Abstract
Context
Rabson-Mendenhall syndrome (RMS) is caused by biallelic pathogenic variants in the insulin receptor gene (INSR) leading to insulin-resistant diabetes, microvascular complications, and growth hormone resistance with short stature. Small, uncontrolled studies suggest that 1-year treatment with recombinant leptin (metreleptin) improves glycemia in RMS.
Objective
This study aimed to determine effects of long-term metreleptin in RMS on glycemia, anthropometrics, the growth hormone axis, and kidney function.
Methods
We compared RMS patients during nonrandomized open-label treatment with metreleptin (≥ 0.15 mg/kg/day) vs no metreleptin over 90 months (5 subjects in both groups at different times, 4 only in metreleptin group, 2 only in control group). Main outcome measures were A1c; glucose; insulin; 24-hour urine glucose; standard deviation scores (SDS) for height, weight, body mass index (BMI), and insulin-like growth factor 1 (IGF-1); growth hormone; and estimated glomerular filtration rate.
Results
Over time, metreleptin-treated subjects maintained 1.8 percentage point lower A1c vs controls (P = 0.007), which remained significant after accounting for changes in insulin doses. Metreleptin-treated subjects had a reduction in BMI SDS, which predicted decreased A1c. Growth hormone increased after metreleptin treatment vs control, with no difference in SDS between groups for IGF-1 or height. Reduced BMI predicted higher growth hormone, while reduced A1c predicted higher IGF-1.
Conclusion
Metreleptin alters the natural history of rising A1c in RMS, leading to lower A1c throughout long-term follow-up. Improved glycemia with metreleptin is likely attributable to appetite suppression and lower BMI SDS. Lower BMI after metreleptin may also worsen growth hormone resistance in RMS, resulting in a null effect on IGF-1 and growth despite improved glycemia.
Keywords: insulin receptor, Rabson-Mendenhall syndrome, leptin, A1c, growth hormone resistance
Insulin resistance is defined as the diminished ability of insulin to decrease blood glucose levels (1, 2). Pathogenic variants in the insulin receptor gene (INSR) impair the ability of insulin to bind to the insulin receptor (3), resulting in severe insulin resistance. These variants may lead to a variety of syndromes with a range in severity of associated symptoms (4). One of these is Rabson-Mendenhall syndrome (RMS), which is caused by homozygous or compound heterozygous pathogenic variants in INSR. In patients with RMS, the pathogenic variants typically lead to impaired insulin binding (1-6). Ultimately, reduced insulin receptor function impairs the ability of the intracellular beta subunit to propagate a signaling cascade that promotes cellular glucose uptake and reduces blood glucose (7). Thus, dysfunction in the INSR gene may lead to development of insulin-resistant diabetes mellitus and compensatory hyperinsulinemia (1). Over time, hyperglycemia in patients with RMS results in microvascular complications and/or diabetic ketoacidosis, often leading to early death within the second and third decades of life (1, 2). Other characteristics of RMS include short stature, hyperandrogenism, ovarian dysfunction, and acanthosis nigricans (1, 2, 8).
Treatments for Rabson-Mendenhall Syndrome
Current treatments for RMS are inadequate and lack standardized guidelines (9). Conventional diabetes treatments such as lifestyle modification, insulin or secretagogues, and insulin sensitizers fails to achieve adequate glycemic control in most patients with RMS, and the extreme insulin resistance in these patients limits the effects of high-dose insulin (6, 9). Experimental treatments have therefore been studied, including recombinant insulin-like growth factor 1 (IGF-1) and metreleptin. Metreleptin has been shown to significantly decrease glycated hemoglobin A1c (A1c) in patients with generalized lipodystrophy, a disorder characterized by leptin deficiency (10). Patients with RMS have reduced adipose tissue development, suggesting that metreleptin may be useful in increasing leptin and improving glycemia for this disorder as well (1). Earlier publications from our group showed that open-label metreleptin improved glycemia over 1 year in 5 subjects with RMS, and suggested sustained benefit in the 2 subjects with long-term data available (11). However, these studies lacked an untreated control population for comparison, did not control for concomitant medication use, and did not examine the effects of metreleptin on other disease characteristics.
Hypothesis and Objectives
In this study, we show the long-term effects (>1 year) of high-dose metreleptin in 9 patients with RMS compared with an untreated control group. Additional parameters beyond glycemia and anthropometrics are presented, including effects of metreleptin on the growth hormone axis and kidney function. We hypothesized that long-term treatment with metreleptin in RMS would result in sustained improvement in glycemic parameters over time vs the control group, potentially delaying the progression of diabetes-related complications.
Methods
Metreleptin Study Design
Patients in the metreleptin-treated group were enrolled between 2010 and 2020 in a Phase II, nonrandomized, open-label study of metreleptin in individuals with severe insulin resistance caused by a pathogenic variant in the insulin receptor (NCT00085982). Metreleptin was administered subcutaneously twice daily throughout follow-up. Patients enrolled in this trial who initiated metreleptin at a supraphysiologic dose of ≥ 0.15 mg/kg/day (either at first initiation of metreleptin or after a minimum 3-month metreleptin withdrawal period in patients previously treated with lower, physiologic doses of metreleptin) were included in the metreleptin-treated group in this analysis (N = 9).
Natural History Study Design
Patients in the control group were enrolled in an observational prospective study of the natural history of disorders of insulin resistance, including lipodystrophy, insulin receptor gene pathogenic variants, and insulin receptor autoantibodies (NCT0001987) between 1998 and 2019. Patients enrolled in this trial with a diagnosis of RMS were included in the control group for this analysis (N = 7).
IRB Approval
These studies were approved by the Institutional Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases. Written, informed consent/assent was provided by patients and/or their parents/guardians.
Patients/Visit Classification
In the metreleptin-treated group, the baseline visit was designated as the starting date of high-dose metreleptin (≥ 0.15 mg/kg/day). In 2 patients who had previously used low-dose metreleptin, their baseline visits were designated as the date of initiation of high-dose metreleptin after a minimum 3-month metreleptin withdrawal.
