypertriglyceridemia (>200 mg/dL). Among participants
in clinical trials, the subgroup eligible for inclusion in this
analysis had echocardiograms at initiation of metreleptin
(range, 9 months prior to 1 week after), and at least 1 time
point thereafter, either after 1 year (range, 6-18 months), and/
or after 3 to 5 years of metreleptin administration. Subjects
<18 years of age were included only if they had achieved
final, adult height based on review of growth charts.
Metreleptin Administration
Metreleptin was administered by subcutaneous injec-
tion once or twice daily, dosed according to weight
(sex and age dependent) as previously published (20).
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11
Doses of concomitant medications for diabetes and
hypertriglyceridemia were not increased during the first
year of metreleptin treatment but were lowered or discon-
tinued if clinically indicated (eg, for hypoglycemia) and
were increased or decreased as clinically indicated after
the first year. Doses of blood pressure (BP) medications
were adjusted as clinically indicated throughout the trials.
Medication adjustments were performed per usual clinical
care in a nonprotocolized manner.
Laboratory Assays and Vital Signs
Blood samples were obtained after an 8- to 12-hour fast
for measurement of triglycerides, low-density lipopro-
tein cholesterol, high-density lipoprotein cholesterol,
C-peptide, insulin, glucose, and hemoglobin A1c using
the standard techniques of the NIH Clinical Center
Laboratory. For patients taking exogenous insulin, the
last dose of insulin was given the day prior to blood
sample collection. The homeostasis model assessment
of insulin resistance (HOMA-IR) was calculated as glu-
cose (mg/dL) × insulin (µU/mL) ÷ 405 for all patients
(including insulin users). Leptin concentration in fasting
serum samples was measured prior to metreleptin initi-
ation by radioimmunoassay (EMD-Millipore, Billerica,
MA). Single measurements of BP and heart rate were
obtained with an automated BP monitor with patient-
appropriate cuff size using oscillometry with stepwise de-
flation pressure (Phillips SureSigns VS3) in the morning
in the fasted, resting state, after sleeping overnight in the
research hospital.
Echocardiography
Transthoracic echocardiograms performed at baseline,
1 year, and 3 to 5 years of follow-up were overread by a
cardiologist (M.N.) in a blinded fashion. Echocardiograms
were performed using commercially available systems
with measurements performed according to American
Society of Echocardiography guidelines. The LF ejection
fraction was calculated using the biplane Simpson’s for-
mula (normal male ≥52%, female ≥54%). LV mass was
indexed to body surface area. Normal ranges for LV mass
indices for women are 43 to 95 g/m2 and for men are 49 to
115 g/m2. LV hypertrophy was defined as LV mass index
>95 g/m2 in women and >115 g/m2 in men (1). LV global
longitudinal strain was quantified by 2D speckle-tracking
echocardiography and was used to detect subclinical
LV dysfunction. Strain analysis was performed offline
using a specialized strain software (Echoinsight, Epsilon
Imaging, Ann Arbor, MI, USA, version 3.1.0.3358).
e4329
Echocardiographic parameters were categorized as
normal or abnormal based on published normative data
for men and women, when applicable (22-26).
Statistical Analysis
Continuous outcomes are summarized as mean ± SD or
median (interquartile range), as appropriate, and categor-
ical outcomes are summarized using frequencies. Non-
normally distributed data were log-transformed prior to
analyses. Missing data were not imputed. Baseline char-
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acteristics between subjects with generalized vs partial
lipodystrophy were compared using the unpaired t-test (for
continuous variables) and chi-squared test (for categor-
ical variables). All analyses were conducted for the entire
cohort (generalized plus partial lipodystrophy) and sep-
arately for the generalized and partial subgroups. Effects
of metreleptin on metabolic and cardiac parameters after
1 year and 3 to 5 years were analyzed using linear mixed
models with post hoc Dunnett-corrected comparisons of
baseline vs 1 year, and baseline vs 3 to 5 years. Changes in
categorization of echocardiographic parameters as within
or outside normal ranges after metreleptin was performed
using generalized estimation equation models, with post
hoc Dunnett-corrected comparisons of baseline vs 1 year,
and baseline vs 3-5 years. Additional models were ana-
lyzed as above with the inclusion of baseline age and
sex, systolic and diastolic BP, with or without number of
antihypertensive medications in addition to BP, and were
performed to assess whether baseline characteristics or
changes in BP or antihypertensive medication use could
account for changes in cardiac structure or function.
Differences in metreleptin effects between generalized and
partial lipodystrophy were assessed using linear mixed
models as described above with inclusion of a group (par-
tial vs generalized) by time interaction term, with P < .1
used to define a likely interaction. To assess potential me-
diators of changes in cardiac parameters after metreleptin,
