Lipodystrophy syndromes: Management

INTRODUCTION — 

Lipodystrophy syndromes are a heterogeneous group of congenital or acquired disorders characterized by either complete or partial lack of adipose tissue (lipoatrophy) [1,2]. In some of these disorders, abnormal accumulation of fat occurs in other regions of the body. Clinically, patients with severe lipodystrophy have severe insulin resistance, severe hyperlipidemia, progressive liver disease, and increased metabolic rate (table 1). Acquired and congenital lipodystrophies may also be associated with proteinuric kidney diseases and cardiovascular disease.

This topic will review the evaluation and management of lipodystrophy-associated complications and comorbidities. Some aspects of management are universal, whereas others are specific to certain forms of lipodystrophy and their attendant complications. The clinical features, classification, and diagnostic evaluation for lipodystrophy syndromes are presented separately. (See "Lipodystrophy syndromes: Clinical manifestations, classification, and diagnosis".)

Human immunodeficiency virus (HIV)-related lipodystrophy is also discussed separately. (See "Treatment of HIV-associated lipodystrophy".)

ASSESSMENT FOR COMPLICATIONS AND COMORBIDITIES

Common lipodystrophy-associated disorders — In individuals with generalized or partial lipodystrophy, management primarily entails identifying and treating the metabolic, kidney, and cardiac disorders associated with lipodystrophy syndromes. Whereas some complications are specific to certain forms of lipodystrophy, other complications are common in most forms of both partial and generalized lipodystrophy and include the following (see "Lipodystrophy syndromes: Clinical manifestations, classification, and diagnosis", section on 'Complications and comorbidities'):

●Insulin resistance and diabetes

●Kidney disease

●Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH)

●Hypertriglyceridemia

●Hypertension

●Abnormal pubertal development (children) or reproductive dysfunction (adults)

The severity of these complications generally correlates with the severity of adipose tissue loss [3].

Clinical and laboratory assessments

Clinical assessments — Key clinical assessments include the following:

●Blood pressure measurement – Blood pressure should be measured at every clinic visit.

●Evaluation of reproductive function (adults) or pubertal stage (children and adolescents) – These assessments should be made upon initial diagnosis and at least annually thereafter. Adult females with generalized or partial lipodystrophy should be evaluated for oligo- or amenorrhea, evidence of hyperandrogenism, and reduced fertility. Men with generalized or partial lipodystrophy should be evaluated for hypoandrogenism. The diagnosis of male hypogonadism is reviewed separately. (See "Clinical features and diagnosis of male hypogonadism", section on 'Diagnosis'.)

Children with generalized lipodystrophy should be monitored for early adrenarche and precocious puberty. (See "Normal puberty", section on 'Pubertal changes'.)

●Complete physical examination – A complete physical examination should be performed upon initial diagnosis and at least annually to assess for evidence of hypertension, cardiovascular and/or proteinuric kidney disease (eg, periorbital or peripheral edema). The examination also should assess for eruptive xanthomas, acanthosis nigricans, hepatomegaly, and other signs of lipodystrophy-associated metabolic disorders. (See "Lipodystrophy syndromes: Clinical manifestations, classification, and diagnosis", section on 'Physical findings'.)

The approach to physical examination in the diagnostic evaluation of lipodystrophy is reviewed elsewhere. (See "Lipodystrophy syndromes: Clinical manifestations, classification, and diagnosis", section on 'History and examination'.)

Laboratory tests — Laboratory tests are critical for evaluating and monitoring potential comorbidities and complications of lipodystrophy. These include the following:

●Chemistry panel with fasting glucose.

●Liver biochemical and function tests, including screening for MASH-related fibrosis (eg, fibrosis [FIB]-4 index) per society guidelines. (See "Clinical features and diagnosis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults", section on 'Targeted screening for advanced fibrosis'.)

●Urinary albumin-to-creatinine ratio (ACR).

●Glycated hemoglobin (A1C).

●Serum lipid panel.

These tests should be obtained at diagnosis and at least annually or more often if indicated.