For patients in the control group, the baseline visit was defined as the earliest visit at which they were not taking metreleptin, were on stable doses of diabetes medications, and for which measurements of fasting glucose, insulin, and A1c were available.
Patients were included in both the metreleptin-treated and control groups if they had longitudinal data available for at least 12 months during periods with and without metreleptin treatment.
Laboratory Techniques
Metabolic testing was conducted approximately every 6 months at the National Institutes of Health using standard clinical methods. Fasting laboratory parameters, including A1c, serum IGF-1, growth hormone, blood glucose, serum insulin, and serum creatinine were measured. 24-hour urine samples were collected to measure 24-hour protein and albumin excretion. Oral glucose tolerance testing (OGTT) was performed with administration of a 1.75 g/kg dextrose oral solution (maximum 75 g) following an overnight fast. Blood samples were obtained at −10, 0, 30, 60, 90, 120, 150, and 180 minutes to measure glucose, insulin, and C-peptide. Patients taking exogenous insulin took their last dose of insulin the day prior to the OGTT. Leptin was measured in the morning after an overnight fast in patients with baseline visits prior to or during 2016 by radioimmunoassay with a commercial kit (Linco Research, Inc., St. Charles, MO), and after 2016 by enzyme linked immunosorbent assay with a commercial kit (MilliporeSigma).
Calculations
Standard deviation scores (SDS) for height, weight, and body mass index (BMI) were calculated based on USA population growth data from the Centers for Disease Control (12). For patients <20 years of age, these represent Z-scores compared with age and sex-matched controls. For patients ≥20 years of age, these represent T-scores compared to sex-matched 20-year-olds. IGF-1 SDS scores based on sex and age were calculated using the methods described in Bidlingmaier et al (13). The pediatric cohort of serum samples for this reference range was from the Canadian Laboratory Initiative on Pediatric Reference Interval Database (CALIPER), while the adult cohort came from 4 regions in Germany (13). Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated using fasting insulin (mcU/L) and fasting glucose (mg/dL) values with the formula: (insulin * glucose/405) (14, 15). Areas under the curve (AUCs) for glucose, insulin, and C-peptide values collected during the OGTT were calculated with the trapezoidal method. Estimated glomerular filtration rate (eGFR) in patients <18 years of age was calculated using the Bedside Schwartz equation, and in patients ≥18 years of age using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, based on race and sex (16-19).
Angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEi/ARB) dosage was classified as low, medium, or high. Dosing classes for benazepril, enalapril, fosinopril, lisinopril, and monopril were: low (<10 mg), medium (10-20 mg/day), or high (>20 mg/day). Captopril dosing classes were: low (<25 mg/day), medium (25-100 mg/day), or high (>100 mg/day). Cilazapril dosing classes were: low (<2.5 mg/day), medium (2.5-4 mg/day), or high (≥4 mg/day).
Statistics
Means and standard deviation (SD) or medians and interquartile range (IQR) are reported based on the distribution of each outcome. Non-normally distributed values were log transformed prior to analyses. A significance threshold of P < 0.05 was used.
Baseline comparisons between the control vs metreleptin-treated groups were conducted using mixed models with a repeated effect for subjects across groups. Within-group comparisons of baseline vs 12 months were conducted using 1-sample t tests or Wilcoxon tests. To test effects of metreleptin treatment over time, linear mixed-effects models were performed for change from baseline for each outcome of interest, with independent variables of treatment group (control vs metreleptin), time, and treatment by time interaction, with subject as a repeated measure. The interaction term was removed if not statistically significant. These models were repeated with inclusion of covariates of interest. For glycemic outcomes (A1c, fasting glucose, glucose AUC, 24-hour urine glucose excretion) covariates of interest were: concomitant medication dosage (insulin, metformin), insulinemia (fasting insulin), and BMI SDS. For kidney function measurements (24-hour urine protein excretion, 24-hour urine albumin excretion, and eGFR), covariates of interest were concomitant medication dosage (ACEi/ARB inhibitors). For the growth and growth hormone axis parameters (height SDS, growth hormone, IGF-1 SDS), covariates of interest were glycemic control (A1c), insulinemia (fasting insulin), and BMI SDS.
Baseline growth hormone values in the total cohort of 11 subjects with RMS were compared with pooled means for fasting, unstimulated growth hormone in healthy males and females (20). For patients who were included in both cohorts, the earliest baseline growth hormone value was selected.
For analyses of height SDS, only visits in which patients had growth potential (including all visits up to and including the first visit at which patients had achieved >90% of adult height) were included. Adult height was defined based on review of growth charts.
Results
Patient Characteristics
In total, 11 unique subjects with RMS were included in this study. The control cohort consisted of 7 subjects, and the metreleptin-treated cohort consisted of 9 subjects. Five subjects were included in both cohorts, 4 of whom received metreleptin after inclusion in the control cohort, and 1 of whom was in the control cohort following metreleptin withdrawal. Baseline characteristics for each group are shown in Table 1.
Table 1.