we analyzed linear mixed models with potential covariates
included based on biological plausibility and statistically
significant changes after metreleptin. Potential covariates
included were endogenous leptin concentration, triglycer-
ides, insulin, hemoglobin A1c, and heart rate. Systolic and
diastolic BP were included as required covariates in vari-
able selection models. As this was an ancillary analysis of
prospectively obtained data, no a priori sample size cal-
culations were performed. Statistical analyses were per-
formed using GraphPad Prism (version 6.05, GraphPad
Software, La Jolla, CA, USA) and SAS 9.4 (SAS Institute
Inc., Cary, NC, USA). Except as noted above, P < .05 was
considered to represent statistical significance.
e4330 
Results
Baseline Characteristics
A flow diagram of subject eligibility is shown in Fig. 1.
One hundred and eight subjects with lipodystrophy who
were treated with metreleptin and had at least 1 echocar-
diogram performed at NIH were considered for inclusion.
Thirty-eight subjects met the inclusion criteria, of whom
27 had echocardiograms performed prior to and after
1 year, and 23 had echocardiograms performed prior to
and after 3 to 5 years of metreleptin.
Of the 38 subjects included, 18 had generalized
lipodystrophy (15 females, 3 males). Of these, 3 had ac-
quired generalized lipodystrophy, 9 had pathogenic vari-
ants in AGPAT2, 3 had pathogenic variants in BSCL2, 2
had pathogenic variants in LMNA (1 with a heterozygous
variant causing atypical progeria, and 1 with biallelic
variants), and in 1 the causal gene was not known. Twenty
subjects had partial lipodystrophy (18 females, 2 males).
Of these, 1 had acquired partial lipodystrophy secondary
to juvenile dermatomyositis, 7 had pathogenic variants in
LMNA, 4 in PPARG, and 8 had unknown genetics (nega-
tive for LMNA and PPARG but with autosomal dom-
inant inheritance pattern).
Baseline metabolic characteristics of the overall co-
hort, and the subgroups with generalized and partial
lipodystrophy, are in Table 1. The median (interquar-
tile range) age at baseline was 20.5 (16.0-39.8) years;
subjects with generalized lipodystrophy were younger
than those with partial lipodystrophy (16.5 [13.8-
21.3] vs 36.0 [17.0-51.5] years, P = .0002). As ex-
pected, serum leptin concentrations prior to metreleptin
initiation were lower in subjects with generalized
lipodystrophy than in those with partial lipodystrophy
(1.0 [0.6-2.3] vs 7.0 [4.0-13.5] ng/mL, P < .0001).
The mean dose of metreleptin was 0.11 mg/kg per day
(range 0.06-0.19) after 1 year, and 0.13 mg/kg per day
(range 0.05-0.21) after 3 to 5 years. Of subjects with
108 metrelepn treated subjects with
at least one echocardiogram
38 included in final analysis
27 with follow-up echo aer 1 year
23 with follow-up echo aer 3-5 years
Figure 1. Flow diagram of subjects participating in the study.
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11
generalized lipodystrophy, 44% were taking at least 1
antihypertensive drug at baseline (including angiotensin
converting enzyme inhibitors and angiotensin receptor
blockers, which may be been prescribed for kidney pro-
tection rather than hypertension), vs 60% of subjects
with partial lipodystrophy (P = .52).
Echocardiographic measurements are shown in Table
2. There were no differences between the cohorts with
generalized lipodystrophy and partial lipodystrophy in
measurements of cardiac structure, systolic function,
global longitudinal strain, or estimates of pulmonary
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artery pressure. However, subjects with generalized
lipodystrophy had greater septal e′ velocity and lateral
e′ velocity, and lower E/e′ lateral ratio than those with
partial lipodystrophy, suggesting better baseline diastolic
function in subjects with generalized lipodystrophy, likely
due to their younger age.
At baseline and prior to metreleptin treatment,
approximately half of subjects in both the general-
ized and partial lipodystrophy cohorts had increased
interventricular septum or posterior wall thickness above
the normal range, and about one-third of subjects in both
the generalized lipodystrophy and partial lipodystrophy
cohorts had LV mass index above the normal range (Table
3). The majority of patients had normal LV systolic func-
tion (median ejection fraction 65 [60-65]%). However,
most (71%) had abnormal global longitudinal strain
(mean –16.2 ± 2.3%; normal <–18%) suggesting subclin-
ical systolic dysfunction. Few subjects with generalized
lipodystrophy had clinically abnormal diastolic param-
eters as evidenced by E/A ratio or septal e′ velocity below
the normal range, whereas abnormal diastolic parameters
were more common in subjects with partial lipodystrophy
(Table 3). There was little evidence of abnormal right
heart parameters including right ventricular (RV) systolic
pressure (Table 3), as well as inferior vena cava diam-
eter and tricuspid regurgitation peak velocity (data not
19 excluded as not at adult height
24 excluded for no baseline echo
27 excluded as no follow-up echo
aer 1 or 3-5 years of metrelepn
Table 1. Clinical characteristics and metabolic effects of metreleptin

