Good afternoon. My name is Suman Srinivasa. I'm an endocrinologist at the Massachusetts General Hospital. I'm so delighted to be here today. Thank you to the Endocrine Society for the invitation and for providing this platform for an educational webinar. Today we will be discussing lipodystrophy. The objectives for this talk are as follows. We'll assess the role of fat and how abnormal distribution of subcutaneous and visceral fat may lead to potential metabolic consequences. We will recognize types of lipodystrophies and classify lipodystrophies into generalized and partial and congenital and acquired forms. We'll identify relevant contributors to HIV-associated lipodystrophy, such as unique growth hormone physiology. And finally, we'll review targeted treatment strategies for lipodystrophy, including metroleptin and tisamorelin and assess indications for use. So let's begin. As a refresher, adipose tissue can be classified as white or brown adipose tissue. Both subcutaneous and visceral adipose tissue are types of white adipose tissue. Brown adipose tissue is a unique fat depot that can regulate metabolism through enhanced energy expenditure and is metabolically favorable. White adipose tissue comprises the majority of our adipose tissue as an adult and will really be the focus of our talk today. The adipose tissue depot itself is also composed of mature adipocytes, as well as the stromovascular fraction, which consists of pre-adipocytes, fibroblasts, macrophages, and endothelial cells. The primary role of white adipose tissue is for energy storage. Here we see the locations of specific depots. You can think of the subcutaneous depot as the pinchable superficial fat and the visceral depot as the fat within the interabdominal cavity and that which deposits in organs. Subcutaneous fat is thought to be protective for energy or triglyceride storage, whereas visceral fat is dysfunctional and inflamed and cannot store energy properly. When subcutaneous adipose tissue typically accumulates in the flanks and hip, that can be protective, whereas when fat accumulates in the abdomen and viscera, this is associated with increased metabolic risk. A key function of adipocytes is the storage of triglycerides for use as an energy substrate and to also release fatty acids to supply other tissues during fasting or times of high energy demand. Most triglycerides and adipocytes are derived from chylomicrons and VLDL from dietary and hepatic sources. Triglycerides are hydrolyzed by lipoprotein lipase, which releases fatty acids that are then taken up by the adipocyte. During the process of lipogenesis, there is conversion of free fatty acids to triglycerides for storage. There is also a small contribution from glucose towards lipogenesis. When metabolic fuels are low and or energy demand is high, the adipocyte can mobilize their storage to the peripheral tissues in a process called lipolysis, in which there is breakdown of triglycerides by hormone-sensitive lipase to free fatty acid and glycerol. Insulin is one of the principal hormones involved in adipocyte function. Insulin promotes triglyceride storage via the regulation of lipoprotein lipase and inhibition of lipolysis. Insulin also stimulates adipocyte differentiation and promotes glucose uptake. So in a state of insulin resistance, these functions are affected and will then affect the adipocyte and triglyceride storage as well. While we commonly associate the adipose depot with adipokines such as leptin and adiponectin, which are really integral to energy balance and insulin sensitivity, there are a vast number of other factors secreted by the adipose which contribute to its role in so many other functions, including vascular tone, inflammation, and reproduction, for example. In this regard, we know the adipose depot to be an important endocrine organ. When we think about lipodystrophy, we can think more broadly about altered fat distribution. In lipodystrophy, there is a selective deficiency of adipose tissue in the absence of any nutritional deprivation or catabolic state. And what we do know is that beyond the total amount of fat, it's really the extent of fat loss and the distribution of fat that contributes to the metabolic state. In this regard, the severity of metabolic dysfunction is proportional to the extent of fat loss. Lipodystrophy can encompass lipoatrophy and lipohypertrophy. Lipoatrophy is reduced subcutaneous adipose tissue or SAT, and there's fat loss. You can see here examples of SAT loss in the extremities and face on the left. This is quite striking as you may see a prominence of veins as shown here and more definition of the musculature. Lipodystrophy is typically seen as increased visceral adipose tissue or VAT and known as fat accumulation. And here you can see an example of increased VAT accumulation in the abdomen. There