Baseline patient characteristics
| Metreleptin | Control | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ID | Sex | Race/ethnicity | Genetic mutation | Age at high-dose metreleptin initiation (Years) | Metreleptin dose (mg/kg/day) a | Serum leptin (ng/mL) b | Fasting insulin (microUnits/mL) | Fasting glucose (mg/dL) | A1c (%) | Duration of treatment (Months) | Age (years) | Fasting insulin (microUnits/mL) | Serum leptin (ng/mL) | Fasting glucose (mg/dL) | A1c (%) | Duration of follow-up prior to metreleptin Initiation (Months) |
| 1 | M | Asian | Pro220Leu | 22.5 | 0.21 | 3.4 | 321 | 186 | 11.6 | 107 | 10.1 | 274 | 4.9 | 159 | 9.9 | 44 |
| Non-Hispanic | Pro220Leu | |||||||||||||||
| 2 | F | Asian | Pro220Leu | 20.3 | 0.23 | 4.5 | 288 | 231 | 12.8 | 107 | 7.8 | 289 | 5.1 | 45 | 8.5 | 46 |
| Non-Hispanic | Pro220Leu | |||||||||||||||
| 3 | M | White | Lys460Glu | 21.8 | 1077 | N/A | 213 | 7.9 | 64 | |||||||
| Non-Hispanic | Premature termination after AA 671 | |||||||||||||||
| 4 | M | White | Lys460Glu | 11.4 | 490 | 2.5 | 182 | 12 | 15 | |||||||
| Non-Hispanic | Glu109Arg | |||||||||||||||
| 5 | F | Black | Ile119Met | 12.8 | 0.24 | N/A | 153 | 55 | 10.1 | 105 | 9.8 | 214 | 8.3 | 65 | 7 | 36 |
| Non-Hispanic | Ile119Met | |||||||||||||||
| 6 | M | White | Ser635Leu | 15.3 | 0.22 | 1.7 | 249 | 172 | 11.9 | 103 | ||||||
| Non-Hispanic | exon 9-10 deletion | |||||||||||||||
| 7 | M | Asian | Tyr30X | 12.5 | 0.22 | 2.8 | 342 | 155 | 10.6 | 93 | ||||||
| Non-Hispanic | Glu238Lys | |||||||||||||||
| 8 | M | White | Leu136Arg | 12.6 | 0.19 | 3.5 | 317 | 98 | 7.8 | 72 | 5.4 | 156 | 3.5 | 70 | 5.6 | 85 |
| Non-Hispanic | 2bp intronic deletion | |||||||||||||||
| 9 | M | White | Asn117Lys | 11.9 | 0.18 | 2.8 | 1000 | 246 | 10.8 | 12 | 13.8 | 1000 | 2.0c | 205 | 10.8 | 23 |
| Hispanic | del exon 3 | |||||||||||||||
| 10 | F | White | Cys293Arg | 6.7 | 0.18 | 2.4c | 638 | 104 | 9.6 | 18 | ||||||
| Hispanic | Gly142Asp | |||||||||||||||
| 11 | F | White | c.1225T>G | 9.4 | 0.15 | 0.7c | 424 | 261 | 11.1 | 12 | ||||||
| Hispanic | c.2944_2945delAG | |||||||||||||||
| Average | 13.8 | 0.20 | 2.7 | 415 | 168 | 10.7 | 70 | 11.4 | 500 | 4.4 | 134 | 8.8 | 45 | |||
| SD | 5.0 | 0.03 | 1.2 | 257 | 72 | 1.5 | 43 | 5.3 | 383 | 2.3 | 72 | 2.2 | 24 |
Patients that were included in the metreleptin-treated and/or control group are shown. In total, 11 unique patients with Rabson-Mendenhall syndrome were included in the control (N = 7) and/or metreleptin (N = 9) groups. 5 patients were part of both groups.
a Dose at time of high-dose (≥ 0.15 mg/kg/day) metreleptin initiation.
b Serum leptin was measured prior to metreleptin initiation. After exposure to metreleptin, it is common to develop antibodies that may result in falsely high leptin levels.
c Serum leptin was measured via ELISA. Except as noted serum leptin levels were measured via RIA.
The metreleptin-treated cohort included 5 men and 4 women, and the control cohort had 5 men and 2 women. Mean follow-up duration in the metreleptin group was greater than the control group (70 ± 43 months vs 45 ± 24 months). There was no difference in mean endogenous leptin in the metreleptin-treated vs control group (2.72 ± 1.16 vs 4.39 ± 2.28 ng/mL; P = 0.30).
Kidney outcomes at baseline are reported in the metreleptin and control groups in Table 2. Three patients in the metreleptin-treated group and 2 in the control group had microalbuminuria. Six patients in the metreleptin-treated group and 2 in the control group had elevated protein excretion. All patients in the metreleptin-treated and control groups had elevated eGFR.
Table 2.
Baseline kidney parameters
| Metreleptin | Control | |
|---|---|---|
| Urinary albumin excretion (mg/24h) | N = 9 | N = 6 |
| Normal, <30 mg/24 h, % | 6 (67%) | 4 (80%) |
| Microalbuminuria, 30-300 mg/24 h, % | 3 (33%) | 2 (20%) |
| Macroalbuminuria, >300 mg/24 h, % | 0 (0%) | 0 (0%) |
| Urinary Protein Excretion (mg/24 h) | N = 9 | N = 4 |
| Normal, ≤150 mg/24 h, % | 3 (33%) | 2 (50%) |
| Elevated > 150 mg/24 h, % | 6 (67%) | 2 (50%) |
| Nephrotic range, >3.5 g/24 h, % | 0 (0%) | 0 (0%) |
| eGFR | N = 9 | N = 6 |
| Normal, ≤ 130 mL/min/1.73 m2, % | 0 (0%) | 0 (0%) |
| Elevated, >130 mL/min/1.73 m2, % | 9 (100%) | 6 (100%) |
Baseline classification of patients (N [%]) with normal or elevated urinary albumin and protein excretion and estimated glomerular filtration rate (eGFR).
Comparisons between the metreleptin-treated and control groups at baseline are shown in Table 3. At baseline, the metreleptin-treated cohort had significantly higher A1c (10.7 ± 1.5 vs 8.8 ± 2.2%; P = 0.03) and 24-hour urine glucose excretion (146.5 ± 82.6 vs 55.6 ± 38.9 g/24 h; P = 0.04). The metreleptin-treated cohort was comparable to the control cohort with respect to age, weight SDS, height SDS, BMI SDS, IGF-1 SDS, growth hormone, glucose AUC, insulin AUC, C-peptide AUC, HOMA-IR, fasting glucose, fasting insulin, urine protein excretion, urine albumin excretion, and eGFR.
Table 3.