All Subjects Generalized Lipodystrophy Partial Lipodystrophy

Baseline 1 year (N = 27) 3-5 years Pa Baseline (N = 18) 1 year 3-5 years Pa Baseline 1 year 3-5 years Pa Baseline GLD
(N = 38) (N = 23) (N = 14) (N = 12) (N = 20) (N = 13) (N = 11) vs PLD
Duration of 0 1.0 ± 0.2 3.7 ± 0.6 NA 0 0.9 ± 0.2 3.7 ± 0.5 NA 0 1.1 ± 0.1 3.7 ± 0.7 NA NA
metreleptin (y)
Age (years) 20.5 20.0 25.0 NA 16.5 (13.8-21.3) 18.0 (14.8- 19.5 (16.3- NA 36.0 (17.0- 28.0 (17.5- 50.0 (30.0- NA .0002
(16.0-39.8) (16.0-34.0) (19.0-50.0) 22.3) 24.5) 51.5) 46.5) 62.0)
Leptin (ng/mL) 3.9 (1.0-8.0) 67.3 (20.8- 70.6 (18.1- <.0001b,c 1.0 (0.6-2.3) 82.1 (32.6- 90.3 (14.5- <.0001b,c 7.0 (4.0-13.5) 56.1 (20.3- 67.6 (33.1- 0.0002b,c <.0001
150.0) 134.1) 262.1)k 142.5) 114.6) 129.5)
Weight (kg) 62.2 ± 15.3 60.3 ± 14.1 58.5 ± 13.8 .022c 54.9 ± 12.7 54.1 ± 11.7 50.6 ± 10.5 .21 68.8 ± 14.6 66.8 ± 14.0 67.2 ± 11.8 0.057 .0036
Systolic BP (mmHg) 119 ± 12 114 ± 11 114 ± 14 .12 120 ± 11 117 ± 10 109 ± 16 .046c 118 ± 14 111 ± 11 119 ± 10 0.33 .49
Diastolic BP (mmHg) 69 ± 10 66 ± 10 70 ± 12 .25 71 ± 10 67 ± 10 70 ± 15 .72 68 ± 9 65 ± 10 70 ± 9 0.47 .52
% taking 52.6 59.3 73.9 .25 44.4 78.6 75.0 .028b 60.0 38.5 73.2 0.32 .34
antihypertensives
# antihypertensive 0.8 ± 0.9 0.7 ± 0.8 0.9 ± 0.7 .58 0.7 ± 1.0 0.9 ± 0.7 0.8 ± 0.6 .21 0.9 ± 0.9 0.5 ± 0.8 1.0 ± 0.9 0.25 .24
drugs per subject
g b,c j b,c
Heart rate (beats per 85 ± 12 81 ± 15 77 ± 16 .0082 89 ± 9 82 ± 12 80 ± 16 .018 82 ± 13 80 ± 18 74 ± 16 0.28 .043
minute)
Total cholesterol 206 (151-262) 148 (126-194) 157 (120-198) <.0001b,c 206 (173-264) 138 (99-185) 155 (119- <.0001b,c 218 (137-271) 153 (148- 158 (124- 0.12 .68
(mg/dL) 190) 217) 261)
HDL-C (mg/dL) 27 (23-33)e 27 (25-34)f 29 (24-37)g .22 25 (21-32)l 30 (25-43) 32 (23-38)m .038b 27 (25-35)h 27 (22-31)j 29 (25-36)p 0.78 .13
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11

LDL-C (mg/dL) 80 ± 38h 78 ± 29i 73 ± 33j .66 87 ± 26n 78 ± 32o 74 ± 32p .76 78 ± 43o 77 ± 25p 71 ± 36q 0.36 .68
Triglycerides (mg/dL) 543 (261-1213) 189 (112-384) 228 (183-487) <.0001b,c 740 (403-1239) 138 (88-196) 211 (136- <.0001b,c 310 (234-989) 345 (236- 230 (189- 0.14 .27
558) 628) 487)
Glucose (mg/dL) 147 (118-221) 104 (87-149) 109 (92-146) .0002b,c 159 (125-315) 96 (85-117) 102 (88-152) .0004b,c 137 (109-177) 109 (87-158) 113 (99-146) 0.21 .15
C-peptide (ng/mL) 3.9 ± 2.2 3.3 ± 1.9 3.2 ± 1.4 .18 4.2 ± 2.6 3.7 ± 2.2 3.1 ± 1.7 .36 3.6 ± 1.7 3.0 ± 1.4 3.3 ± 1.1 0.42 .39
Insulin (µU/mL) 39 (17-86) 29 (11-67) 20 (10-58) .0080b,c 55 (25-100) 36 (8-70) 31 (9-57) .032 32 (13-77) 22 (13-72) 12 (10-73) 0.19 .10
HOMA-IR 18.1 (6.2-36.6) 8.5 (2.7-17.5) 5.7 (2.1-16.6) <.0001b,c 34.1 (15.2-43.5) 8.7 (2.4- 8.9 (2.1-16.4) .0002b,c 13 (3.9-27.5) 8.0 (3.4-17.5) 5.4 (2.9- 0.0015b,c .028
16.0) 17.8)
Hemoglobin A1c (%) 8.9 ± 5.6 7.2 ± 2.0 7.0 ± 1.6 .0001b,c 9.5 ± 3.0 6.5 ± 1.6 6.5 ± 1.9 .0003b,c 8.4 ± 2.0 7.9 ± 2.2 7.6 ± 1.2 0.15 .20

Data are presented as mean ± SD or median (interquartile range) based on data distribution.
Abbreviations: BP, blood pressure; GLD, generalized lipodystrophy; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; LDL-C, low-density lipoprotein cholesterol;
PLD, partial lipodystrophy.
a
Overall P value for mixed model;
b
Dunnett-adjusted P < .05 for baseline to 1 year comparison;
c
Dunnett-adjusted P < .05 for baseline to 3-5 year comparison;
d
N = 22, eN = 30; fN = 25; gN = 19; hN = 16; iN = 21; jN = 17; kN = 13; jN = 11; lN = 14; mN = 10; nN = 4; oN = 12; pN = 9; qN = 8.
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 e4332 