are further implications of fat redistribution as illustrated by the lipid overflow ectopic fat deposition model. Under this model, the body's ability to cope with the surplus of calories may ultimately determine the individual susceptibility to metabolic disease. If the excess energy can be channeled into insulin sensitive SAT or subcutaneous adipose tissue, there's protection against the development of metabolic syndrome. However, in cases where the adipose tissue is absent, deficient, or insulin resistant with a limited ability to store energy excess, the triglyceride or lipid surplus will then be deposited at undesirable sites such as the liver, heart, skeletal muscle, and in the visceral adipose tissue described all as ectopic fat deposition. In response to caloric excess, healthy expansion of white adipose tissue occurs through an increase in adipocyte number or hyperplasia. Pre-adipocytes are recruited and de novo adipocyte differentiation occurs, whereas with pathologic expansion, there's an enlargement of existing adipocytes or hypertrophy, and this is associated with inflammation, hypoxia, and fibrosis. Of course, the adipocyte dysfunction leads to the spillover of lipids into non-adipose organs as we previously just discussed. The potential pathophysiology of metabolic dysfunction and lipodystrophy is shown here. With atrophy of the adipose tissue, there's loss of energy storage as well as a decrease in adipocytokines, including leptin. Both of these mechanisms can lead to ectopic fat deposition and hypertriglyceridemia, which then results in insulin resistance and hyperinsulinemia mainly, and this leads to cardiometabolic dysfunction and other complications, including PCOS and hyperandrogenism. In addition, with the decrease in leptin, this can contribute to hyperphagia and hypogonadism. Of course, there are metabolic consequences to lipid accumulation, as you can see here, which results in increased morbidity and mortality. For example, increased intramyocellular lipid results in fatty liver. When there's increased lipid in the epicardial, pericardial, perivascular, intramyocardial regions, this can lead to atherosclerosis or myocardial dysfunction, and intramyocellular lipid in the muscle can lead to insulin resistance. And shown here in the right lower corner, we can see that really there's an exponential rise in mortality with increasing VAT. So in research protocols, we have the advantage of assessing fat redistribution using imaging. These are representative MRI images from participants, which are taken as a single slice below L4. On the left, you'll see a patient with relatively increased VAT. You see there's increased density in the intraabdominal cavity and reduced SAT, and this is consistent with a lipodystrophy or fat redistribution phenotype. And on the right, you'll see a patient with less VAT and more SAT present. And these highlight the point that even with similar BMIs or even waist circumferences, the clinical picture can really vary and may not give us the whole metabolic picture. But a good physical exam to evaluate fat redistribution is essential. This person on the left is the one that we worry about that may have increased cardiometabolic risk. So that brings us to our first pretest question. We have a 12-year-old female with a history of juvenile dermatomyositis who presents with a progressive loss of fat over the past year. She reports hyperphagia. There's a family history of hemolytic anemia and rheumatoid arthritis. Her physical exam is notable for a diffuse loss of fat, hirsutism, acanthosnagercans, hepatomegaly, and prominent veins on her lower extremities. Laboratories reveal a leptin of 0.9 and A1C of 10.9, triglycerides of 862. You believe this presentation is most likely consistent with A, congenital generalized lipodystrophy, B, acquired generalized lipodystrophy, C, familial partial lipodystrophy, or D, acquired partial lipodystrophy. And we'll return to this. So here's the basic classification schema for lipodystrophy. When you are trying to classify fat loss, you are going to think about the pattern of fat loss, whether it's generalized, meaning the fat loss is affecting the whole body, or whether it's partial, meaning fat loss is only affecting some areas. With the generalized lipodystrophies, you may even want to think about whether it started from birth, being congenital, or later in life, being acquired. Within the partial lipodystrophies, you're going to start thinking about whether this is familial or acquired. Based on what we do know about genetic mutations related to lipodystrophy, these alterations seem to occur anywhere along the pathway from development, differentiation, and death of the adipocyte. So we'll go through each subtype and highlight key points to differentiate between them. With the congenital generalized