Metreleptin (Myalept)

Number: 0882

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Note: Requires Precertification

Precertification of metreleptin (Myalept) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of metreleptin (Myalept) call (866) 752-7021 or fax (888) 267-3277. 

1. Criteria for Initial Approval

   Aetna considers metreleptin (Myalept) medically necessary for the treatment of lipodystrophy when all of the following criteria are met:
   
   
   1. Member has a diagnosis of congenital generalized lipodystrophy (i.e., Berardinelli-Seip syndrome), acquired generalized lipodystrophy (i.e., Lawrence syndrome), or partial lipodystrophy, and
   2. Member has leptin deficiency confirmed by laboratory testing (i.e., less than 12 ng/mL), and
   3. Member has at least one complication of lipodystrophy (e.g., diabetes mellitus, hypertriglyceridemia, increased fasting insulin level).

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers the continuation of metreleptin (Myalept) therapy medically necessary for the treatment of lipodystrophy when the member has experienced an improvement from baseline in metabolic control (e.g., improved glycemic control, decrease in triglycerides, decrease in hepatic enzyme levels).

3. Exclusions

   General obesity not associated with congenital leptin deficiency is contraindicated and considered an exclusion for Myalept therapy.

Dosage and Administration

Metreleptin is available as Myalept for subcutaneous (SC) injection supplied as a sterile, white, solid, lyophilized cake of 11.3 mg metreleptin per vial to deliver 5 mg per mL when reconstituted in 2.2 mL of bacteriostatic water for injection (BWFI) or preservative-free sterile water for injection (WFI). Individuals and caregivers should receive proper training in how to prepare and administer the correct dose of Myalept prior to self-administration. The first dose of should be administered by the individual or caregiver under the supervision of a qualified healthcare professional.

The recommended daily dosage for subcutaneous injection includes the following based on body weight:

• Body weight 40 kg or less: starting dose 0.06 mg/kg/day, increase or decrease by 0.02 mg/kg to a maximum daily dose of 0.13 mg/kg.
• Males greater than 40 kg body weight: starting dose 2.5 mg/day, increase or decrease by 1.25 mg to 2.5 mg/day to a maximum dose of 10 mg/day. 
• Females greater than 40 kg body weight: starting dose 5 mg/day, increase or decrease by 1.25 mg to 2.5 mg/day to a maximum dose of 10 mg/day.

Source: Aegerion Pharmaceuticals, 2022

Experimental and Investigational

Aetna considers metreleptin experimental and investigational for all other indications, including all of the following (not an all-inclusive list):

• Anti-retroviral therapy-associated acquired lipodystrophy (HALS)
• Celia’s encephalopathy
• Dementia
• Depression
• Early-onset extreme obesity
• HIV-related lipodystrophy
• Liver disease, including non-alcoholic steato-hepatitis (NASH)
• Metabolic diseases without concurrent evidence of lipodystrophy
• Non-alcoholic fatty liver disease (NAFLD; including obesity-associated NAFLD)
• Rabson-Mendenhall syndrome.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered for indications listed in the CPB:
Metreleptin (Myalept) - no specific code:
ICD-10 codes covered if selection criteria are met:
E08.00 - E13.9	Diabetes mellitus [not covered for acquired diabetes lipodystrophy]
E16.1	Other hypoglycemia [hyperinsulinemia with concurrent congenital generalized or acquired generalized leptin]
E78.1	Pure hyperglyceridemia [with concurrent congenital generalized or acquired generalized leptin]
E88.1	Lipodystrophy [congenital generalized or acquired generalized leptin] [not covered for acquired diabetes lipodystrophy]
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
B20	Human immunodeficiency virus [HIV] disease
E66.01 - E66.9	Overweight and obesity
G93.49	Other encephalopathy [Celia’s encephalopathy]
K70.0 - K70.9	Chronic liver disease and cirrhosis
K72.00 - K72.01	Acute and subacute hepatic failure without/with coma
K73.0 - K73.9	Chronic hepatitis
K75.0 - K76.9	Other diseases of liver

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Myalept is indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.
  