Table 2. Changes in echocardiographic parameters after metreleptin

All subjects Generalized Lipodystrophy Partial Lipodystrophy Baseline GLD vs PLD

Baseline 1 year 3-5 years Pa Baseline 1 year 3-5 years Pa Baseline 1 year 3-5 years Pa
(N = 38) (N = 27) (N = 23) (N = 18) (N = 14) (N = 12) (N = 20) (N = 13) (N = 11)
Interventricular 9.6 ± 1.9 8.9 ± 1.4 9.1 ± 2.0 .033 9.6 ± 2.1 9.0 ± 1.3 8.4 ± 2.2 .096 9.7 ± 1.7 8.7 ± 1.5 9.8 ± 1.6 .29 .88
septum (mm)
b,c b,c
Posterior wall (mm) 9.7 ± 1.6 8.9 ± 1.2 8.9 ± 1.7 .0008 9.8 ± 1.7 9.1 ± 1.3 8.3 ± 1.7 .0068 9.6 ± 1.5 8.7 ± 1.2 9.5 ± 1.6 .10 .58
LVEDD (mm) 43.8 ± 4.9 44.2 ± 4.7 44.0 ± 5.2 .65 42.9 ± 4.7 43.3 ± 5.0 42.5 ± 5.4 .86 44.6 ± 5.1 45.0 ± 4.4 45.7 ± 4.7 .51 .32
LVESD (mm) 28.6 ± 3.5 28.2 ± 3.6 28.1 ± 6.5 .67 28.5 ± 3.2 28.3 ± 3.6 26.5 ± 8.2 .36 28.8 ± 3.8 28.2 ± 3.8 29.8 ± 3.4 .80 .81
LV mass (g) 144.7 ± 49.8 129.9 ± 39.3 131.7 ± 48.5 .018c 140.7 ± 45.9 128.7 ± 37.9 110.9 ± 29.1 .0088c 148.3 ± 53.9 131.2 ± 42.3 154.3 ± 56.3 .69 .65
LV mass index (g/m2) 84.7 ± 22.7 78.4 ± 17.4 79.5 ± 20.5 .068 88.6 ± 22.0 81.6 ± 16.9 81.6 ± 16.9 .0056c 81.3 ± 23.3 74.9 ± 17.9 86.4 ± 22.7 .97 .32
LA volume index 26.4 ± 7.1 27.3 ± 8.0 25.8 ± 7.8 .99 25.9 ± 8.1 29.0 ± 8.4 22.7 ± 7.2 .13 26.8 ± 6.2 25.5 ± 7.4 28.8 ± 7.5 .070 .49
(mL/m2)
Ejection fraction (%) 65 (60–65) 60 (60–65) 64 (60–65) .59 62(60–65) 61 (60–65) 65 (61–65) .058 65 (60–65) 60 (60–66) 62 (60–65) .81 .24
E/A ratio 1.2 ± 0.4n 1.5 ± 0.4 j 1.3 ± 0.5 .085 1.4 ± 0.4i 1.6 ± 0.3q 1.6 ± 0.5 .12 1.2 ± 0.4 1.3 ± 0.4 1.0 ± 0.3 .20 .087
Septal e′ velocity 8.0 ± 1.8 9.0 ± 2.1 9.0 ± 2.7 .0088b,c 8.6 ± 1.7 10.0 ± 2.1 10.7 ± 2.4 .0032b,c 7.4 ± 1.7 7.9 ± 1.7 7.2 ± 1.6 .86 .034
(cm/second)
E/e′ septal 10.6 ± 2.5 10.7 ± 2.5 j 10.3 ± 3.9 .90 10.6 ± 2.9 10.4 ± 2.9q 9.2 ± 3.5 .39 10.6 ± 2.0 11.0 ± 2.1 11.5 ± 4.0 .60 .98
Lateral e′ velocity 12.1 ± 3.7 13.2 ± 2.9 12.6 ± 4.3 .29 14.3 ± 3.2 14.6 ± 3.1 16.0 ± 2.4 .60 10.1 ± 3.1 11.8 ± 1.9 8.8 ± 2.0 .30 .0002
(cm/second)
E/e′ lateral 7.4 ± 2.5 7.3 ± 2.0j 7.2 ± 2.6 .77 6.5 ± 2.2 7.0 ± 1.6q 5.8 ± 1.8 .90 8.1 ± 2.5 7.6 ± 2.4 8.6 ± 2.6 .56 .047
RV systolic pressure 25 ± 8m 20 ± 6h 24 ± 7r .56 24 ± 10t 30 ± 8s 21 ± 4s .2 26.5 ± 4.8t 24.2 ± 7.2x 29.8 ± 6.8y .10 .53
(mmHg)
LV global longitu- –16.2 ± 2.3u –16.9 ± 1.4j –16.8 ± 2.3 .20 –16.0 ± 2.6 –16.6 ± 1.1 –16.8 ± 2.1 .44 –16.4 ± 2.1i –17.3 ± 1.7u –16.9 ± 2.6 .43 .91
dinal strain (%)

Abbreviations: GLD, generalized lipodystrophy; LA, left atrial; LV left ventricular; LVESD, left ventricular end systolic diameter; LVEDD, left ventricular end diastolic diameter; PLD, partial lipodystrophy; RV, right ventricular.
a
Overall P-value for mixed model;
b
P<.05 for baseline to 1 year comparison;
c
P<.05 for baseline to 3 to 5-year comparison;
d
N = 33; eN = 22; fN = 20; gN = 15; hN = 11; iN = 17; jN = 26; kN = 14; lN = 10; mN = 16; nN = 37; oN = 35; pN = 25; qN = 13; rN = 10; sN = 6; tN = 8; uN = 12; vN = 9; wN = 7; xN = 5; yN = 4; zN = 19.
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11

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 The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11 e4333

shown). There was no echocardiographic evidence of di-

Baseline GLD vs PLD
lated cardiomyopathy or volume overload (eg, increased
LV end systolic or diastolic diameter, data not shown).