Outcomes in the control and metreleptin groups at 0 and 12 months
| Metreleptin | Control | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Baseline (N = 9) | 12 months (N = 9) | Delta (N = 9) | P for 0-12 month difference | Baseline (N = 7) | 12 months (N = 6) | Delta (N = 6) | P for 0-12 month difference | P for baseline between groups | P for deltas; Tx across all time points | |
| Age (years) | 13.8 ± 5.0 | 14.8 ± 5.0 | <0.0001 | 11.4 ± 5.3 | 12.8 ± 5.7 | <0.0001 | 0.67 | - | ||
| A1c (%) | 10.7 ± 1.5 | 9.3 ± 1.7 | -1.4 ± 1.1 | 0.006 | 8.8 ± 2.2 | 9.4 ± 2.2 | 0.2 ± 0.7 | 0.43 | 0.03 | 0.007 |
| Fasting glucose (mg/dL) | 168 ± 72 | 125 ± 75 | -43 ± 54 | 0.04 | 134 ± 72 | 132 ± 62 | -14 ± 70 | 0.64 | 0.23 | 0.19 |
| 24-hour urine glucose excretion (g/24 h) | 146.5 ± 82.6 | 86.9 ± 42.5b | -62.1 ± 71.2d | 0.12 | 55.6 ± 38.9 | 72.4 ± 43.2e | 3.7 ± 38.2e | 0.86 | 0.04 | 0.93 |
| OGTT | ||||||||||
| Glucose AUC (mg/dL 190 min) | 62 536 ± 13 231 | 52 163 ± 19 242 | -10 373 ± 8036 | 0.005 | 46 397 ± 19 231c | 52 865 ± 24 911f | 673 ± 4413f | 0.82 | 0.08 | 0.07 |
| Insulin AUC (mcU/mL 190 min) | 90 665 [42 488, 134 420] | 90 383 [4 5931, 145 903] | -568 [-10 424,28 473] | 0.99 | 81 070 [43 226, 286 888]d | 183 480 [85 585, 309 775]f | -14 625 [-163 790, 102 410] f | 0.86 | 0.85 | 0.70 |
| C-peptide AUC (ng/mL 190 min) | 1879 ± 1512 | 1847 ± 1457 | -32 ± 850 | 0.91 | 1862 ± 81f | 3114 ± 1036g | 1283 ± 948g | 0.31 | 0.98 | 0.20 |
| Fasting insulin (U/mL) | 321 [269,531] | 232 [161,742] | -17 [-158,15] | 0.25 | 289 [214,1000] | 360 [229,699]d | -63 [-405,-22]d | 0.15 | 0.76 | 0.42 |
| HOMA-IR | 147 [91, 219] | 82 [33, 229] | -43 [-73,34] | 0.08 | 108 [32,506] | 153 [69,186]d | -26 [-382,9]d | 0.27 | 0.30 | 0.68 |
| Weight SDS | -2.8 ± 1.8 | -3.8 ± 1.9 | -1.1 ± 0.5 | 0.0001 | -2.5 ± 1.4 | -2.7 ± 1.2 | 0.2 ± 1.0 | 0.67 | 0.30 | 0.03 |
| Height SDS | -2.9 ± 1.5d | -3.0 ± 1.8d | -0.08 ± 0.4d | 0.70 | -2.5 ± 1.5c | -3.0 ± 1.2d | -0.1 ± 0.2d | 0.23 | 0.13 | 0.65 |
| BMI SDS | -1.0 ± 1.5 | -2.3 ± 1.6 | -1.3 ± 0.6 | 0.0001 | -1.2 ± 1.2 | -1.0 ± 0.7 | 0.4 ± 1.2 | 0.48 | 0.77 | 0.01 |
| IGF-1 SDS | -3.6 ± 0.5 | -3.4 ± 0.7a | 0.2 ± 0.5a | 0.43 | -3.3 ± 0.8c | -3.6 ± 1.0e | -0.4 ± 0.3f | 0.18 | 0.38 | 0.16 |
| Growth hormone (ng/mL) | 2.28 ± 2.0b | 7.29 ± 7.56d | 7.59 ± 6.56e | 0.10 | 2.82 ± 2.72 c | 1.07 ± 0.87e | -2.60 ± 3.55e | 0.24 | 0.79 | 0.04 |
| 24-hour urine protein excretion (mg/24 h) | 194.2 ± 158.2 | 138 ± 107b | -107.1 ± 193.9b | 0.35 | 204.0 ± 203.9e | 151.3 ± 21.6g | -162.3h | N/A | 0.49 | 0.21 |
| 24-hour urine albumin excretion (mg/24 h) | 26.1 [15.6,54.7] | 35.7 [30.4,59.5] b | 9.1 [-25.2,16.9] b | 0.80 | 17.5 [8.2,69.2]c | 31.1 [26.6,257.4] e | 9.8 [-2.0,11.2] f | 0.26 | 0.42 | 0.69 |
| eGFR (mL/min/1.73 m 2 ) | 253 [177,289] | 218 [169,339] | -11 [-55,11] | 0.49 | 215 [161,254]c | 152 [124,229] | -16 [-91,45] d | 0.55 | 0.34 | 0.08 |
Glycemia, anthropometrics and kidney function for the metreleptin-treated group and control group at 0 and 12 months. P for deltas represents the linear mixed effects models to determine a difference in change from baseline between the control and metreleptin groups across all time points. Data are presented as mean ± SD or median [IQR: 25th, 75th]. Height SDS only includes patients who had achieved ≤ 90% of adult height, based on review of growth charts.
aN = 8;
bN = 7;
cN = 6;
dN = 5;
eN = 4;
fN = 3;
gN = 2;
hN = 1.
At baseline, the metreleptin-treated and control cohorts had short stature (height SDS in metreleptin-treated −2.9 ± 1.5 [N = 5]; control −2.5 ± 1.5 [N = 6]) and low BMI SDS (metreleptin-treated −1.0 ± 1.5 [N = 9], control −1.2 ± 1.2 [N = 7]). Growth hormone was significantly higher in patients with RMS compared with previously published data in a healthy cohort (2.7 ng/mL vs 0.64 ng/mL; P < 0.0001) (20). IGF-1 SDS was low at baseline in both groups (metreleptin-treated −3.6 ± 0.5 [N = 9]; control −3.3 ± 0.8 [N = 6]).