  

  Limitations of use: 

  • The safety and effectiveness of Myalept for the treatment of complications of partial lipodystrophy have not been established.
  • The safety and effectiveness of Myalept for the treatment of liver disease, including nonalcoholic steatohepatitis (NASH), have not been established.
  • Myalept is not indicated for use in patients with HIV-related lipodystrophy.
  • Myalept is not indicated for use in patients with metabolic disease, without concurrent evidence of generalized lipodystrophy.

Compendial Use

• Partial lipodystrophy in patients with confirmed leptin deficiency and metabolic abnormalities.

Metreleptin is available as Myalept (Aegerion Pharmaceuticals, Inc.) which is a recombinant human leptin analog. Metreleptin exerts its function by binding to and activating the human leptin receptor (ObR), which belongs to the Class I cytokine family of receptors that signals through the JAK/STAT transduction pathway.

Myalept carries a black box warning for risk of anti-metreleptin antibodies with neutralizing activity and risk of lymphoma. Anti-metreleptin antibodies with in vitro neutralizing activity to leptin associated with adverse events consistent with loss of endogenous leptin activity and/or loss of efficacy have been identified in two patients with generalized lipodystrophy treated with Myalept (severe infections, increases in HbA1c and triglycerides), and in three patients without lipodystrophy who received Myalept in clinical studies (excessive weight gain, development of glucose intolerance or diabetes mellitus). The clinical implications associated with development of anti-metreleptin antibodies with neutralizing activity are not well characterized at this time due to the small number of reports (Aegerion, 2022).

In addition to the black box warning, Myalept carries warnings and precautions for T-cell lymphoma, hypoglycemia, autoimmunity, hypersensitivity reactions (e.g., anaphylaxis, urticaria or generalized rash), and benzyl alcohol toxicity, for which preservative-free sterile water for injection (WFI) is recommended for neonates and infants. The most common adverse reactions in clinical trials (10% or more) include headache, hypoglycemia, decreased weight, and abdominal pain (Aegerion, 2022).

Because of the risks associated with the development of neutralizing antibodies and lymphoma, Myalept is available only through the Myalept Risk Evaluation and Mitigation Strategy (REMS) Program.  Under this REMS program, prescribers must be certified with the program by enrolling in and completing training.  Pharmacies must be certified with the program and only dispense Myalept after receipt of the Myalept REMS Prescription Authorization Form for each new prescription.

Myalept is contraindicated in general obesity not associated with congenital leptin deficiency, and hypersensivity to metreleptin. Myalept has not been shown to be effective in treating general obesity, and the development of anti-metreleptin antibodies with neutralizing activity has been reported in obese patients treated with Myalept.

Lipodystrophy

The U.S. Food and Drug Administration (FDA) approved metreleptin (Myalept), an analog of leptin made through recombinant DNA technology, as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy.  

Generalized lipodystrophy is a condition associated with a lack of fat tissue.  Patients with congenital generalized lipodystrophy are born with little or no fat tissue.  Patients with acquired generalized lipodystrophy generally lose fat tissue over time.  Because the hormone leptin is made by fat tissue, patients with generalized lipodystrophy have very low leptin levels.  Leptin is known to regulate food intake and other hormones, such as insulin.

Patients with both types of generalized lipodystrophy often develop severe insulin resistance at a young age and may have diabetes mellitus that is difficult to control or hypertriglyceridemia that can lead to pancreatitis.

The safety and effectiveness of Myalept were evaluated in an open-label, single-arm study that included 48 patients with congenital or acquired generalized lipodystrophy who also had diabetes mellitus, hypertriglyceridemia, or elevated levels of fasting insulin.  The trial showed reductions in glycated hemoglobin A1c (HbA1c), fasting glucose, and triglycerides.

Anti-drug antibodies with neutralizing activity to leptin or metreleptin may develop, which could result in severe infections or loss of treatment effectiveness. The consequences of these neutralizing antibodies are not well characterized but could include inhibition of endogenous leptin action and/or loss of Myalept efficacy. Severe infection and/or worsening metabolic control have been reported. Test for anti‐metreleptin antibodies with neutralizing activity in patients who develop severe infections or show signs suspicious for loss of Myalept efficacy during treatment.