.096

.026
.54
.97
.20
.56
.49
.29
.30

.84
.24

.34
.91
P

Effects of Metreleptin Treatment on Metabolic

Parameters

.0097 b
.057
.31
.42
.10
.18

.99

.68
N/Ad
N/Ad
N/Ad

N/Ad

N/Ad
a

Consistent with prior analyses in overlapping cohorts of

P

subjects (20, 21), metreleptin led to substantial improve-

Table 3. Numbers (percent) of subjects with selected echocardiographic parameters outside normal ranges before and after metreleptin treatment

Partial Lipodystrophy

Baseline 1 year 3-5 years

ment in multiple metabolic parameters in subjects with

6 (55)
5 (45)
3 (27)
2 (18)
3 (27)

1 (25)

3 (27)
2 (18)
8 (73)

6 (55)
0 (0)

0 (0)

0 (0)
generalized lipodystrophy, including total cholesterol,

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high-density lipoprotein cholesterol, triglycerides, glu-
3 (23)
4 (31)
2 (15)

2 (15)

7 (58)
cose, hemoglobin A1c, insulin, and HOMA-IR, whereas
1 (8)
1 (8)
0 (0)
0 (0)
1 (8)

0 (0)
1 (8)
0 (0)
only HOMA-IR improved in subjects with partial

P value could not be determined as all subjects were within the normal range or too few subjects were outside the normal range to meet model estimation criteria.
lipodystrophy (Table 1).
12 (60)
.087 11 (55)
7 (35)
6 (30)

3 (15)
5 (25)

7 (35)

12 (71)
1 (5)
0 (0)
0 (0)

1 (5)

1 (5)

Effects of Metreleptin Treatment on Cardiac

Abbreviations: GLD, generalized lipodystrophy; LV left ventricular; LA, left atrial; N/A, not available; PLD, partial lipodystrophy; RV, right ventricular.
.0042
N/Ad

N/Ad
N/Ad
N/Ad
N/Ad

N/Ad
N/Ad
.18

.61

.81

.34
a

Parameters
P
Generalized Lipodystrophy

Although antihypertensive drugs were adjusted over the

3-5 years

course of the study, there were no statistically signifi-

2 (17)
2 (16)

8 (67)
0 (0)
1 (8)
1 (9)
1 (8)
0 (0)
1 (8)
1 (8)
1 (8)
0 (0)
0 (0)

cant changes in the number of antihypertensive drugs

used per subject (Table 1). However, the proportion of
5 (36)
5 (36)
2 (14)

3 (23)

2 (33)

2 (15)

13 (93)
1 year

1 (7)

0 (0)

0 (0)
0 (0)

0 (0)
0 (0)

subjects with generalized lipodystrophy using 1 or more

antihypertensive drugs increased from 44% at baseline
Baseline

to 78% after 1 year of metreleptin, and systolic BP de-

9 (50)
.027c 10 (56)
3 (17)
7 (39)
2 (11)

1 (13)

5 (22)
3 (17)

13 (72)
1 (6)

0 (0)

1 (6)
0 (0)

creased from 120 ± 11 to 109 ± 16 after 3 to 5 years of

metreleptin. Six subjects with generalized lipodystrophy
.0018b
.011b,c

.011b
N/Ad

initiated antihypertensive drug use during follow-up; in

.15

.23

.56
.74
.21
.75

.46
a

N/A
P

all cases this consisted of low-dose angiotensin converting

3-5 years

enzyme inhibitor or angiotensin receptor blocker use for

8 (35)
7 (30)
3 (13)
3 (13)
4 (18)

1 (10)

4 (17)
3 (13)
8 (35)

20 (77) 14 (61)
1 (4)

1 (4)

0 (0)

kidney protection. There was no change in either systolic

All Subjects

or diastolic BP in the overall cohort or the subgroup with

8 (30)
9 (33)
4 (15)

4 (15)

2 (18)

partial lipodystrophy. Baseline heart rate was higher in

1 year

2 (7)

0 (0)

1 (4)
2 (7)
2 (8)
1 (4)
0 (0)

subjects with generalized lipodystrophy, most likely due

to their younger age. Heart rate decreased during the
Baseline
21 (55)
21 (55)
10 (26)
13 (34)

9 (24)
4 (11)
8 (21)

25 (71)

study in subjects with generalized lipodystrophy (89 ± 9

3 (8)
1 (3)
1 (6)
3 (8)

1 (3)

at baseline, 82 ± 12 at 1 year, 80 ± 16 at 3 to 5 years,

P = .018) but not in those with partial lipodystrophy
Interventricular septum (male 6-10; female 6-9 mm)

