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 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.
Keywords: Leptin, lipodystrophy, cardiomyopathy, left ventricular hypertrophy
Lipodystrophy syndromes are a rare group of heterogenous 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, associated 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 combination of hyperphagia from leptin deficiency and low adipose tissue storage capacity leads to ectopic lipid deposition 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 autonomic dysregulation, coronary artery disease, and hypertrophic 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 abnormalities in patients with generalized lipodystrophy include diastolic dysfunction (5, 9-11) and dilated cardiomyopathy (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 metabolic complications of lipodystrophy, including insulin resistance, hyperglycemia, and hypertriglyceridemia. More dramatic benefits have been observed in patients with generalized lipodystrophy and very low leptin concentrations, vs those with partial lipodystrophy who have higher leptin concentrations (2, 16-21). This is consistent with leptin biology being most relevant in the transition from leptin deficiency to sufficiency. The effects of metreleptin administration on cardiac structure and function in patients with lipodystrophy are not known. 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 approved by the Institutional Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases. All subjects or their legal guardians provided written consent, 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 injection once or twice daily, dosed according to weight (sex and age dependent) as previously published (20). Doses of concomitant medications for diabetes and hypertriglyceridemia were not increased during the first year of metreleptin treatment but were lowered or discontinued 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 lipoprotein 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 glucose (mg/dL) × insulin (µU/mL) ÷ 405 for all patients (including insulin users). Leptin concentration in fasting serum samples was measured prior to metreleptin initiation 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 deflation 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 formula (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). 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 categorical outcomes are summarized using frequencies. Non-normally distributed data were log-transformed prior to analyses. Missing data were not imputed. Baseline characteristics between subjects with generalized vs partial lipodystrophy were compared using the unpaired t-test (for continuous variables) and chi-squared test (for categorical variables). All analyses were conducted for the entire cohort (generalized plus partial lipodystrophy) and separately 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 analyzed 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 (partial vs generalized) by time interaction term, with P < .1 used to define a likely interaction. To assess potential mediators 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, triglycerides, insulin, hemoglobin A1c, and heart rate. Systolic and diastolic BP were included as required covariates in variable selection models. As this was an ancillary analysis of prospectively obtained data, no a priori sample size calculations were performed. Statistical analyses were performed 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.
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 echocardiogram 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.
Figure 1.
Flow diagram of subjects participating in the study.
Of the 38 subjects included, 18 had generalized lipodystrophy (15 females, 3 males). Of these, 3 had acquired generalized lipodystrophy, 9 had pathogenic variants 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 (negative for LMNA and PPARG but with autosomal dominant inheritance pattern).
Baseline metabolic characteristics of the overall cohort, and the subgroups with generalized and partial lipodystrophy, are in Table 1. The median (interquartile 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 expected, 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 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 protection rather than hypertension), vs 60% of subjects with partial lipodystrophy (P = .52).
Table 1.
Clinical characteristics and metabolic effects of metreleptin
| All Subjects | Generalized Lipodystrophy | Partial Lipodystrophy | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline (N = 38) | 1 year (N = 27) | 3-5 years (N = 23) | P a | Baseline (N = 18) | 1 year (N = 14) | 3-5 years (N = 12) | P a | Baseline (N = 20) | 1 year (N = 13) | 3-5 years (N = 11) | P a | Baseline GLD vs PLD | |
| Duration of metreleptin (y) | 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 |
| Age (years) | 20.5 (16.0-39.8) | 20.0 (16.0-34.0) | 25.0 (19.0-50.0) | NA | 16.5 (13.8-21.3) | 18.0 (14.8-22.3) | 19.5 (16.3-24.5) | NA | 36.0 (17.0-51.5) | 28.0 (17.5-46.5) | 50.0 (30.0-62.0) | NA | .0002 |
| Leptin (ng/mL) | 3.9 (1.0-8.0) | 67.3 (20.8-150.0) | 70.6 (18.1-134.1) | <.0001b,c | 1.0 (0.6-2.3) | 82.1 (32.6-262.1)k | 90.3 (14.5-142.5) | <.0001b,c | 7.0 (4.0-13.5) | 56.1 (20.3-114.6) | 67.6 (33.1-129.5) | 0.0002b,c | <.0001 |
| 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 antihypertensives | 52.6 | 59.3 | 73.9 | .25 | 44.4 | 78.6 | 75.0 | .028b | 60.0 | 38.5 | 73.2 | 0.32 | .34 |
| # antihypertensive drugs per subject | 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 |
| Heart rate (beats per minute) | 85 ± 12 | 81 ± 15 | 77 ± 16g | .0082b,c | 89 ± 9 | 82 ± 12 | 80 ± 16j | .018b,c | 82 ± 13 | 80 ± 18 | 74 ± 16 | 0.28 | .043 |
| Total cholesterol (mg/dL) | 206 (151-262) | 148 (126-194) | 157 (120-198) | <.0001b,c | 206 (173-264) | 138 (99-185) | 155 (119-190) | <.0001b,c | 218 (137-271) | 153 (148-217) | 158 (124-261) | 0.12 | .68 |
| 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 |
| 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 (136-558) | <.0001b,c | 310 (234-989) | 345 (236-628) | 230 (189-487) | 0.14 | .27 |
| 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 (2.4-16.0) | 8.9 (2.1-16.4) | .0002b,c | 13 (3.9-27.5) | 8.0 (3.4-17.5) | 5.4 (2.9-17.8) | 0.0015b,c | .028 |
| 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,
e N = 30;
f N = 25;
g N = 19;
h N = 16;
i N = 21;
j N = 17;
k N = 13;
j N = 11;
l N = 14;
m N = 10;
n N = 4;
o N = 12;
p N = 9;
q N = 8.