T-cell lymphoma has been reported in patients with acquired generalized lipodystrophy, both treated and not treated with metreleptin.  The FDA approved labeling advises that healthcare professionals should carefully consider the benefits and risks of treatment with metreleptin in patients with significant hematologic abnormalities or acquired generalized lipodystrophy. 

The FDA is requiring 7 studies (post-marketing requirements) for Myalept, including a long-term prospective observational study (product exposure registry) of patients treated with metreleptin, a study to assess for the immunogenicity (antibody formation) of metreleptin, and an assessment and analysis of spontaneous reports of potential serious risks related to the use of metreleptin.  Eight additional studies are being requested as post-marketing commitments.

Acquired Diabetes Lipodystrophy

Nagayama and colleagues (2019) stated that most childhood cancer survivors who undergo hematopoietic stem cell transplantation (HSCT) subsequently develop impaired glucose tolerance and hypertriglyceridemia.  These conditions are presumably associated with total-body irradiation (TBI)-related acquired lipodystrophy and may lead to cardiovascular disease. Metreleptin may help improve the lipoprotein profile, insulin sensitivity, and quality of life (QOL) of patients with TBI-related lipodystrophy.  In a single-case study, these investigators reported the safety and effectiveness on the use of metreleptin supplementation for insulin resistance and dyslipidemia in acquired incomplete lipodystrophy.  A 24-year old Japanese woman with diabetes mellitus (DM) and hypertriglyceridemia was admitted to the authors’ hospital.  She was diagnosed with acute lymphocytic leukemia at 3 years of age and had undergone systemic chemotherapy and TBI before allogeneic SCT.  She was also diagnosed with hypertriglyceridemia and DM at 11 years of age.  She had a low adiponectin level, low-normal leptin level, and DM with marked insulin resistance; and acquired incomplete lipodystrophy was diagnosed.  Her serum triglyceride and lipoprotein profiles improved within 1 month of treatment initiation.  Glycemic metabolism and insulin sensitivity in the skeletal muscles improved after 6 months.  As previously reported, metreleptin therapy was effective in improving lipid and glycemic profiles in generalized lipodystrophy.  In the present case, these researchers considered that metreleptin supplementation could reduce the remnant very low density lipoprotein (VLDL) cholesterol fraction and improve DM.  The authors concluded that these findings suggested that metreleptin supplementation may be an effective alternative therapy for improving the expected prognosis of patients with acquired incomplete lipodystrophy, including improvement of metabolic disorders in childhood cancer survivors.

Partial Lipodystrophy

Ajluni and associates (2016) stated that patients with lipodystrophy have severe metabolic abnormalities (insulin resistance, diabetes, and hypertriglyceridemia) that may increase morbidity and mortality.  Metreleptin is approved by the FDA for treatment of generalized forms of lipodystrophy.  In an open-label study, these researchers determined the long-term safety and effectiveness of metreleptin among patients with partial lipodystrophy using an expanded-access model.  A total of 23 patients with partial lipodystrophy and diabetes and/or hypertriglyceridemia with no pre-specified leptin level were enrolled in this trial.  Metreleptin was administered subcutaneously at 0.02 mg/kg twice-daily (BID) at week 1, followed by 0.04 mg/kg BID at week 2.  Dose adjustments thereafter were based on patient response (maximum dose of 0.08 mg/kg BID); 1-year changes in HbA1c, fasting plasma glucose, triglycerides, alanine and aspartate aminotransferases, and treatment-emergent adverse events (TEAEs) were evaluated.  HbA1c, fasting plasma glucose, and triglycerides were numerically decreased throughout 1 year, with mean (standard error) changes from baseline of -0.88 (0.62) %, -42.0 (22.4) mg/dL, and -119.8 (84.1) mg/dL, respectively, which were greater among patients with higher baseline abnormalities.  Liver enzymes did not worsen, and the most frequently observed TEAEs (greater than or equal to 10 % incidence) were mild-to-moderate and included nausea (39.1 %), hypoglycemia (26.1 %), and urinary tract infections (26.1 %) -- all reported previously.  There were no reports of clinically significant immune-related AEs or new safety signals.  The authors concluded that these clinical observations documented the large heterogeneity and disease burden of partial lipodystrophy syndromes and suggested that metreleptin treatment benefits may extend to patients with partial lipodystrophy.  Moreover, they stated that additional studies are needed to confirm these preliminary findings.