Liver ultrasound — At diagnosis, all patients should undergo noninvasive tests, including liver ultrasound and/or elastography as appropriate, to assess for MASLD. The approach to MASLD evaluation, diagnosis, and management is presented separately. (See "Clinical features and diagnosis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults" and "Management of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults".)

Cardiac evaluation (selected patients) — In patients with congenital generalized lipodystrophy or progeria-associated lipodystrophy, electrocardiogram and echocardiogram should be performed at diagnosis and at least annually [4].

In other individuals with partial or generalized lipodystrophy, these tests and additional evaluation for ischemic or structural heart disease should be performed as indicated based on symptoms, age, and other cardiovascular risk factors. (See "Stress testing for the diagnosis of obstructive coronary artery disease", section on 'Our approach to diagnostic stress testing'.)

MANAGEMENT

General approach — The approach to treatment discussed below is based on observational and interventional studies and clinical experience. The guidance is generally consistent with the Endocrine Society clinical practice guidelines for the management of lipodystrophy [4].

●Initial management – The initial treatment of the metabolic disturbances associated with lipodystrophy (eg, diabetes, hypertriglyceridemia) is generally the same as for patients without lipodystrophy. Lifestyle modification (appropriate dietary and exercise interventions) and glucose- and lipid-lowering therapy are typically the cornerstones of treatment. (See 'Lifestyle measures' below and 'Pharmacotherapy for metabolic complications and comorbidities' below.)

●Persistent metabolic complications – In some individuals with lipodystrophy, metabolic disorders are refractory to treatment.

•Partial lipodystrophy – For patients with familial partial lipodystrophy who have diabetes, glucagon-like peptide 1 (GLP-1) receptor agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors are potential options, although clinical data for these drugs specifically in patients with lipodystrophy are scarce [3]. In some regions, metreleptin (recombinant leptin) has regulatory approval for use in individuals with partial lipodystrophy who have treatment-refractory metabolic complications. (See 'Partial lipodystrophy' below.)

•Generalized lipodystrophy – In patients with acquired generalized or congenital generalized lipodystrophy, metreleptin is an option either for initial therapy or for management of metabolic disturbances that persist despite standard treatment. Metreleptin is prescribed only as part of a Risk Evaluation and Mitigation Strategy (REMS) program and requires careful monitoring. Evidence is limited for the risks and benefits of metreleptin in these patient populations. (See 'Generalized lipodystrophy (metreleptin)' below.)

Treatment of human immunodeficiency virus (HIV)-associated lipodystrophy is discussed in detail separately. (See "Treatment of HIV-associated lipodystrophy".)

Lifestyle measures — In all individuals with partial or generalized lipodystrophy, lifestyle measures are essential for managing metabolic complications.

Diet — No diet reverses lipoatrophy; rather, specific dietary patterns should be tailored to mitigate the metabolic complications of lipodystrophy. For all patients, a diet with balanced macronutrient content that avoids excessive fat content is generally advised [4].

Whereas energy-restricted diets are often helpful in adolescents and adults, they should be avoided in infants and children. In patients with generalized lipodystrophy, such diets may present adherence challenges due to hyperphagia.

●Moderate to severe hypertriglyceridemia – When moderate to severe hypertriglyceridemia is present, a balanced low-fat, low-carbohydrate diet that does not increase serum triglyceride concentrations is preferable. The degree of dietary fat restriction depends on the severity of hypertriglyceridemia. Patients also should be counseled to completely abstain from alcohol. (See "Hypertriglyceridemia in adults: Management", section on 'General approach' and "Hypertriglyceridemia in adults: Management", section on 'Severe hypertriglyceridemia'.)

●Diabetes mellitus – Medical nutrition therapy for individuals with diabetes is reviewed in detail separately. (See "Medical nutrition therapy for type 2 diabetes mellitus".)

●Metabolic dysfunction-associated liver disease – If metabolic dysfunction-associated steatotic liver disease (MASLD) or steatohepatitis (MASH) is present, dietary modification should be targeted to achieve energy restriction and body weight reduction. (See "Management of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults", section on 'Weight loss'.)