Effects of 12 Months of High-Dose Metreleptin
The difference from baseline to 12 months for each variable in the metreleptin-treated and control groups is shown in Table 3. In the metreleptin-treated group, weight and BMI SDS decreased from 0 to 12 months (Δ weight SDS −1.1 ± 0.5, P = 0.0001; Δ BMI SDS −1.3 ± 0.6, P = 0.0001), whereas no change was observed in the control cohort (Δ weight SDS 0.2 ± 1.0, P = 0.67; Δ BMI SDS 0.4 ± 1.2, P = 0.48). After 12 months of metreleptin treatment, mean A1c decreased (−1.4% ± 1.1%, P = 0.006) with no change in the control cohort (0.2 ± 0.7%, P = 0.4). Similarly, other glycemic parameters including fasting glucose and glucose AUC during OGTT decreased after 12 months of metreleptin but did not change over 12 months in the control cohort.
Long-term Effects of Metreleptin Treatment
After 1 year of metreleptin treatment, serum leptin levels increased from 2.7 ± 1.2 ng/mL to 25.8 ± 24.0 ng/mL in the metreleptin-treated group (P = 0.04).
Diabetes Management
The mean doses of insulin and metformin for the metreleptin-treated and control groups from baseline to 90 months of follow-up are shown in Fig. 1. In the metreleptin-treated group, all patients were on metformin at baseline, with a mean dose of 1505 ± 526 mg/day (N = 9). All metreleptin-treated patients with a follow-up visit at 90-months were taking 2000 mg/day of metformin (N = 6). In the control group, 2 patients were on metformin at baseline and 5 were initiated on metformin during follow-up. Mean metformin dose in the control cohort increased from 250 ± 433 mg/day at baseline (N = 7) to 2275 ± 389 mg/day at 90 months (N = 2).
Figure 1.
Concomitant medications during follow-up. Diabetes medications were recorded for patients in the control and metreleptin groups at each visit throughout follow-up. A) Mean ± SEM insulin dose (units/day), B) Mean ± SEM metformin dose (mg/day), and C) Mean ± SEM metreleptin dose (mg/kg/day) are shown from 0 to 90 months in the control group (white squares) and metreleptin group (black circles). The number of patients with data available at each visit are provided. Patients who were never treated with insulin are included (as 0 units per day at all time points).
In the metreleptin-treated group, 4 patients were taking insulin at baseline, 2 were initiated on insulin during follow-up, and 3 were never on insulin throughout follow-up. In the control group, 4 patients were taking insulin at baseline, 1 was initiated on insulin during follow-up and 2 were never on insulin throughout follow-up. There was enormous variability in insulin doses across subjects and over time. In the metreleptin group, baseline insulin dosage (N = 9) was mean ± SD: 489 ± 737 units/day (median [IQR]: 0 [0, 1075]; range, 0-1955), and at 90 months (N = 6) the dosage was mean ± SD: 1183 ± 1192 units/day (median [IQR]: 1000 [75, 2250]; range, 0-3000). In the control group, baseline insulin dosage (N = 7) was mean ± SD: 733 ± 89 units/day (median [IQR]: 252 [0, 1800]; range, 0-2035) and at 90 months (N = 2) was mean ± SD: 900 ± 1273 units/day (median [IQR]: 900 [0, 1800]; range, 0-1800).
At baseline, insulin dosage was not significantly different between the metreleptin-treated group vs the control group (P = 0.97). Across all time points, insulin dosage was statistically higher in the metreleptin-treated group vs the control group (P = 0.02); however, the least square mean (LSM) difference was only 7.6 units/day. In both the metreleptin-treated and control groups, insulin dose significantly increased over time (P = 0.02) but the change in insulin dose did not differ between the 2 groups (P = 0.41). Metformin dose was higher in the metreleptin-treated group vs the control group at baseline (P = 0.009) and across all time points (LSM difference 481 mg/day; P = 0.02). In both the metreleptin-treated and control groups, metformin dose significantly increased over time (P = 0.0007); this increase was smaller in the metreleptin-treated group vs the control group (LSM difference −697 mg/day; P = 0.009).
Glycemic Outcomes
Glycemic outcomes across all time points for the metreleptin-treated vs control cohorts are shown in Table 3 and Fig. 2. In the metreleptin-treated group, the greatest reduction in A1c occurred at month 6 (−2.3 ± 1.1%), followed by a rise to baseline by month 90 (−0.3 ± 3.1%). By contrast, A1c increased over time in the control group. Thus, over the course of the entire follow-up period, the metreleptin-treated cohort maintained lower A1c compared with the control group. The LSM change in A1c in the metreleptin-treated group across all time points was −0.9%, compared with 1.0% rise in A1c in the control group. The LSM difference between the groups over time was 1.8% (P = 0.007). The between-group difference in A1c change over time remained statistically significant after accounting for changes in insulin dose (P = 0.04). There were no significant differences between the metreleptin-treated vs control groups for change over time in fasting glucose (LSM change: −22.3 vs 1.77 mg/dL; P = 0.19), fasting insulin (LSM change: −0.02 vs −0.10 mcU/mL; P = 0.42), HOMA-IR (LSM change: −0.1 vs −0.05; P = 0.68), glucose AUC (LSM change: −2608 vs 5527 mg/dL 190 min; P = 0.07), insulin AUC (LSM change: 0.06 vs 0.09 mcU/mL 190 min; P = 0.7), or C-peptide AUC (LSM change: 27 vs 1040 ng/mL 190 min; P = 0.2). However, the metreleptin-treated group trended toward greater decreases in fasting glucose and glucose AUC vs the control group.
Figure 2.
