Thomas Morrow, MD

Given the current state of obesity in the United States and the explosion of associated diabetes and metabolic syndrome, some people may assume that fat is an enemy of good health. But fat actually is a metabolically active human tissue and its absence can lead to severe disease.

Lipodystrophy comprises a group of rare disorders characterized by extensive to near-complete loss of body fat. Such dramatic loss of fat in turn causes the loss of a critical hormone derived from fat tissue: leptin. In normal circumstances, leptin plays a significant role in energy homeostasis, lipid levels, and insulin resistance. The loss of leptin can result in severe metabolic abnormalities with hypertriglyceridemia, insulin resistance, hyperglycemia, and type 2 diabetes. Circulating levels of leptin closely correlate with the amount of adipose tissue present.

From the discovery of leptin to the characterization of its effect to its replication through recombinant technology to clinical trial to approval, the process took about 18 years.

These disorders can also result in the deposition of triglyceride material in organs, the most common being muscle and liver. When the deposition occurs in the liver, it can lead to steatohepatitis, cellular injury, inflammation, and cirrhosis. Additional complications are the result of the metabolic as well as the infiltrative effects of this disorder, and can include pancreatitis and accelerated cardiovascular disease. Of note, the loss of leptin, which communicates to the central nervous system the status of energy stores within the body, results in excess caloric intake, which exacerbates the metabolic abnormalities.

Clinicians have classified lipodystrophy based on etiology (genetic or acquired) and the extent of adipose loss (generalized or partial).

The genetic diseases are Berardinelli-Seip syndrome (also called congenital generalized lipodystrophy) and familial partial lipodystrophy.

Berardinelli-Seip syndrome is the worst form of lipodystrophy. It occurs in about 1 in 10 million births, is characterized by a nearly complete absence of adipose tissue, and can be recognized at birth. It is associated with the most severe levels of hyperinsulinemia and hypertriglyceridemia, and results in recurrent acute pancreatitis and a voracious appetite in early childhood. Liver failure is common. Several distinct genetic subtypes of this syndrome are described in the literature.

Autosomal dominant disorders

There are several forms of familial partial lipodystrophy; all are autosomal dominant disorders. The most prevalent is the Dunnigan variety, which is associated with mutations of the LMNA gene. These infants are born with normal fat distribution, but during puberty the subcutaneous fat gradually disappears from arms and legs – giving the appearance of a muscular build. Later fat loss occurs from the anterior abdomen and chest. Interestingly, many patients, women in particular, gain fat in the face and neck and intra-abdominal region resulting in a Cushingoid appearance. This disorder is difficult to diagnose, particularly in males, as the muscular appearance is not as distinctive as it is in women. These patients develop diabetes, hypertriglyceridemia, atherosclerotic vascular disease, and low levels of HDL.

The acquired form of lipodystrophy, also called Barraquer-Simons syndrome, typically follows autoimmune disease, particularly systemic lupus erythematosus and dermatomyositis. Barraquer-Simons syndrome primarily causes loss of fat in the face, neck, arms, thorax, and upper abdomen.

Prevalence of this group of diseases is difficult to determine, but about 1,350 cases are known to exist in the world, with approximately 1,000 patients with the inherited form and 350 with the acquired forms.

Treatments have historically been supportive and have been aimed at the metabolic derangements of elevated triglycerides and blood glucose. Recently, the FDA approved a new drug, Myalept, that gets closer to the heart of the matter.

Myalept, an analog of leptin, is a 147 amino aid recombinant polypeptide produced in E. coli that differs from leptin by one added amino acid on its terminal end. The FDA approved Myalept “as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.”

HIV can also cause lipodystrophy, but this drug was not studied in HIV patients and thus is not approved in that setting.

The development of Myalept came directly from the knowledge that the loss of fat can lead to a deficiency of leptin. Hence, treatment with leptin or its analog was thought to be of benefit to those with a leptin deficiency. Soon after the discovery of leptin in 1996, an analog (metreleptin) was developed and empirically tried in a small group of patients with lipodystrophy. The findings were so compelling that it was thought to be unethical to use a placebo in future studies. But because of the absence of the placebo control arm, results of clinical trials will be difficult for managed care plans to interpret.

Approval of Myalept

The clinical trial leading to the approval of Myalept consisted of a 48-patient, open-label, single-arm study comprising patients with congenital generalized lipodystrophy (32 subjects) and acquired lipodystrophy (16 subjects) with a median age of 15 years. The median duration of treatment was 2.7 years. Although studied in either once- or twice-daily dosing, the final recommended subcutaneous injection dosage is weight-based and contains a dose escalation schedule to a maximum dose of 10 mg per day.

The FDA label cautions that “possible large reductions” of insulin and other antidiabetes drugs may be necessary to prevent hypoglycemia.

The subjects had a mean drop in HbA1c of 2 percentage points, a drop in fasting glucose of 49 g/dL, and a drop in fasting triglycerides of 184 mg/dL.

Myalept contains a black box warning concerning the “risk of antimetreleptin antibodies with neutralizing activity and risk of lymphoma.” During early development with normal subjects, neutralizing antibodies developed, resulting in metabolic derangements that were due to loss of endogenous leptin activity. Lymphoma has been reported in patients with acquired generalized lipodystrophy, both treated and untreated. Therefore, Myalept is available only through a risk evaluation and mitigation strategy program.

The development and approval of Myalept have followed a course similar to other drug approvals. From the discovery of leptin to the characterization of its effect to its replication through recombinant technology to clinical trial to approval, the process took about 18 years.

Given the pace of scientific discovery, evidenced by nearly hourly news reports, we can only imagine what Tomorrow’s Medicine holds for mankind.

Thomas Morrow, MD, is the immediate past president of the National Association of Managed Care Physicians. He has 24 years of managed care experience at the payer or health plan level. Contact him at

The author is the chief medical officer of Next IT. He has had no other industry affiliations in the past three years. The views expressed in Tomorrow’s Medicine are the author’s alone.

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