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 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.
Table 2.
Changes in echocardiographic parameters after metreleptin
| All subjects | Generalized Lipodystrophy | Partial Lipodystrophy | Baseline GLD vs PLD | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline (N = 38) | 1 year (N = 27) | 3-5 years (N = 23) | P a | Baseline (N = 18) | 1 year (N = 14) | 3-5 years (N = 12) | P a | Baseline (N = 20) | 1 year (N = 13) | 3-5 years (N = 11) | P a | ||
| Interventricular septum (mm) | 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 |
| Posterior wall (mm) | 9.7 ± 1.6 | 8.9 ± 1.2 | 8.9 ± 1.7 | .0008b,c | 9.8 ± 1.7 | 9.1 ± 1.3 | 8.3 ± 1.7 | .0068b,c | 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 (mL/m2) | 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 |
| 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 (cm/second) | 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 |
| 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 (cm/second) | 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 |
| 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 (mmHg) | 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 |
| LV global longitudinal strain (%) | –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 |
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;
e N = 22;
f N = 20;
g N = 15;
h N = 11;
i N = 17;
j N = 26;
k N = 14;
l N = 10;
m N = 16;
n N = 37;
o N = 35;
p N = 25;
q N = 13;
r N = 10;
s N = 6;
t N = 8;
u N = 12;
v N = 9;
w N = 7;
x N = 5;
y N = 4;
z N = 19.
At baseline and prior to metreleptin treatment, approximately half of subjects in both the generalized 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 function (median ejection fraction 65 [60-65]%). However, most (71%) had abnormal global longitudinal strain (mean –16.2 ± 2.3%; normal <–18%) suggesting subclinical systolic dysfunction. Few subjects with generalized lipodystrophy had clinically abnormal diastolic parameters 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 diameter and tricuspid regurgitation peak velocity (data not shown). There was no echocardiographic evidence of dilated cardiomyopathy or volume overload (eg, increased LV end systolic or diastolic diameter, data not shown).
Table 3.