Akinci and colleagues (2018) state that lipodystrophy syndromes are a group of diseases that are typically progressive and can lead to multi-organ involvement and increased mortality. Partial lipodystrophy is a type of lipodystrophy that is categorized into inherited (familial partial lipodystrophy, FPLD) and acquired forms, in which individuals affected start losing fat at some point during their life. In FPLD, fat loss occurs most frequently in the lower limbs; however, there might be accumulation of adipose tissue in the face and neck. In acquired partial lipodystrophy (APL), fat loss spreads though a cephalocaudal distribution from the face that extends to the thoracic region and upper abdomen. Individuals with partial lipodystrophy may develop metabolic abnormalities such as diabetes, hypertriglyceridemia, low HDL cholesterol levels and hepatic steatosis in later stages of the disorder. The authors state that "there is no cure for these syndromes. For the metabolic disturbances, lifestyle modification (diet and exercise as needed), metformin, and fibrates (and/or statins) are generally required. Insulin or other antidiabetics (e.g., metformin, thiazolidinediones) can also be used if needed. Metreleptin, a leptin analog, is indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with generalized lipodystrophy." The authors concluded that "so far, the most exciting therapeutic development for the treatment of lipodystrophy syndromes has been the approval of leptin replacement therapy for generalized lipodystrophy in the form of metreleptin. While Metreleptin is not approved for treatment of partial lipodystrophy syndromes in the United States, there are a number of global studies ongoing for the treatment of predominant partial lipodystrophy syndromes with other agents at this time."

Oral et al. (2019) evaluated the long-term effectiveness and safety of metreleptin in the treatment of patients with partial lipodystrophy (PL). The study included patients (n=41) 6 months of age and older with PL, circulating leptin < 12.0 ng/mL, and diabetes mellitus, insulin resistance, or hypertriglyceridemia. Patients received metreleptin doses (once or twice daily) titrated to a mean of 0.124 mg/kg/day. Changes from baseline to month 12 in glycated hemoglobin (HbA1c) and fasting serum triglycerides (TGs; co-primary endpoints), fasting plasma glucose (FPG), and liver volume were evaluated. Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at month 12, long-term treatment effects, and treatment-emergent adverse events (TEAEs). Significant (p < 0.05) reductions in HbA1c (-0.6%), fasting TGs (-20.8%), FPG (-1.2 mmol/L), and liver volume (-13.4%) were observed in the overall PL population at month 12. In a subgroup of patients with baseline HbA1c ≥ 6.5% or TGs ≥ 5.65 mmol/L, significant (p < 0.05) reductions were seen in HbA1c (-0.9%), fasting TGs (-37.4%), FPG (-1.9 mmol/L), and liver volume (-12.4%). In this subgroup, 67.9% of patients had a ≥ 1% decrease in HbA1c or ≥ 30% decrease in fasting TGs, and 42.9% had a ≥ 2% decrease in HbA1c or ≥ 40% decrease in fasting TGs. Long-term treatment in this subgroup led to significant (p < 0.05) reductions at months 12, 24, and 36 in HbA1c, fasting TGs, and FPG. Metreleptin was well tolerated with no unexpected safety signals. The most common TEAEs were abdominal pain, hypoglycemia, and nausea. The authors concluded that in patients with PL, treatment with metreleptin was well tolerated and resulted in improvements in glycemic control, hypertriglyceridemia, and liver volume. 