lipodystrophy, this is usually diagnosed soon after birth. There will be a diffuse or generalized loss of fat and associated fat accumulation. There may be hyperphasia and accelerated linear growth. The more fat redistribution, the more likely there are metabolic complications. So there will likely be insulin resistance, diabetes, high triglycerides, and fatty liver. There may be acromegaloid features on exam due to the lack of fat and muscle prominence. Evidence of hyperandrogenism and hypogonadism may be present. We would also expect a low leptin and adiponectin level due to the low amount of fat. There are four types that have been identified thus far based on genetic mutations that are relevant to adipocyte biology. Phenotype 2, which is associated with defects in the sepian protein, presents with a more severe phenotype with accelerated onset and mortality, cardiomyopathy, and intellectual impairment. Acquired generalized lipodystrophy usually presents during childhood or before adolescence, so later than the congenital form. It tends to be more common in females and may develop over a period of weeks to months. Being characterized as generalized, there is a diffuse loss of sat as well, and you may even see a loss of fat in mechanically important areas such as the palms and soles. Given the extent of fat loss, again, metabolic complications are present, and adiponectin and leptin are low. There could be evidence of paniculitis as well or positive antiparalypin antibodies. The acquired lipodystrophies may be associated with autoimmune disease, and there have been recent reports of autoimmune lipodystrophy associated with immune checkpoint inhibitors as well. You can see here sample photos of patients with congenital and acquired generalized lipodystrophy respectively. The time to onset history may help distinguish these. You can see that there is diffuse sat loss in both. In the leftmost pictures, you'll see that there is prominent musculature and some agromegaloid-type features. You can see a prominence of the veins in the lower extremities here as well. There's also umbilical protuberance. In the rightmost picture, there's some abdominal lipohypertrophy, which suggests fat accumulation. And aside from a diffuse loss of fat, there may be a loss of fat in the hands, feet, and we see some fat loss here even around the knees. Familial partial lipodystrophy occurs around puberty typically, and often will have other family members affected. There's a loss of fat in the limbs as well as the buttocks and hips. However, the upper adipose regions are typically spared, and there may be fat accumulation in the upper areas and in the abdomen. And these individuals may happen to have a cushionoid-type appearance as well. Metabolic abnormalities are present. Again, in proportion to the fat loss, the leptin and diponectin are actually only moderately reduced. There are six types that have been identified thus far based on genetic mutations. Type 2 or Dunigan's is the most common of these and involves an LMNA mutation, which affects the lamin protein. There are a few other miscellaneous types that may fall under this categorization as well. Acquired partial lipodystrophy occurs in childhood or adolescence and into adulthood. There's also a female predominance. On exam, there is a cephalocaudal progression of fat loss from face to abdomen. There are rarely metabolic complications, and this is why the presentation may be more delayed in this category. Again, in proportion to the fat loss, the leptin and adiponectin are only moderately reduced. Similar to acquired congenital lipodystrophy, acquired partial lipodystrophy may be associated with autoimmune history. In addition, there's an association to membranal glomerulonephritis, and labs may show a low C3 or presence of nephritic factor C3. On history, the presentation may also be preceded by an infection, and a type of regional lipodystrophy has also been described that may occur from injectable meds. Here you can see sample photos of patients with familial and acquired partial lipodystrophy respectively. Again, the time to onset in history may help distinguish these. In the leftmost pictures, you can see in familial partial lipodystrophy, the fat loss is prominent in the extremities, and there's sparing of fat loss in the upper regions. In addition, there may be a cushionary appearance. You can see there may be some fat accumulation actually in the mons pubis area as well here. In the third picture from the left, you can see in contrast in acquired partial lipodystrophy that there may be progressive fat loss from head to toe. And the picture farthest on the right is of a patient with HIV lipodystrophy who has dorsal cervical and abdominal lipohypertrophy. So it's important to note that leptin has different physiology in lipodystrophy