(P = .28).
LV mass index (male 49-115, female 43-95 g/m2)

Overall P value for generalized estimation equation;

Ejection fraction (male ≥ 52%, female ≥ 54%)

In the overall cohort of subjects with generalized and

Posterior wall (male 6-10, female 6-9 mm)

partial lipodystrophy, improvements in measures of LV

LV mass (male 88-224, female 67-162 g)

P < 0.05 for baseline to 3-5 year comparison;

LV global longitudinal strain (<–18%)

hypertrophy and diastolic parameters were observed after

P < .05 for baseline to 1 year comparison;
Lateral e′ velocity (≥10 cm/second)

metreleptin, which largely were driven by the subgroup

RV systolic pressure (<36 mmHg)

Septal e′ velocity (≥7 cm/second)

LA volume index (<34 mL/m2)

with generalized lipodystrophy (Table 2). In the overall

cohort, interventricular septum thickness decreased after
metreleptin (P = .033), by 0.5 ± 1.1 mm after 1 year, and
Data are shown as N (%)

by 0.7 ± 1.7 mm after 3 to 5 years (Fig. 2A), although nei-

E/e′ lateral (≤14)
E/e′ septal (≤14)
E/A ratio (≥0.8)

ther timepoint individually reached statistical significance.

In subjects with generalized lipodystrophy, posterior wall
thickness decreased (P = .0068) by 0.9 ± 1.1 mm after
1 year, and by 1.1 ± 1.7 mm after 3 to 5 years (Fig. 2B).
b

d
a

c
e4334  The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11

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Figure 2. Changes in measures of left ventricular (LV) hypertrophy, including (A) interventricular septum thickness, (B) posterior wall thickness, (C)
LV mass, (D) LV mass index, and diastolic parameters including (E) septal e′ velocity and (F) E/A ratio from baseline (prior to metreleptin), to after 1
and 3 to 5 years of metreleptin. The subgroup with generalized lipodystrophy is shown as black circles with solid lines, and the subgroup with partial
lipodystrophy as white squares with dashed lines. P values derive from mixed models including all time points. Asterisks indicate Dunnett-corrected
P < .05 from baseline to 1 year or 3-5 years on post hoc testing. Graphs show mean and 95% confidence interval.

Both LV mass (P = .0088) and LV mass index (P = .0056)
decreased in subjects with generalized lipodystrophy,
by 16.2 ± 24.6 g and 7.9 ± 13.5 g/m2, respectively, after
1 year, and by 24.3 ± 31.8 g and 13.5 ± 14.6 g/m2, respect-
ively, after 3 to 5 years (Fig. 2C and 2D). Septal e′ vel-
ocity, a measure of early diastolic function, also improved
in subjects with generalized lipodystrophy (P = .0032),
by 1.4 ± 1.8 m/second after 1 year, and by 1.6 ± 2.0 m/
second after 3 to 5 years.
All changes in echocardiographic parameters remained
statistically significant after adjustment for systolic and
diastolic BP and number of antihypertensive medications
with the exception of change in interventricular septum
thickness in the overall cohort (P = .11 after adjustment
for BP, P = .10 after adjustment for both BP and number
of antihypertensive drugs). Likewise, all changes in echo-
cardiographic parameters remained statistically signifi-
cant after adjustment for age and sex except for change
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11 e4335

in interventricular septum thickness in the overall cohort

(P = .14). No statistically significant changes in echocar-
diographic parameters were seen in subjects with partial
lipodystrophy (Table 2 and Fig. 2). All echocardiographic
parameters that showed no change after metreleptin on
unadjusted analyses also showed no change in adjusted
analyses, with the exception of RV systolic pressure,
which decreased after 3 to 5 years of metreleptin after ad-
justment for age, sex, BP, and number of antihypertensive
drugs (P = .048). Changes in LV mass index (P = .048),
septal e′ velocity (P = .059), and RV systolic pressure

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(P = .082) after metreleptin were greater in subjects with
generalized compared to partial lipodystrophy.
Changes in categorical classification of echocardio-
graphic parameters (normal vs abnormal) are shown in
Table 3 and Fig. 3. In the overall cohort of generalized plus
partial lipodystrophy, the estimated probability of elevated
interventricular septum thickness decreased from 55% to
31%, posterior wall thickness from 55 to 29%, and LV
mass index from 34% to 12%. However, with the excep-
tion of reduced probability of elevated LV mass index,
there was insufficient power to demonstrate significant
changes in the subgroup with generalized lipodystrophy.