Change from baseline in glycemic outcomes throughout follow-up. Mean change from baseline in A) mean A1c, B) individual patient A1c in the metreleptin-treated group and C) control group, D) 24-hour urine glucose excretion, E) fasting glucose, F) fasting insulin, (F) glucose AUC, H) insulin AUC, I) C-peptide AUC are shown for patients in the metreleptin (black circles) and control (white square) cohorts. Data are presented as mean ± SEM or median and IQR change from baseline from 0 to 90 months for each group depending on data distribution. The number of patients with data available at each visit are provided. P values for comparison of mean change from baseline between groups across all time points are presented for each outcome. Using a mixed-model test, the metreleptin-treated group had greater improvements in A1c across all time points vs the control group (P = 0.007, least square mean [LSM] change in metreleptin group: −0.9%, LSM change in control group: +1.0%).
Growth Outcomes
Growth outcomes across all time points for the metreleptin-treated vs control cohorts are shown in Table 3 and Fig. 3. Over the course of follow-up, the metreleptin-treated cohort had greater reductions compared to the control group in weight SDS (LSM change −0.7 vs 0 kg; P = 0.03) and BMI SDS (LSM change −1.0 vs 0.1 kg/m2; P = 0.01). Additionally, the metreleptin-treated group had a greater increase compared to the control group in growth hormone (LSM change 4.77 vs −1.69 ng/mL; P = 0.04). There were no significant between-group differences for change over time in height SDS or IGF-1 SDS.
Figure 3.
Change from baseline in growth parameters throughout follow-up. Mean change from baseline in growth and growth axis parameters A) weight SDS, B) height SDS, C) BMI SDS, D) IGF-1 SDS, E) growth hormone are shown for patients in the metreleptin (black circles) and control (white square) cohorts. Data are presented as mean ± SEM or median and IQR change from baseline from 0 to 90 months for each group depending on data distribution. The number of patients with data available at each visit are provided. P values for comparison of mean change from baseline between groups across all time points are presented for each outcome. Using a mixed-model test, the metreleptin-treated group had larger least square mean (LSM) changes from baseline across all time points compared to the control group in weight SDS (P = 0.03, LSM change in metreleptin group: −0.74, control group: 0), BMI SDS (P = 0.01, LSM change in metreleptin group: −1.03, control: 0.14), and growth hormone (P = 0.04, LSM change in metreleptin group: 4.77 ng/mL, control: −1.69 ng/mL).
Kidney Outcomes
In the metreleptin-treated group, 1 patient was on medium-dose ACEi/ARB inhibitors at baseline, which was increased to high-dose during follow-up. Six patients initiated low-dose ACEi/ARB inhibitors during follow-up. In the control group, 1 patient was on medium-dose ACEi/ARB inhibitors at baseline, which was continued throughout follow-up. One patient initiated medium-dose ACEi/ARB inhibitors during follow-up.
Kidney outcomes across all time points for the metreleptin-treated vs control cohorts are shown in Table 3 and Fig. 4. There were no significant differences between the metreleptin-treated and control groups for change over time in 24-hour urine protein excretion, 24-hour urine albumin excretion, or eGFR. There were no significant differences after adjustment for doses of ACEi/ARB (24-hour urine protein excretion, P = 0.42; 24-hour urine albumin excretion, P = 0.5; eGFR, P = 0.15).
Figure 4.
Change from baseline in kidney parameters throughout follow-up. Mean change from baseline in kidney function A) 24-hour urine protein, B) albumin excretion, C) eGFR is shown for patients in the metreleptin (black circles) and control (white square) cohorts. Data are presented as mean ± SEM or median and IQR change from baseline from 0 to 90 months for each group depending on data distribution. The number of patients with data available at each visit are provided. Using a mixed-model test, there were no differences between the metreleptin-treated and control groups for changes from baseline across all time points.
Correlations Among Outcomes
Correlations among outcomes are shown in Table 4. We analyzed whether BMI SDS was a predictor of glycemic outcomes and growth hormone axis parameters. BMI SDS was positively associated with A1c. Change in BMI SDS was positively associated with change in A1c and negatively associated with change in growth hormone.
Table 4.
Correlation analyses
| Correlation analyses (predictor vs dependent variable) | ß | P |
|---|---|---|
| Weight/BMI as predictor | ||
| BMI SDS vs A1c | 0.4 | 0.004 |
| Δ BMI SDS vs Δ A1c | 0.3 | 0.04 |
| BMI SDS vs fasting glucose | 9.5 | 0.10 |
| Δ BMI SDS vs Δ fasting glucose | 0.9 | 0.89 |
| BMI SDS vs fasting insulin | 0.03 | 0.40 |
| Δ BMI SDS vs Δ fasting insulin | 0.03 | 0.39 |
| Weight SDS vs height SDSa | 0.2 | 0.05 |
| BMI SDS vs IGF-1 SDS | -0.04 | 0.61 |
| Δ BMI SDS vs Δ IGF-1 SDS | 0.03 | 0.71 |
| BMI SDS vs growth hormone | 0.1 | 0.84 |
| Δ BMI SDS vs Δ growth hormone | -1.6 | 0.03 |
| Glycemia as predictor | ||
| A1c vs height SDSa | -0.04 | 0.31 |
| A1c vs IGF-1 SDS | -0.2 | 0.0002 |
| Δ A1c vs Δ IGF-1 SDS | -0.1 | 0.005 |
| A1c vs growth hormonea | -0.5 | 0.29 |
| Insulinemia as predictor | ||
| Fasting insulin vs A1c | 0.8 | 0.16 |
| Δ Fasting insulin vs Δ A1c | 0.3 | 0.55 |
| Fasting insulin vs fasting glucose | 48.2 | 0.01 |
| Δ Fasting insulin vs Δ fasting glucose | 33.3 | 0.12 |
| Fasting insulin vs height SDS a | 0.2 | 0.06 |
| Fasting insulin vs IGF-1 SDS | -0.1 | 0.57 |
| Δ Fasting insulin vs Δ IGF-1 SDS | -0.02 | 0.92 |
| Fasting insulin vs growth hormone | -4.3 | 0.03 |
| Δ Fasting insulin vs Δ growth hormone | -2.9 | 0.36 |
The results of correlations with BMI SDS, Δ BMI SDS, A1c, Δ A1c, fasting insulin, and Δ fasting insulin as predictors of glycemia, insulinemia, and growth are presented.
aCorrelation analyses with deltas did not converge.