Physical activity

●Most people with lipodystrophy – For most people with lipodystrophy, recommendations for physical activity are the same as those for adults with type 2 diabetes. Most adults should try to achieve 30 to 60 minutes of moderate-intensity aerobic exercise on most days of the week. Recommendations for physical activity are reviewed in detail separately. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Exercise'.)

●Exercise precautions for selected individuals

•Type 4 congenital generalized lipodystrophy (CGL) – Individuals with type 4 CGL who have a history of cardiomyopathy and/or cardiac arrythmias should avoid strenuous exercise. These patients should undergo cardiac evaluation prior to starting an exercise regimen. (See 'Cardiac evaluation (selected patients)' above.)

•Severe hepatosplenomegaly – Individuals with any form of lipodystrophy who have severe hepatosplenomegaly (eg, due to MASLD) should avoid contact sports.

Alcohol abstention and smoking cessation — Alcohol abstention is important for managing moderate to severe hypertriglyceridemia and/or MASLD/MASH. (See "Hypertriglyceridemia in adults: Management", section on 'Severe hypertriglyceridemia' and "Management of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults", section on 'Alcohol use'.)

Smoking cessation is a cornerstone of cardiovascular risk reduction. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Smoking cessation'.)

Pharmacotherapy for metabolic complications and comorbidities — Few drugs are available specifically for lipodystrophy. The initial pharmacologic treatment of lipodystrophy-associated metabolic disturbances (eg, hyperglycemia, hypertriglyceridemia) is generally the same as in patients without lipodystrophy. Patients with generalized lipodystrophy often have severe, treatment-refractory metabolic complications. Thus, treatment with metreleptin (recombinant leptin) is also a reasonable option for initial therapy in these patients. (See 'Generalized lipodystrophy (metreleptin)' below.)

Diabetes mellitus — In individuals with lipodystrophy and type 2 diabetes, metformin is typically prescribed as first-line therapy for glucose lowering. For individuals with partial lipodystrophy, the thiazolidinedione pioglitazone, which increases adiponectin levels and insulin sensitivity, is also often beneficial. Metformin [5] and thiazolidinediones [6-9] may reduce both hyperglycemia and hyperlipidemia. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Hypertriglyceridemia in adults: Management", section on 'Treatment goals'.)

In such patients, insulin therapy is effective and often needed. Nonetheless, as these patients typically have marked insulin resistance, insulin usually must be administered in very high doses, and concentrated insulins (eg, U-500 regular insulin) are often required. In individuals with extreme insulin resistance, even concentrated insulin may fail to adequately manage glycemia [2]. (See 'Treatment-refractory metabolic complications' below and "Insulin therapy in type 2 diabetes mellitus", section on 'Insulin resistance'.)

Very limited clinical evidence suggests that GLP-1-based therapies or SGLT2 inhibitor therapy may be beneficial in patients with diabetes due to familial partial lipodystrophy [10]. Given the limited evidence, these agents are generally reserved for individuals with treatment refractory hyperglycemia as off-label use. (See 'Treatment-refractory metabolic complications' below.)

Hyperlipidemia

●Low density lipoprotein-cholesterol lowering – Adequate low-density lipoprotein cholesterol (LDL-C) lowering is essential for mitigating cardiovascular risk. If LDL-C lowering is needed, the approach is similar as for other patients with type 2 diabetes. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)

●Triglyceride lowering – Adequate management of hypertriglyceridemia is critical for reducing risk of acute pancreatitis. Management is the same as for other populations and is guided by the severity of hypertriglyceridemia. (See "Hypertriglyceridemia in adults: Management".)

Hypertension — Hypertension management is an important aspect of care and does not differ from management in other individuals with type 2 diabetes. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Blood pressure control'.)

Steatotic liver disease — Pharmacologic treatments for MASLD/MASH have not been studied specifically in individuals with lipodystrophy. Thus, the approach to pharmacologic therapy is the same as for individuals without lipodystrophy and largely depends on whether comorbid diabetes is present. (See "Management of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults", section on 'Pharmacologic therapies'.)