Influence of Changes in Metabolic Parameters

on Changes in Cardiac Parameters
Potential mediators of changes in echocardiographic
parameters after metreleptin were explored using stepwise
variable selection (Table 4). In the overall cohort, changes
in heart rate were included as predictors of changes in
all echocardiographic parameters that changed after
metreleptin (interventricular septum, posterior wall, LV
mass, and septal e′ velocity). Triglycerides were a signifi-
cant predictor of improvements in septal e′ velocity. In
the subgroup with generalized lipodystrophy, triglycer- Figure 3. Probability of having (A) interventricular septum thickness,
ides were included as a predictor of change in the pos- (B) posterior wall thickness, and (C) left ventricular mass index above
the normal range at time 0 (prior to metreleptin), and after 1 and 3 to
terior wall and LV mass index, and hemoglobin A1c was
5 years of metreleptin. The combined cohort of generalized plus par-
a predictor of change in septal e′ velocity. Changes in the tial lipodystrophy is shown in gray bars, the subgroup with generalized
posterior wall, LV mass index, and septal e′ velocity in lipodystrophy in black bars, and the subgroup with partial lipodystrophy
in white bars. P values and probabilities derive from mixed models
subjects with generalized lipodystrophy were no longer
including all time points. Asterisks indicate Dunnett-corrected P < .05
statistically significant after inclusion of metabolic param- from time 0 to time 1 or 3 to 5 on post hoc testing. Error bars indicate
eters in multivariate models. standard error of the mean.

consistent with our hypothesis that metreleptin would

Discussion
In this study, the prevalence of LV hypertrophy in subjects
with generalized lipodystrophy decreased from ~40%
prior to metreleptin to less than 10% after metreleptin.
Improvements in LV hypertrophy and septal e′ velocity
(1 measure of diastolic function) were observed in pa-
tients with generalized, but not partial lipodystrophy,
have larger effects in more leptin deficient patients.
Furthermore, improvements in cardiac parameters ap-
peared to be clinically significant, as evidenced by a large
percentage of patients who transitioned from pathologic
to normal ranges for some cardiac parameters. The ob-
served reduction in LV hypertrophy in patients with gen-
eralized lipodystrophy after metreleptin is likely to have
e4336  The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11

Table 4. Changes in echocardiographic parameters after metreleptin: multivariate analyses with stepwise variable selection

All Subjects

P for metreleptin effect without P for metreleptin effect P for covariates in final model
covariatesa with covariatesa
Interventricular septum .033 .099 Heart rate .43
Diastolic blood pressure .89
Systolic blood pressure .19
Posterior wall .0008b,c .079 Heart rate .082
Endogenous leptin .63
Diastolic blood pressure .091
Systolic blood pressure .69

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LV mass .018c .011c Heart rate .027
Diastolic blood pressure .33
Systolic blood pressure .68
Septal e′ velocity .0088b,c .21 Heart rate .041
Triglycerides .0033
Diastolic blood pressure .59
Systolic blood pressure .65
Generalized lipodystrophy

P for metreleptin effect without P for metreleptin P for covariates in final model
covariatesa effect (time)a
Posterior wall .0068b,c .15 Triglycerides .13
Diastolic blood pressure .20
Systolic blood pressure .67
LV mass .0088c .012c Diastolic blood pressure .19
Systolic blood pressure .62
LV mass index .0056c .067 Triglycerides .063
Diastolic blood pressure .75
Systolic blood pressure .27
Septal e′ velocity .0032b,c .27 A1c .17
Diastolic blood pressure .30
Systolic blood pressure .38

Variables initially included for stepwise variable selection were: A1C, heart rate, Triglycerides, Insulin, and endogenous leptin. Systolic and diastolic blood pressure
were included in all models.
a
Overall P value for metre leptin effect (time) in mixed model;
b
P < .05 for baseline to 1 year comparison;
c
P < 0.05 for baseline to 3-5 year comparison.