Sekizkardes and colleagues (2019) state that familial partial lipodystrophy (FPLD) is most commonly caused by pathogenic variants in LMNA and PPARG, and that leptin replacement with metreleptin has largely been studied in the LMNA group. The authors conducted a subgroup analysis of a prospective open-label study of metreleptin in lipodystrophy to understand the efficacy of metreleptin in PPARG vs LMNA pathogenic variants and investigate predictors of metreleptin responsiveness. Patients with LMNA (n=22) or PPARG pathogenic variants (n=7), leptin less than 12 ng/mL, and diabetes, insulin resistance, or high triglycerides, were included. Metreleptin (0.08 to 0.16 mg/kg) was given for 12 months to evaluate outcome of hemoglobin A1c (HbA1c), lipids, and medication use at baseline and after 12 months. The authors found that triglycerides decreased to 293 mg/dL in LMNA (p < 0.05), but changes were not significant in PPARG: 680mg/dL at 12 months (p = 0.2). Both groups were more likely to experience clinically relevant triglyceride (≥30%) or HbA1c (≥1%) reduction with metreleptin if they had baseline triglycerides ≥500 mg/dL or HbA1c >8%. The authors concluded that metreleptin resulted in similar metabolic improvements in patients with LMNA and PPARG pathogenic variants, and that their findings support the efficacy of metreleptin in patients with the two most common genetic causes of FPLD.

Anti-Retroviral Therapy-Associated Acquired Lipodystrophy (HALS), Familial Partial Lipodystrophy (FPLD), and Non-Alcoholic Fatty Liver Disease (NAFLD)

Tchang and colleagues (2015) stated that metreleptin was recently approved by the FDA for the treatment of generalized lipodystrophy, a condition characterized by leptin deficiency.  Its effectiveness as hormone replacement therapy suggested broader applications in diseases also characterized by leptin abnormalities, such as familial partial lipodystrophy (FPLD), non-alcoholic fatty liver disease (NAFLD), and common obesity.  Metreleptin, in conjunction with other pharmacologic interventions, has the potential to address one of the most widespread epidemics of our time, obesity.  These investigators discussed the physiology of leptin, the pharmacologic properties of recombinant methionyl human leptin (R-metHu-Leptin, metreleptin), evidence for metreleptin's effectiveness in the treatment of generalized lipodystrophy from both completed and ongoing clinical trials, safety concerns, and future directions in metreleptin research.  The authors concluded that metreleptin's approval for generalized lipodystrophy is the first step in defining and expanding its role to other metabolic diseases; clinical trials are underway to delineate its effectiveness in FPLD, HIV/highly active anti-retroviral therapy-associated acquired lipodystrophy (HALS), and NAFLD.  Furthermore, there is growing data that support a therapeutic role in obesity.  One of the barriers to development, however, is metreleptin's safety and immunogenicity.  They stated that further advances in biologic compatibility are needed before metreleptin can be approved for additional indications.

Celia's Encephalopathy

Araujo-Vilar and colleagues (2018) stated that Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy, PELD) is a recessive neurodegenerative disease that is fatal in childhood.  It is caused by a c.985C>T variant in the BSCL2/seipin gene that results in an aberrant seipin protein.  These researchers evaluated neurological development before and during treatment with(metreleptin plus a dietary intervention rich in poly-unsaturated fatty acids (PUFA) in the only living patient.  A 7 years and 10 months old girl affected by PELD was treated at age 3 years with metreleptin, adding at age 6 omega-3 fatty acid supplementation.  Her mental age was evaluated using the Battelle Developmental Inventory Screening Test (BDI), and brain PET/MRI was performed before treatment and at age 5, 6.5, and 7.5 years.  At age 7.5 years, the girl remained alive and led a normal life for her mental age of 30 months, which increased by 4 months over the last 18 months according to BDI.  PET images showed improved glucose uptake in the thalami, cerebellum, and brainstem.  This patient showed a clear slowdown in neurological regression during leptin replacement plus a high PUFA diet.  The aberrant BSCL2 transcript was over-expressed in SH-SY5Y cells and was treated with docosahexaenoic acid (200 µM) plus leptin (0.001 mg/ml) for 24 hours.  The relative expression of aberrant BSCL2 transcript was measured by qPCR.  In-vitro studies showed significant reduction (32 %) in aberrant transcript expression.  The authors concluded that this therapeutic approach should be further studied in this devastating disease.