Lifestyle measures targeting body weight reduction are a cornerstone of MASLD/MASH management. (See 'Lifestyle measures' above and "Management of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults", section on 'Weight loss'.)

Cosmetic treatment — Facial reconstruction with free flaps and silicone or other implants have been used to "replace" adipose tissue. Liposuction or lipectomy has been used for removal of excess fat. The indications for these treatments are not defined, and use is largely based on patient preference. Cosmetic outcomes are variable.

Contraception — Oral estrogens should not be used in females with partial or generalized lipodystrophy due to risk of marked increases in serum triglycerides and consequent risk of acute pancreatitis. Nonhormonal or progestin-only contraceptives may be used. (See "Contraception: Counseling and selection", section on 'Special populations'.)

TREATMENT-REFRACTORY METABOLIC COMPLICATIONS

Partial lipodystrophy

Glucose-lowering therapies — Limited data support the use of newer glucose-lowering agents in individuals with partial lipodystrophy. Glucagon-like peptide 1 (GLP-1)-based therapies may be a reasonable option for individuals with partial lipodystrophy with treatment-refractory diabetes. Use of GLP-1-based therapies has been limited by concern regarding the risk of acute pancreatitis with these agents, particularly given the elevated baseline risk of hypertriglyceridemia-associated acute pancreatitis with many lipodystrophy syndromes. In individuals with familial partial lipodystrophy, GLP-1-based therapies may help reduce both glycemia and serum triglycerides, although they also have been associated with acute pancreatitis in this population [11,12]. Given the potential risks of treatment, such therapies should only be considered by providers with expertise in treating lipodystrophy syndromes. GLP-1-based therapies are reviewed in detail separately. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus".)

Similarly, limited evidence suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors may improve glycemia and reduce insulin requirements in individuals with partial lipodystrophy [10]. Given the paucity of safety data in this population, we reserve SGLT2 inhibitor use for individuals with partial lipodystrophy who have treatment-refractory hyperglycemia.

Bariatric-metabolic surgery — Gastric bypass surgery has been evaluated in individuals with familial partial lipodystrophy (FPLD) type 1 and type 2 [13,14]. Although the evidence is limited to case reports and small case series, gastric bypass surgery is an option for individuals with severe, treatment-refractory hyperglycemia, progressive metabolic dysfunction-associated steatotic liver disease, or extreme ectopic adipose tissue deposition who meet criteria for bariatric-metabolic surgery. (See "Bariatric surgery for management of obesity: Indications and preoperative preparation", section on 'Indications'.)

Metreleptin (selected regions) — In selected regions, including Europe and Japan, metreleptin has regulatory approval for the treatment of partial lipodystrophy. Metreleptin therapy is an option for individuals with partial lipodystrophy and verified leptin deficiency who experience persistent and severe metabolic complications. In Europe, metreleptin therapy has regulatory approval for use in individuals aged ≥12 years who have treatment-refractory metabolic complications [15]. Metreleptin treatment is reviewed in detail immediately below.

Generalized lipodystrophy (metreleptin)

Indications and contraindications — Metreleptin is recombinant human leptin. For patients with acquired or congenital generalized lipodystrophy with persistent metabolic disturbances, metreleptin may be administered as part of a Risk Evaluation and Mitigation Strategy (REMS) program. The safety and efficacy of metreleptin have only been evaluated in small numbers of patients with congenital or acquired generalized lipodystrophy [2,16], and metreleptin therapy should be provided under specialist care.

●Indications – In individuals with congenital or acquired generalized lipodystrophy, leptin (metreleptin by subcutaneous injection) may be used either as first-line therapy or for management of metabolic complications that are refractory to standard pharmacotherapies [17].

In 2014, metreleptin received regulatory approval from the US Food and Drug Administration (FDA) for the treatment of metabolic complications in patients with congenital or acquired generalized lipodystrophy, in conjunction with diet and other behavioral measures [18].

In Europe and Japan, metreleptin has regulatory approval as an adjunct to diet for the treatment of metabolic complications associated with either generalized or partial lipodystrophy [19]. In Europe, metreleptin is approved for use in individuals with acquired or congenital generalized lipodystrophy who are aged ≥2 years [15].