important health implications. In the general population
without lipodystrophy, LV hypertrophy is a significant
risk factor for cardiovascular mortality and morbidity
(27-29). Studies have shown that regression of LV hyper-
trophy is associated with reduced risk of cardiovascular
events such as stroke, myocardial infarction, angina, con-
gestive heart failure, cardiovascular deaths, and all-cause
mortality (30-33).
LV hypertrophy is a common finding in patients with
generalized lipodystrophy, with prevalence estimates of up
to 71% (5, 9). Other cardiac abnormalities may also occur
in familial partial lipodystrophy due to certain LMNA
pathogenic variants; however, this appears to relate to
the underlying laminopathy and not to lipodystrophy
per se (34). The pathophysiology of LV hypertrophy in
non-LMNA–associated forms of lipodystrophy is not
clear, but may include glucotoxicity, lipotoxicity, or ex-
cess insulin action via cardiac insulin-like growth factor-1
receptors. Glucotoxicity following glucose overload of
myocytes is a well demonstrated phenomenon in uncon-
trolled diabetes (13). Blood glucose lowering using sodium
glucose cotransporter type 2 inhibition improved cardiac
hypertrophy in a rodent model of lipodystrophy (35), but
this may be due to glucose-independent effects as sug-
gested by improved cardiac function with sodium glucose
cotransporter type 2 inhibition in patients both with and
without diabetes (36). Supporting the lipotoxicity model,
patients with generalized lipodystrophy and elevated LV
mass index were shown by magnetic resonance spectros-
copy to have a 3-fold elevation in myocardial triglyceride
The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11
content compared with age-, gender-, and body mass
index–matched controls (37). Excess insulin action has
been postulated as a causal factor for cardiomyopathy
based on clinical observations suggesting that heart size is
linked to body size and nutritional status partly through
serum insulin levels (15). This may become maladaptive in
the context of excessive nutrition, as in obesity, type 2 dia-
betes, or lipodystrophy, with pathologic cardiac growth
mediated by hyperinsulinemia (38-40). However, direct
experimental evidence to support excess insulin action as
a cause of cardiac hypertrophy is lacking, and this mech-
anism was not supported by our data.
The exact roles of leptin in regulating cardiac struc-
tural changes are not well understood. Prohypertrophic
and antihypertrophic effects of leptin have been reported,
perhaps related to temporal effects (acute vs chronic) or
synergistic interactions with circulating lipids, glucose, and
central nervous system activation (11). Leptin has also been
associated with coronary artery disease and LV systolic and
diastolic function (41). Intact cardiac leptin signaling is im-
portant for normal diastolic function and possibly related
to the regulation of myocardial triglyceride accumulation
(14, 42). A study by Kamimura et al. showed an inverse re-
lationship between leptin levels and LV myocardial stiffness
among obese Black women (43). However, other studies
have shown a positive relationship between leptinemia and
diastolic dysfunction (44, 45). The difference in these find-
ings may be related to the methods of assessing diastolic
function, but also suggests that leptin’s actions in the heart
are complex and not fully understood.
Consistent with prior studies (2, 16, 18, 46, 47),
metreleptin treatment in the current study dramatically
reduced triglycerides, hemoglobin A1c, and HOMA-IR
in patients with generalized lipodystrophy, whereas only
HOMA-IR improved in patients with partial lipodystrophy.
We hypothesized that improvements in echocardiographic
parameters might be caused by metreleptin-mediated re-
ductions in glucose toxicity or lipotoxicity from myocar-
dial steatosis. While we did not have direct measures of
glucose or lipid utilization or storage by the myocardium
in this study, using proxies of circulating glucose and lipids,
we found that after metreleptin, changes in triglycerides
and hemoglobin A1c were predictors of changes in sev-
eral echocardiographic parameters, including measures of
hypertrophy and diastolic function. Furthermore, changes
in some echocardiographic parameters were no longer
statistically significant after accounting for changes in tri-
glycerides and hemoglobin A1c, meaning that changes in
cardiac parameters could be explained by changes in meta-
bolic disease. Our analyses did not support a role of im-
proved hyperinsulinemia in the improvements in cardiac
hypertrophy and diastolic function after metreleptin.
e4337
This study had several weaknesses. BP medications
were adjusted during the study, and thus the decline in
BP after metreleptin may have contributed to decreased
cardiac hypertrophy. All changes in echocardiographic
parameters in patients with generalized lipodystrophy
remained statistically significant after adjustment for
BP and antihypertensive drug use; however, single BP
measurements obtained during study visits may not ac-
curately reflect the preceding months of BP control that
affected cardiac structure and function. Our sample size
is small and reflects the rare prevalence of lipodystrophy.
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In addition, some subjects had no echocardiographic
data or were missing certain echocardiographic param-
eters at either 1 year or 3 to 5 years of follow-up on
metreleptin. Regardless, the degree of LV hypertrophy
regression is significant, with a 15% reduction in LV
mass after 3 to 5 years in patients with generalized
lipodystrophy. This suggests a slightly larger effect size
from metreleptin than from antihypertensive agents
(7.6-12.8%) (48). Finally, due the lack of a placebo
control group, this study can only show associations
between metreleptin and cardiovascular outcomes and
cannot prove causation. Furthermore, the small sample
size precludes robust evaluation of associations be-
tween metabolic changes and cardiac changes due to
possible model overfitting. However, the larger effect of
metreleptin in more leptin-deficient patients with gener-
alized lipodystrophy is consistent with known effects of
metreleptin. Effects of metreleptin on diastolic param-
eters were only observed for septal e′ velocity and RV
systolic pressure (in adjusted analyses only) and were
not conclusive for improved diastolic function.
In conclusion, our findings suggest that metreleptin
improves cardiac hypertrophy and 1 measure of dia-
stolic function in patients with generalized lipodystrophy,
and these improvements may be mediated by reduced
lipotoxicity and glucose toxicity. The applicability of these
findings to a broader, leptin-sufficient population with LV
hypertrophy and/or diabetic cardiomyopathy remains to
be determined.
Acknowledgments
This work was supported by the Intramural Research Programs
of the National Institute of Diabetes and Digestive and Kidney
Diseases and the National Heart, Lung, and Blood Institute.
Funding:This work was supported by the Intramural Research
Programs of the National Institute of Diabetes and Digestive
and Kidney Diseases and the National Heart, Lung, and Blood
Institute.
Clinical Trial Information: NCT00025883 (registered October
28, 2001), NCT00001987 (registered January 31, 2000),
NCT01778556 (registered January 29, 2013).
e4338  The Journal of Clinical Endocrinology & Metabolism, 2021, Vol. 106, No. 11
Additional Information
Correspondence: Rebecca J. Brown, National Institute of Dia-
betes and Digestive and Kidney Diseases, Building 10, Room
6-5940, 10 Center Dr., Bethesda, MD 20892, USA. Email:
brownrebecca@mail.nih.gov.
Disclosures: R.J.B. has received metreleptin for this study through
research collaboration agreements with Amgen, Amylin Pharma-
ceuticals, Bristol Myers Squibb/Astra Zeneca, and Aegerion Phar-
maceuticals. M.L.N., V.S., T.B., W.L., M.S., and S.A. have nothing
to disclose.
Data Availability: Some or all datasets generated during and/or
analyzed during the current study are not publicly available but are
available from the corresponding author on reasonable request.
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