Numbers (percent) of subjects with selected echocardiographic parameters outside normal ranges before and after metreleptin treatment
| All Subjects | Generalized Lipodystrophy | Partial Lipodystrophy | Baseline GLD vs PLD | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | 1 year | 3-5 years | P a | Baseline | 1 year | 3-5 years | P a | Baseline | 1 year | 3-5 years | P a | P | |
| Interventricular septum (male 6-10; female 6-9 mm) | 21 (55) | 8 (30) | 8 (35) | .011b,c | 9 (50) | 5 (36) | 2 (17) | .18 | 12 (60) | 3 (23) | 6 (55) | .057 | .54 |
| Posterior wall (male 6-10, female 6-9 mm) | 21 (55) | 9 (33) | 7 (30) | .027c | 10 (56) | 5 (36) | 2 (16) | .087 | 11 (55) | 4 (31) | 5 (45) | .31 | .97 |
| LV mass (male 88-224, female 67-162 g) | 10 (26) | 4 (15) | 3 (13) | .15 | 3 (17) | 2 (14) | 0 (0) | N/Ad | 7 (35) | 2 (15) | 3 (27) | .42 | .20 |
| LV mass index (male 49-115, female 43-95 g/m2) | 13 (34) | 2 (7) | 3 (13) | .0018b | 7 (39) | 1 (7) | 1 (8) | .0042 | 6 (30) | 1 (8) | 2 (18) | .10 | .56 |
| LA volume index (<34 mL/m2) | 3 (8) | 4 (15) | 4 (18) | .23 | 2 (11) | 3 (23) | 1 (9) | .61 | 1 (5) | 1 (8) | 3 (27) | .18 | .49 |
| Ejection fraction (male ≥ 52%, female ≥ 54%) | 1 (3) | 0 (0) | 1 (4) | N/Ad | 1 (6) | 0 (0) | 1 (8) | N/Ad | 0 (0) | 0 (0) | 0 (0) | N/Ad | .29 |
| RV systolic pressure (<36 mmHg) | 1 (6) | 2 (18) | 1 (10) | .56 | 1 (13) | 2 (33) | 0 (0) | N/Ad | 0 (0) | 0 (0) | 1 (25) | N/Ad | .30 |
| E/A ratio (≥0.8) | 3 (8) | 1 (4) | 1 (4) | .74 | 0 (0) | 0 (0) | 1 (8) | N/Ad | 3 (15) | 1 (8) | 0 (0) | N/Ad | .096 |
| Septal e′ velocity (≥7 cm/second) | 9 (24) | 2 (7) | 4 (17) | .21 | 5 (22) | 0 (0) | 1 (8) | N/Ad | 5 (25) | 2 (15) | 3 (27) | .99 | .84 |
| E/e′ septal (≤14) | 4 (11) | 2 (8) | 3 (13) | .75 | 3 (17) | 2 (15) | 1 (8) | .81 | 1 (5) | 0 (0) | 2 (18) | N/Ad | .24 |
| Lateral e′ velocity (≥10 cm/second) | 8 (21) | 1 (4) | 8 (35) | .011b | 1 (6) | 0 (0) | 0 (0) | N/Ad | 7 (35) | 1 (8) | 8 (73) | .0097 b | .026 |
| E/e′ lateral (≤14) | 1 (3) | 0 (0) | 0 (0) | N/Ad | 0 (0) | 0 (0) | 0 (0) | N/Ad | 1 (5) | 0 (0) | 0 (0) | N/Ad | .34 |
| LV global longitudinal strain (<–18%) | 25 (71) | 20 (77) | 14 (61) | .46 | 13 (72) | 13 (93) | 8 (67) | .34 | 12 (71) | 7 (58) | 6 (55) | .68 | .91 |
Data are shown as N (%)
Abbreviations: GLD, generalized lipodystrophy; LV left ventricular; LA, left atrial; N/A, not available; PLD, partial lipodystrophy; RV, right ventricular.
a Overall P value for generalized estimation equation;
b P < .05 for baseline to 1 year comparison;
c P < 0.05 for baseline to 3-5 year comparison;
d 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.
Effects of Metreleptin Treatment on Metabolic Parameters
Consistent with prior analyses in overlapping cohorts of subjects (20, 21), metreleptin led to substantial improvement in multiple metabolic parameters in subjects with generalized lipodystrophy, including total cholesterol, high-density lipoprotein cholesterol, triglycerides, glucose, hemoglobin A1c, insulin, and HOMA-IR, whereas only HOMA-IR improved in subjects with partial lipodystrophy (Table 1).
Effects of Metreleptin Treatment on Cardiac Parameters
Although antihypertensive drugs were adjusted over the course of the study, there were no statistically significant changes in the number of antihypertensive drugs used per subject (Table 1). However, the proportion of subjects with generalized lipodystrophy using 1 or more antihypertensive drugs increased from 44% at baseline to 78% after 1 year of metreleptin, and systolic BP decreased from 120 ± 11 to 109 ± 16 after 3 to 5 years of metreleptin. Six subjects with generalized lipodystrophy initiated antihypertensive drug use during follow-up; in all cases this consisted of low-dose angiotensin converting enzyme inhibitor or angiotensin receptor blocker use for kidney protection. There was no change in either systolic or diastolic BP in the overall cohort or the subgroup with partial lipodystrophy. Baseline heart rate was higher in subjects with generalized lipodystrophy, most likely due to their younger age. Heart rate decreased during the study in subjects with generalized lipodystrophy (89 ± 9 at baseline, 82 ± 12 at 1 year, 80 ± 16 at 3 to 5 years, P = .018) but not in those with partial lipodystrophy (P = .28).