●Contraindications – Metreleptin should not be used in individuals with the following:

•Human immunodeficiency virus (HIV)-related lipodystrophy

•Metabolic diseases (eg, diabetes mellitus and hypertriglyceridemia) in the absence of lipodystrophy

•Obesity in the absence of lipodystrophy

Metreleptin does not have regulatory approval for use during pregnancy. In the United States, metreleptin does not have regulatory approval for the treatment of partial lipodystrophy.

Efficacy — Leptin replacement therapy with metreleptin may be effective in patients with generalized lipodystrophy and verified leptin deficiency. Open-label, nonrandomized, uncontrolled studies have included small numbers of patients with congenital or acquired generalized lipodystrophy who had diabetes, hypertriglyceridemia, and/or elevated levels of fasting insulin. In these studies, recombinant leptin administered subcutaneously once or twice daily (dosed to achieve physiologic serum leptin concentrations for up to 12 months) resulted in significant clinical benefits [2,16,20-27]. These treatment benefits include reductions in A1C, fasting glucose, and triglycerides [2,16,20-27]. Metreleptin also has been shown to normalize pubertal development and reproductive function.

In a subset of patients undergoing hyperinsulinemic-euglycemic clamp studies, leptin therapy improved peripheral glucose disposal and decreased both hepatic glucose output and hepatic steatosis [21]. Satiation (time to voluntary cessation of eating) and satiety (inter-meal interval) also improved with exogenous leptin therapy [22]. Long-term (12 months) recombinant human leptin therapy also was effective for treating insulin resistance in two individuals with type 1 diabetes and acquired lipodystrophy with insulin resistance [28].

Randomized trials of metreleptin in patients with lipodystrophy and various metabolic abnormalities are necessary to confirm its therapeutic role, mechanisms of action, and longer-term safety, but approval "under exceptional circumstances" has been granted given the rarity and severity of these syndromes.

Adverse effects — Metreleptin causes adverse effects in approximately one-third of treated individuals. The most common side effects observed in patients treated with metreleptin were fatigue, hypoglycemia, headache, decreased body weight, and abdominal pain [2,16]. The development of non-neutralizing and, very rarely, neutralizing antibodies to leptin has been reported [23,24]. Neutralizing antibodies have been associated with worsening metabolic complications, as well as severe infections. Thus, the risk of neutralizing antibodies is the primary reason for the US FDA's restriction of metreleptin use exclusively to individuals with generalized lipodystrophy who have minimal or undetectable circulating leptin levels at baseline. In addition, the development of T-cell lymphoma has been described in patients with acquired lipodystrophy who had autoimmunity and immunodeficiency before beginning metreleptin treatment; thus, whether metreleptin is causally related to T-cell lymphoma remains uncertain [16,23,27].

Precautions and monitoring

●Risk of hypoglycemia – Patients with lipodystrophy and type 2 diabetes who initiate metreleptin treatment are at risk for hypoglycemia, particularly if they use insulin or insulin secretagogues as part of their glucose-lowering regimen. Close monitoring of glucose levels is critical, either with frequent blood glucose monitoring or with continuous glucose monitoring. In patients who are close to glycemic goals (eg, A1C ≤1 percent above target), an empiric reduction in insulin dose is reasonable as glycemic response is closely monitored.

●Autoimmune conditions – Progression of autoimmune disorders has been observed in patients treated with metreleptin. In patients with existing autoimmune conditions, the relative risks and benefits of treatment should be weighed carefully.

●Neutralizing antibodies – Routine testing for neutralizing antibodies to leptin is not needed. Patients should be tested for neutralizing antibodies (when possible) in either of the following settings (see 'Adverse effects' above):

•Severe infection

•Apparent loss of therapeutic response to metreleptin treatment

●Hypersensitivity reactions – Hypersensitivity reactions (eg, urticaria, generalized rash) have been reported during metreleptin treatment. Patients should be counseled about this risk and advised to promptly seek medical care if a suspected hypersensitivity reaction occurs.