Combined Metreleptin and SGLT2 Inhibitor Therapy for the Treatment of Acquired Incomplete Lipodystrophy

Nagayama et a l(2021) noted that childhood cancer survivors (CCSs) who have undergone bone marrow transplantation (BMT) with systemic chemotherapy and whole-body irradiation often experience impaired glucose tolerance with marked insulin resistance.  Incomplete acquired diabetic lipodystrophy should be considered as a late complication of BMT.  A 24-year-old Japanese woman with incomplete acquired lipodystrophy, a CCS of acute lymphocytic leukemia (ALL) at the age of 3 years, was treated for DM and dyslipidemia at the authors’ hospital.  Administration of multiple daily insulin injections (70 units/day), and oral administration of 500 mg/day metformin, 15 mg/day pioglitazone, and 200 mg/day bezafibrate had proven ineffective for her metabolic disorders.  Subcutaneous administration of metreleptin improved her insulin resistance and hypertriglyceridemia within a month; however, it failed to maintain adequate plasma glucose levels in the long-term.  When oral administration of 10 mg/day empagliflozin was added to the metreleptin supplementation, her HbA1c value (National Glycohemoglobin Standardization Program) improved from 11 % to 8 %, which was maintained for an additional 18 months.  This was the 1st case report of incomplete lipodystrophy that showed effectiveness of a combination therapy with metreleptin and a sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of DM and dyslipidemia.  An SGLT2 inhibitor attenuated hyperglycemia via urinary glucose excretion and has been suggested to enhance lipid catabolism in the extra-adipose tissues, especially in the liver and skeletal muscles.  Furthermore, metreleptin supplementation could enhance the action of the SGLT2 inhibitor by promoting satiety and lipolysis via the central nervous system.  Combination therapy with metreleptin and an SGLT2 inhibitor was suggested to recover the volume of adipose tissue, possibly through improvement of insulin resistance in the adipose tissue.  The authors concluded that this report highlighted the pathophysiological mechanism of an SGLT2 inhibitor in the improvement of glucose metabolism in non-healthy lean CCSs with insulin resistance.  These investigators stated that administration of SGLT2 inhibitor, along with metreleptin supplementation, could be a good alternative therapy for diabetic lipodystrophy observed in CCSs. 

The authors stated that this case study had several drawbacks.  Administration of the SGLT2 inhibitor alone might have improved the glucose impairment and dyslipidemia in this case.  Additional observation needed to examine the long-term safety and effectiveness of SGLT2 inhibitors in CCSs.  These researchers believed that further case studies or large-scale studies might confirm these findings.

Metreleptin for the Treatment of Non-Alcoholic Steato-Hepatitis (NASH)

Akinci et al (2021) noted that recombinant leptin therapy reverses NASH in leptin-deficient lipodystrophy.  These researchers examined if leptin therapy would improve NASH in more common forms of this heterogeneous condition.  A total of 9 male patients with relative leptin deficiency (RLD; level of less than 25th percentile of body mass index (BMI)- and gender-matched U.S. population) and biopsy-proven NASH and 23 patients with partial lipodystrophy (PL) and NASH were recruited for 2 distinctive open-label trials.  Subjects received leptin therapy in the form of metreleptin for 12 months.  The primary endpoints were the global NASH scores from paired liver biopsies scored blindly.  Of 9 participants recruited in the relative leptin deficiency treatment study, 7 completed 12 months of therapy.  Mean global NASH scores were reduced from 8 ± 3 to 5 ± 2 (range of 1 to 6, p = 0.004).  In the partial lipodystrophy study, 19 of 22 subjects completed 12 months of treatment, and 18 completed a 2nd liver biopsy.  Global NASH scores also reduced significantly from 6 ± 2 to 5 ± 2 (range of -2 to 4, p = 0.008).  In both studies, the predominant changes were in steatosis and hepatic injury scores.  The authors concluded that these findings showed that patients with NASH associated with both relative leptin deficiency and partial lipodystrophy had reductions in hepatic steatosis and injury in response to exogenous leptin therapy.  Moreover, leptin deficiency may have regulatory effects in mediating fat deposition and ensuing injury in the liver. 