We analyzed whether A1c was a predictor of growth hormone axis parameters. A1c was negatively associated with IGF-1 SDS. Likewise, change in A1c was negatively associated with change in IGF-1 SDS.
We analyzed whether fasting insulin was a predictor of glycemic outcomes and growth hormone axis parameters. Fasting insulin was positively associated with fasting glucose and negatively associated with growth hormone.
Discussion
In this study, we demonstrated that open-label, high-dose metreleptin treatment in patients with RMS decreased A1c, fasting glucose, glucose AUC, weight SDS, and BMI SDS over 12 months. When compared with a control cohort of RMS patients not treated with metreleptin, high-dose metreleptin led to significantly lower A1c, weight SDS, and BMI SDS across all follow-up visits from 0 to 90 months. Additionally, high-dose metreleptin led to significantly higher growth hormone across all follow-up visits from 0 to 90 months without significant change in height SDS or IGF-1 SDS.
While all patients included in this study had homozygous or compound heterozygous pathogenic variants in INSR, there are factors that may contribute to individual variation in the progression of the disease including the specific variants, baseline characteristics including A1c, beta cell function, age, sex, and medication compliance. Detailed functional characterization of each pathogenic variants’ function has not been reported, but the majority have been linked to severe phenotypes such as Donohue syndrome, suggesting little residual insulin receptor signaling. There was no obvious correlation between genotype and response. Due to small sample size, detailed analyses predicting response to metreleptin were not possible.
There were no differences between the metreleptin-treated and control groups in measured kidney outcomes over time. We did not have direct data on retinopathy or neuropathy in this group and there were insufficient data on nephropathy to assess effects of metreleptin. However, we showed that the metreleptin-treated cohort had a 1.8 percentage point lower A1c over time compared to the control cohort. The Diabetes Control and Complications Trial demonstrated that a 10% lower mean A1c was associated with a 45% reduction in risk of sustained progression in retinopathy (21), and lower A1c has been associated with reduced risk of nephropathy and neuropathy as well (22, 23). While the current study was underpowered to detect changes in microvascular disease, these trends suggest that metreleptin treatment may reduce the risk of microvascular complications through reduction in A1c.
The majority of the patients in this study were on concomitant medications in both the metreleptin-treated group and the control cohort. We could not directly control for the dosage of concomitant medications in patients. However, in the control cohort, we selected baseline visits based on a stable initial insulin regimen. We looked at whether the effects of metreleptin were independent of other medications, including insulin and metformin. Insulin dose changes were unlikely to have accounted for lower A1c over time in the metreleptin-treated group, as increases in insulin dose over time were comparable in both groups, and reductions in A1c remained statistically significant in the metreleptin group when insulin dose was included as a covariate. Similarly, changes in metformin dose were unlikely to have accounted for lower A1c over time in the metreleptin-treated group, as metformin dose increases were substantially larger in the control cohort, which should have biased any difference in A1c between groups toward the null hypothesis.
Figure 5 shows the proposed pathway for the mechanism of action of metreleptin in patients with RMS. We hypothesize that metreleptin improves A1c in patients with RMS by suppressing appetite, leading to weight loss. Consistent with a prior study from our group (11), weight and BMI SDS decreased significantly across all follow-up visits during metreleptin treatment compared with the control group. Similar effects of metreleptin on weight have also been found in other patient populations with low baseline leptin levels, including healthy adults, congenital leptin deficiency, and lipodystrophy (24-28). Furthermore, decreased BMI SDS was associated with decreased A1c, suggesting a causal relationship between reduced body weight and improved glycemia. Another possible mechanism of metreleptin to improve glycemic control is its activation of PI3K, a component of the insulin signaling pathway. Stable levels of circulating insulin with improved glycemic control suggest that metreleptin may be directly exerting an effect on the insulin signaling pathway. However, in this study, we could not assess effects of metreleptin on PI3K-mediated signal transduction. While leptin increases energy expenditure in rodents, multiple studies have failed to demonstrate an effect of metreleptin on energy expenditure in humans (29-31), including in the initial report of metreleptin in 2 subjects with RMS (32). Thus, while energy expenditure was not measured in the current study, it is unlikely that metreleptin improved A1c by increasing energy expenditure.
Figure 5.
Proposed model for glycemic and growth observations in Rabson Mendenhall syndrome (RMS). The proposed model for the natural history of RMS is shown in white squares with gray arrows. RMS (1) is caused by pathogenic variants in the insulin receptor gene, leading to severe insulin resistance. Severe insulin resistance perpetuates uncontrolled glycemia (2), as glucose is not effectively transported from the blood into cells. Continuous uncontrolled glycemia leads to increased risk of neuropathy, nephropathy, retinopathy, and macrovascular complications (3). Uncontrolled glycemia also leads to cellular starvation (4), as glucose cannot enter cells. Growth hormone resistance develops in response to persistent cellular starvation (5). IGF-1 secretion is not stimulated by growth hormone (6), and growth hormone levels increase as a compensatory response (7). Changes in this pathway in response to metreleptin are shown in black squares with black arrows. Metreleptin use is associated with improved glycemia control (A). Improved glycemia is associated with increased IGF-1 SDS (B). Metreleptin use is also associated with decreased BMI, likely due to suppression of appetite (C). Decreased appetite with metreleptin treatment may exacerbate cellular starvation (D), thus worsening GH resistance and lowering IGF-1. The resultant decrease in IGF-1 is counterbalanced by increased IGF-1 from improved glycemia, leading to net zero change in IGF-1 after metreleptin.