Risk Evaluation and Mitigation Strategy (REMS) program — In the United States, metreleptin can be obtained exclusively through a REMS program due to the rare but severe treatment-associated risks of neutralizing antibodies and lymphoma. The REMS program mandates that metreleptin may only be prescribed and dispensed by certified prescribers and pharmacies, respectively. Each new metreleptin prescription requires a REMS Prescription Authorization Form and must be dispensed along with complete instructions for use in an accompanying medication guide. Patients should receive extensive counseling about the potential risks and benefits of metreleptin therapy.

Additional information is available at the Myalept REMS program website [29] or 1-855-6MYALEPT.

SUMMARY AND RECOMMENDATIONS

●Common lipodystrophy-associated complications – Whereas some complications are specific to certain forms of lipodystrophy, other complications are common in most forms of both partial and generalized lipodystrophy and include the following (see 'Common lipodystrophy-associated disorders' above):

•Insulin resistance and diabetes

•Kidney disease

•Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH)

•Hyperlipidemia and hypertriglyceridemia

•Hypertension

•Abnormal pubertal development or reproductive dysfunction

●Assessment for complications – In all individuals with lipodystrophy, clinical assessments, laboratory tests, and liver ultrasound should be performed routinely to evaluate for lipodystrophy-associated complications. (See 'Clinical and laboratory assessments' above and 'Liver ultrasound' above.)

Routine cardiac evaluation is also warranted for individuals with specific forms of lipodystrophy. (See 'Cardiac evaluation (selected patients)' above.)

●Treatment of lipodystrophy-associated complications

•Lifestyle modification – Lifestyle modification (appropriate dietary and exercise interventions) may reduce serum triglyceride levels and improve glycemic management. (See 'Lifestyle measures' above.)

•Initial pharmacotherapy – The initial pharmacologic treatment of lipodystrophy-associated metabolic disturbances (eg, hyperglycemia, hypertriglyceridemia) is generally the same as in patients without lipodystrophy. Patients with generalized lipodystrophy often have severe, treatment-refractory metabolic complications. Thus, treatment with metreleptin (recombinant leptin) is also a reasonable option for initial therapy in these patients. (See 'Pharmacotherapy for metabolic complications and comorbidities' above and 'Generalized lipodystrophy (metreleptin)' above.)

-Type 2 diabetes – In individuals with type 2 diabetes, insulin sensitizers (metformin, pioglitazone) are typically used. Insulin, usually administered in very high doses, is effective but may fail to provide adequate glycemic management in individuals with extreme insulin resistance. (See 'Diabetes mellitus' above.)

-Hyperlipidemia – Adequate low-density lipoprotein cholesterol (LDL-C) and triglyceride lowering are essential for reducing risk of cardiovascular disease and acute pancreatitis, respectively. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Hypertriglyceridemia in adults: Management".)

•Contraception – Oral estrogens should not be used in females with partial or generalized lipodystrophy due to risk of marked increases in serum triglycerides and consequent risk of acute pancreatitis. Nonhormonal or progestin-only contraceptives may be used. (See "Contraception: Counseling and selection", section on 'Special populations'.)

●Persistent metabolic disturbances – For patients with acquired or congenital generalized lipodystrophy who have persistent metabolic disturbances, metreleptin therapy could be considered as part of a Risk Evaluation and Mitigation Strategy (REMS) program. In Europe and Japan, metreleptin has regulatory approval as an adjunct to diet for the treatment of metabolic complications associated with either generalized or partial lipodystrophy. In the United States, regulatory approval is for the treatment of generalized lipodystrophy only. Metreleptin therapy should be provided under specialist care. (See 'Indications and contraindications' above and 'Efficacy' above.)

Randomized trials of metreleptin in patients with lipodystrophy are necessary to confirm its therapeutic role, mechanisms of action, and longer-term safety, but approval "under exceptional circumstances" has been granted given the rarity and severity of these syndromes. Metreleptin treatment requires close monitoring as well as careful consideration of both the extremely high cost and the risk-to-benefit ratio in each patient. (See 'Adverse effects' above and 'Precautions and monitoring' above.)