The authors stated that the main drawbacks of these studies were the open-label designs, the small sample sizes, and the lack of placebo control.  These investigators also followed the designed protocols in the dosing regimen and used the maximum practicable dose as the ultimate ceiling in daily dose.  It was possible that higher level of efficacy could be noted if higher doses could be used in both cohorts.  A lack of control group made it difficult to interpret if the noted improvements were a direct effect of metreleptin or indirect effects due to reduction in food intake and/or weight loss especially in the RLD study and it was impossible to eliminate the possible effect of other confounding factors.  Background medications, and recruitment related factors may have contributed additional confounders.  Although these researchers tried not to increase or change background medications during the 12 months of the studies, this was not always achievable; in the PL study the authors had to change some of the concomitant metabolic medications (even though the majority of the changes made were down-titrations) and this may have impacted some of their observations.  Moreover, these researchers stated that keeping in mind that these types of studies are essentially uncontrolled and biased, these findings were still of importance because they laid the groundwork for concepts of RLD and/or “preserved leptin responsiveness” in metabolic diseases. 

Other Conditions

Paz-Filho et al (2015) noted that leptin has key roles in the regulation of energy balance, body weight, metabolism, and endocrine function.  Leptin levels are undetectable or very low in patients with lipodystrophy, hypothalamic amenorrhea, and congenital leptin deficiency (CLD) due to mutations in the leptin gene.  For these patients, leptin replacement therapy with metreleptin has improved or normalized most of their phenotypes, including normalization of endocrine axes, decrease in insulin resistance, and improvement of lipid profile and hepatic steatosis.  Remarkable weight loss has been observed in patients with CLD.  Due to its effects, leptin therapy has also been evaluated in conditions where leptin levels are normal or high, such as common obesity, diabetes (types 1 and 2), and Rabson-Mendenhall syndrome.  The authors concluded that a better understanding of the physiological roles of leptin may lead to the development of leptin-based therapies for other prevalent disorders such as obesity-associated non-alcoholic fatty liver disease, depression and dementia.

Wabitsch et al (2015) stated that mutations in the gene encoding leptin (LEP) typically lead to an absence of circulating leptin and to extreme obesity.  These investigators described the case of a 2-year old boy with early-onset extreme obesity due to a novel homozygous transversion (c.298G→T) in LEP, leading to a change from aspartic acid to tyrosine at amino acid position 100 (p.D100Y) and high immunoreactive levels of leptin.  Over-expression studies confirmed that the mutant protein is secreted but neither binds to nor activates the leptin receptor.  The mutant protein failed to reduce food intake and body weight in leptin-deficient ob/ob mice.  The authors noted that treatment of the patient with recombinant human leptin (metreleptin) rapidly normalized eating behavior and resulted in weight loss.  These preliminary findings need to be validated by well-designed studies.

Type 1 Diabetes Mellitus

In a pilot study, Vasandani and colleagues (2017) examined the safety and effectiveness of metreleptin therapy in patients with sub-optimally controlled type 1 diabetes mellitus (T1DM).  After a baseline period of 4 weeks, 5 women and 3 men patients with T1DM (mean age of 33 years, body mass index [BMI] of 23.8 kg/m2) received metreleptin (0.08 mg/kg/day in women and 0.04 mg/kg/day in men) subcutaneously twice-daily for 20 weeks followed by an off-therapy period of 4 weeks.  Metreleptin therapy did not lower HbA1c significantly compared with the baseline value (mean difference [MD] -0.19 % [-2.0 mmol/mol] and -0.04 % [-0.5 mmol/mol] at 12 and 20 weeks, respectively).  Mean body weight reduced significantly by 2.6 and 4.7 kg (p = 0.003) and daily insulin dose by 12.6 % and 15.0 % at week 12 and 20 (p = 0.006), respectively.  The authors concluded that metreleptin was safe but may not be effective in improving glycemic control in patients with T1DM, although it reduced body weight and daily insulin dose modestly.

The authors stated that the heterogeneity in individual response may be a potential drawback.  Whether higher doses of metreleptin are more effective in improving hyperglycemia in T1DM by more potently suppressing plasma glucagon remains to be explored in future studies with larger cohorts and different study designs.  These researchers used relatively low metreleptin doses in this pilot study that were similar to those used in patients with lipodystrophy to maximize safety and reduce the likelihood of hypoglycemia.

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References