and obesity. Adiponectin sensitizes the liver and muscle to insulin. Adiponectin is increased in lean states and healthy with healthy fat and is reduced with increased visceral fat. Leptin functions to suppress appetite. So low levels will lead to hyperphagia as we've described. It's produced by the white adipose tissue and it's proportionate to the amount of body fat. So in this way, we see in obesity that leptin levels are increased and is often characterized by leptin resistance. In generalized lipodystrophy, there is a low leptin as you would expect in the absence of fat. In acquired and HIV lipodystrophy, you may actually only see modestly low or as often the case, normal leptin levels. And this might not actually help with the diagnosis. You will likely see reduced adiponectin in all of these states, however. So what is the natural history of lipodystrophy? This was taken from an international chart review of patients with confirmed generalized or partial lipodystrophy. Diabetes and insulin resistance were identified in about 60% of the patients. All patients had one metabolic abnormality and almost 80% had at least one organ abnormality with liver being the most common, followed by kidney, heart, and pancreas. In general, the prevalence of abnormalities were higher in the general versus partial lipodystrophies as would be expected given the extent of fat loss relates to worse metabolic disease. A key point here is that there will be some metabolic abnormalities or organ affected that should raise your suspicion for lipodystrophy. And if there are no metabolic issues, then it may be unlikely that the patient has lipodystrophy or maybe that it hasn't fully presented yet. With regards to natural progression of metabolic disease and lipodystrophy, they observed similarly, it is not unexpected the amount of fat loss seems to be related to the quicker onset of complications such that all of these occur more quickly in the generalized lipodystrophy group. As you can see, it can take some time for metabolic complications to present as well. So if you have suspicion, you may need continued monitoring. And in general, those with lipodystrophy have reduced life expectancy, which can be attributed to the morbidity and mortality associated with metabolic complications. Lipodystrophy is very much a clinical diagnosis. On physical exam, a whole body exam should be performed for fat redistribution. It will be best to ask the patient to gown up. You really want to assess body composition from head to toe, paying attention to the face, upper body, limbs, trunk, abdomen, hips, buttocks, the whole body. In addition, you want to evaluate for hepatomegaly, prominent veins, muscle hypertrophy, acanthosnigricans, xanthomas, an agromegaloid, cushionoid, or progeroid appearance, and hyperandrogenism in females. Anthropometrics may be helpful to assess abdominal lipopertrophy using the waist circumference or waist to hip ratio. The waist circumference is measured by placing the tape around the abdomen at the level of the iliac crest and ethnic-specific cutoffs for elevated waist circumference from the IDF are shown here. Imaging techniques are actually the gold standard to quantify SAT and VAT, but unfortunately are not available for clinical use. So on labs, you're evaluating for metabolic abnormalities and may check the leptin and adiponectin levels. Though again, leptin may not distinguish the diagnosis in partial lipodystrophies, and there have also been additional issues with the assays for leptin. Based on your suspicion, you may also evaluate a C3 or obtain a liver ultrasound or echo to check for liver and heart disease. A subcutaneous biopsy may be helpful to look for paniculitis. If a genetic lipodystrophy is suspected, there's testing available for known mutations. As there are probably some undiscovered mutations, negative testing for genetics does not rule out a diagnosis. Lipodystrophy is rare, so really keep your differential wide relating to other disease states which may result in body composition changes. If these are ruled out, the presentation may be consistent with lipodystrophy. And as I say it is rare, there are actually newer epidemiologic studies suggesting that partial lipodystrophies are actually present in one out of every 20,000 individuals. Putting together all this information as we've discussed, a comprehensive diagnostic approach to lipodystrophy is suggested here. You may want to obtain information about the age of onset. As we discussed, the fiscal exam for fat redistribution is key. Metabolic evaluation will also be helpful to raise suspicion of lipodystrophy. From there, you'll obtain a family history. If there's a positive family history, early onset at birth or progeny features, this will point you towards a congenital generalized lipodystrophy. If there's later