Patients with RMS have linear growth impairment (1). To better understand this phenotype, as well as the role of leptin in the growth hormone-IGF-1 axis, we analyzed growth hormone, IGF-1, and auxologic parameters in the metreleptin-treated and control groups in this study. Our baseline data support a pattern of growth hormone resistance in patients with RMS, in which growth hormone fails to stimulate IGF-1 production, ultimately resulting in high growth hormone levels and low IGF-1 levels (33). The growth hormone resistance pattern observed in RMS is similar to other states of undernutrition such as fasting, protein-calorie malnutrition, anorexia nervosa, injury, or infection (34, 35). By contrast, obese subjects have low resting levels of growth hormone, which increases after fasting (34). Growth hormone resistance in undernutrition represents an appropriate compensatory response to low nutrient availability, by reducing linear growth via reduced IGF-1, yet preserving blood glucose by increasing growth hormone, a counterregulatory hormone. Although patients with RMS have adequate energy intake, the lack of insulin signaling presumably provides a cellular starvation signal leading to growth hormone resistance. This is supported by rodent data showing that partial knockout of the insulin receptor in mice led to increased activation of AMP-activated protein kinase, which generally occurs as a response to reduced intracellular energy availability (36). This suggests that patients with insulin receptor pathogenic variants may be experiencing a starvation state due to inadequate insulin signaling and decreased entry of glucose into cells independent of caloric intake.
We hypothesized that metreleptin would improve growth in patients with RMS. Metreleptin was shown to increase IGF-1 and height SDS in children with congenital leptin deficiency (37), consistent with a direct effect of leptin to increase IGF-1. Furthermore, improved diabetes control from metreleptin might be expected to increase IGF-1, as better glycemic control in patients with type 1 diabetes correlates with higher IGF-1 (38). As expected, better glycemic control in patients was positively correlated with IGF-1 SDS; however, IGF-1 and height SDS did not change in either the metreleptin-treated or control cohorts. In the metreleptin-treated cohort, growth hormone significantly increased over time and higher growth hormone was associated with lower BMI SDS. This suggests that weight loss from metreleptin led to worsened cellular starvation despite improved glycemic control, thus exacerbating growth hormone resistance. Thus, the null effect of metreleptin on IGF-1 may be due to opposing effects of leptin to increase IGF-1 via direct effects and improved glycemia, counterbalanced by effects of worsening growth hormone resistance to decrease IGF-1. Fasting insulin was independently and positively associated with height SDS, suggesting that there may still be a growth-promoting effect of insulin in patients with RMS, perhaps via IGF-1 receptors.
Among the strengths of this study are the inclusion of more patients on metreleptin over a longer duration than previously studied, and the evaluation of long-term effects of metreleptin on factors beyond glycemic control, including growth and kidney function. Furthermore, this study not only supports previous results that demonstrate the potential of metreleptin to improve glycemia in RMS, but also for the first time provides comparison with a non–metreleptin-treated control cohort. Prior publications from our group have shown that, despite ongoing metreleptin treatment, A1c tends to increase over time in metreleptin-treated subjects with RMS. In the current analysis, comparison with an untreated control group shows that A1c increased over time in both treated and untreated groups, consistent with the natural history of diabetes in this condition, and that metreleptin treatment was associated with a sustained, clinically relevant reduction in A1c.
This study was limited by the small number of patients in both the metreleptin-treated and control cohorts, missing data due to variable visit intervals, and missing study data at some visits, such as 24-hour urine protein/albumin excretion, growth hormone, and IGF-1. Furthermore, concomitant medications were not controlled, although in the case of diabetes medications, this would have biased against seeing a benefit of metreleptin. Finally, while the metreleptin-treated and control groups were comparable with respect to age, BMI SDS, and fasting glucose, some of the patients in the control cohort were not on metreleptin because they had better glycemic control as reflected by lower A1c.
Of note, in this study we included treatment periods of high-dose metreleptin. In early studies, patients with RMS were treated with estimated physiologic replacement doses of metreleptin. However, because patients with RMS are not truly leptin deficient, better responses were observed over time using higher metreleptin doses (11, 32). Thus, the effects reported in the current study are representative of supraphysiological levels of leptin treatment, rather than leptin replacement. At this dose, we demonstrate that metreleptin improves glycemia; however, its effects on growth hormone and BMI SDS suggest that it exacerbates cellular starvation. Additional studies are required to determine an optimal dose that achieves glycemic improvement while avoiding negative impacts on cellular starvation that could impact cellular viability and to determine the long-term impacts of metreleptin on linear growth and cardiovascular function.
In conclusion, this study demonstrates that long-term use of high-dose metreleptin in RMS leads to sustained improvement in glycemia and increased growth hormone resistance, both of which are likely due to weight loss associated with metreleptin therapy. Health care providers treating patients with RMS may consider experimental use of high-dose metreleptin in patients in whom the benefits of improved glycemia control are likely to outweigh the risks from appetite suppression. Although the findings in this study likely are not generalizable to forms of diabetes associated with high leptin (ie, obesity-associated type 2 diabetes) there is emerging evidence that metreleptin may be efficacious for a variety of metabolic complications of insulin resistance in individuals with low-normal leptin levels, such as familial partial lipodystrophy and nonalcoholic steatohepatitis (39, 40).
Glossary
Abbreviations
- A1c
glycated hemoglobin A1c
- ACEi/ARB
angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker
- AUC
area under the curve
- BMI
body mass index
- eGFR
estimated glomerular filtration rate
- GH
growth hormone
- HOMA-IR
homeostasis model assessment of insulin resistance
- IGF-1
insulin-like growth factor 1
- LSM
least square mean (difference)
- OGTT
oral glucose tolerance test
- RMS
Rabson-Mendenhall syndrome
- SDS
standard deviation score
Financial Support
This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases.
Disclosures
Metreleptin for this study was provided by Amgen, Bristol Myers Squib, AstraZeneca, Aegerion Pharmaceuticals, and Amryt Pharma under research collaboration agreements (R.J.B.).
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.
Clinical Trial Information
ClinicalTrials.gov registration no. NCT00085982, NCT0001987.
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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.