In the overall cohort of subjects with generalized and partial lipodystrophy, improvements in measures of LV hypertrophy and diastolic parameters were observed after metreleptin, which largely were driven by the subgroup 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 by 0.7 ± 1.7 mm after 3 to 5 years (Fig. 2A), although neither 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). 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, respectively, after 3 to 5 years (Fig. 2C and 2D). Septal e′ velocity, 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.
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.
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 echocardiographic parameters remained statistically significant after adjustment for age and sex except for change in interventricular septum thickness in the overall cohort (P = .14). No statistically significant changes in echocardiographic 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 adjustment 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 (P = .082) after metreleptin were greater in subjects with generalized compared to partial lipodystrophy.
Changes in categorical classification of echocardiographic 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 exception of reduced probability of elevated LV mass index, there was insufficient power to demonstrate significant changes in the subgroup with generalized lipodystrophy.
Figure 3.
Probability of having (A) interventricular septum thickness, (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 5 years of metreleptin. The combined cohort of generalized plus partial lipodystrophy is shown in gray bars, the subgroup with generalized lipodystrophy in black bars, and the subgroup with partial lipodystrophy in white bars. P values and probabilities derive from mixed models including all time points. Asterisks indicate Dunnett-corrected P < .05 from time 0 to time 1 or 3 to 5 on post hoc testing. Error bars indicate standard error of the mean.
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 significant predictor of improvements in septal e′ velocity. In the subgroup with generalized lipodystrophy, triglycerides were included as a predictor of change in the posterior wall and LV mass index, and hemoglobin A1c was a predictor of change in septal e′ velocity. Changes in the posterior wall, LV mass index, and septal e′ velocity in subjects with generalized lipodystrophy were no longer statistically significant after inclusion of metabolic parameters in multivariate models.
Table 4.
Changes in echocardiographic parameters after metreleptin: multivariate analyses with stepwise variable selection
| All Subjects | |||
|---|---|---|---|
| P for metreleptin effect without covariatesa | P for metreleptin effect with covariatesa | P for covariates in final model | |
| 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 | |||
| 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 covariatesa | P for metreleptin effect (time)a | P for covariates in final model | |
| 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.
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 patients with generalized, but not partial lipodystrophy, consistent with our hypothesis that metreleptin would have larger effects in more leptin deficient patients. Furthermore, improvements in cardiac parameters appeared to be clinically significant, as evidenced by a large percentage of patients who transitioned from pathologic to normal ranges for some cardiac parameters. The observed reduction in LV hypertrophy in patients with generalized lipodystrophy after metreleptin is likely to have 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 hypertrophy is associated with reduced risk of cardiovascular events such as stroke, myocardial infarction, angina, congestive 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 excess insulin action via cardiac insulin-like growth factor-1 receptors. Glucotoxicity following glucose overload of myocytes is a well demonstrated phenomenon in uncontrolled 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 suggested 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 spectroscopy to have a 3-fold elevation in myocardial triglyceride 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 diabetes, 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 mechanism was not supported by our data.
The exact roles of leptin in regulating cardiac structural 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 important 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 relationship 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 findings 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 reductions in glucose toxicity or lipotoxicity from myocardial 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 several 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 triglycerides and hemoglobin A1c, meaning that changes in cardiac parameters could be explained by changes in metabolic disease. Our analyses did not support a role of improved hyperinsulinemia in the improvements in cardiac hypertrophy and diastolic function after metreleptin.
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 accurately 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. In addition, some subjects had no echocardiographic data or were missing certain echocardiographic parameters 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 between metabolic changes and cardiac changes due to possible model overfitting. However, the larger effect of metreleptin in more leptin-deficient patients with generalized lipodystrophy is consistent with known effects of metreleptin. Effects of metreleptin on diastolic parameters 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 diastolic 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).
Glossary
Abbreviations
- BP
blood pressure
- GLD
generalized lipodystrophy
- HOMA-IR
homeostasis model assessment of insulin resistance
- LV
left ventricular
- PLD
partial lipodystrophy
- RV
right ventricular
Additional Information
Disclosures: R.J.B. has received metreleptin for this study through research collaboration agreements with Amgen, Amylin Pharmaceuticals, Bristol Myers Squibb/Astra Zeneca, and Aegerion Pharmaceuticals. 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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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
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.