onset and the extent of fat loss will be helpful to distinguish further. If there is extremity fat loss only, this may point more towards a familial partial lipodystrophy. If there's generalized fat loss or upper body fat loss, this will point towards acquired generalized or acquired partial lipodystrophy respectively. And if there's an autoimmune disease history, this may also increase suspicion for the acquired lipodystrophies. So turning back to our pre-test question one, here the answer is B. There's a diffuse loss of fat in this patient with a very low leptin level along with metabolic disease. So we're starting to think more about a generalized lipodystrophy. The presentation was later in adolescence and the history is notable for autoimmune disease, which may be consistent with how acquired generalized lipodystrophy would present. And now our second pre-test question. A 31-year-old female with known diabetes diagnosed at age 23 presents with worsening and difficult to control diabetes. The physical exam is consistent with the picture shown on the right. You suspect lipodystrophy and genetic testing reveals a mutation in the LMNA gene. You perform some laboratory work. In which scenario might the patient receive the most benefit from leptin replacement? And we have four options here, reporting leptin levels, A1C levels, triglyceride and ALT levels. And again, we'll return to this. So the treatment for lipodystrophy is quite challenging. Limited options exist and are aimed at targeting comorbidities. With regards to diet, you may recommend balanced macronutrients, consider energy-restricted diets and a very low fat diet if severe hypertriglyceridemia is present. Restricting diets may be difficult with hyperfasia, however. In terms of exercise, aerobic activity will help decrease insulin resistance. Resistance training may be important to decrease fat mass and triglycerides and improve insulin sensitivity. With the caveat that exercise may actually exacerbate fat loss further in those with severe lipoatrophy. Few therapies have been tested in lipodystrophy. Metroleptin is an FDA approved medication for generalized lipodystrophy. Tisamrolan is an FDA approved medication for HIV lipodystrophy. And we'll review the data for both of these in the coming slides. You may also treat metabolic disturbances associated with lipodystrophy as you normally would approach them in a patient without lipodystrophy. And from the physician viewpoint, the concern is mainly metabolic disease. While from the patient viewpoint, lipodystrophy can actually be very distressing because of the physical changes. There are facial fillers that can be used for facial atrophy. Some of the patients may ask about liposuction, especially those with HIV lipodystrophy or partial lipodystrophies who have areas of lipohypertrophy and evidence would suggest against liposuction as you're really removing the subcutaneous fat and not the ectopic or visceral fat. And actually this can actually worsen the metabolic picture as it can lead to a compensatory increase in visceral fat by removing the subcutaneous fat further. If there's any concern that this is affecting the patient's mental health, they should be referred for appropriate services. Since forms of lipodystrophy can be associated with leptin deficiency, this led to the landmark trial of leptin replacement for lipodystrophy. It was a small but powerful study. Nine female patients with low leptin levels, less than four, received subcutaneous leptin for four months. The leptin levels increased dramatically with replacement as would be expected. Following leptin treatment, they also saw a triglycerides decreased by 60%. Insulin sensitivity and glucose response to oral glucose tolerance testing improved. And there was a decrease in A1C by about 2%. In addition, antidiabetic therapy was discontinued or largely reduced in the women with diabetes. Benefits of leptin replacement were seen in the liver such that liver volume decreased by 28%. And there's also been studies demonstrating that leptin reduces steatosis and ballooning leading to reduced non-alcoholic steatohepatitis activity. Studies have shown additional benefits of leptin replacement and lipodystrophy. Among those with generalized lipodystrophy, studies suggest leptin replacement, attenuated cardiac hypertrophy, significantly reduced albuminuria and proteinuria, and decreased androgens, normalized gonadotropin secretion, restored menses, and improved fertility in females. In addition, there is some more studies In addition, there is some mortality benefit. Metroleptin-treated patients with lipodystrophy had an estimated 65% decrease in mortality risk compared to metroleptin-naive patients with lipodystrophy. So there's really broad potential to leptin in these patients. Based on these studies, leptin is approved for use in generalized lipodystrophy. The successful use of leptin in generalized lipodystrophy is fundamental to their physiology that they present with leptin deficiency. Metroleptin is not approved for use in partial lipodystrophies. It is a daily subcutaneous injection with weight-based dosing. Metroleptin is only available for prescribing through the REMS program. There is a black box warning related to the development of anti-metroleptin antibodies with neutralizing activities and T-cell lymphoma. Other side effects also include fatigue, low blood sugars, headache, and abdominal pain. So additional studies were aimed at understanding the potential use of metroleptin in partial lipodystrophy, in which case you remember there's not always frank leptin deficiency. So the goal of this study was to compare the response between those with generalized and partial lipodystrophy. Men and women were included based on the leptin cutoff and had to have one metabolic abnormality. You can see here at baseline on the right, the partial lipodystrophy group had relatively higher leptin levels and body fat compared to the generalized lipodystrophy group, which highlights the differing physiologies. And while the metabolic parameters were otherwise similar between these two groups. Both groups were then treated with metroleptin. To summarize the response to metroleptin, BMI, A1c, fasting glucose, and triglycerides all significantly improved in both the generalized and partial lipodystrophy groups. Most change in A1c and triglycerides occurred at six months. The number of antidiabetic and lipid-lowering meds per patient, rate of insulin users, and total daily insulin dose decreased significantly in the generalized lipodystrophy group. No changes of this nature were seen in the partial lipodystrophy group. The key data from the study also came from a subgroup analysis using cutoffs for leptin, A1c, and triglycerides. What they saw was that the decrease in A1c and triglycerides in partial lipodystrophy patients was significant among those with baseline triglycerides in subgroups of triglycerides greater than 300 or greater than 500, A1c subgroups of greater than seven or eight, and baseline leptin less than four. So with a low leptin level and metabolic abnormalities, those were the individuals that were most likely to benefit in the partial lipodystrophy group. In generalized lipodystrophy patients, the decrease in A1c and triglycerides were significant across all subgroups with the exception of those who were in the category with a baseline triglyceride less than 300. So as we reviewed, metroleptin is not approved for use in partial lipodystrophies, including HIV, but these data highlight that leptin could be considered for hypoleptinemic patients with a leptin less than four and patients with partial lipodystrophy who also have severe metabolic derangements of A1c greater than four or triglycerides greater than 500. Metroleptin in this situation could be obtained through clinical trials and compassionate use programs. So returning back to our pre-test question two, there's sparing of fat loss in the upper region with an associated cushionoid appearance. In addition, the genetics demonstrated an LMNA mutation. This is consistent with a familial partial lipodystrophy. Leptin replacement would provide most benefit with a leptin less than four, hemoglobin A1c greater than eight and triglycerides greater than 500. So the correct answer is B. So let's review and synthesize the non-HIV related lipodystrophies before we move on. The adipose depot is an important endocrine system to metabolic health. Fat redistribution can have detrimental effects on cardiometabolic disease. Congenital and acquired lipodystrophies are largely a clinical diagnosis based on abnormal fat redistribution. You should perform a careful physical exam for body composition and assess for metabolic complications. Leptin levels may be useful in generalized phenotypes. Treatment of lipodystrophies is challenging. Leptin is only approved for use in generalized lipodystrophies in which its use has metabolic benefit and may also improve liver and heart disease as well as other functions. Leptin can have a benefit in a subset of those with partial lipodystrophy with relatively low leptin and increased triglycerides in A1c. So let's take a look at our pre-test question three. We have a 64 year old male with a history of HIV well treated with bactegravir, emtricitabine, tenofovir, alafenone, and prediabetes who presents with complaints of increasing waking. His exam is consistent with central adiposity, severe facial atrophy and mild lipohypertrophy of the extremities. Labs are notable for an A1c level of A1c for an A1c of 6.7, a HOMA-IR of 5.29, an AST of 54, ALT88, triglycerides 469. Liver ultrasound demonstrates hepatic steatosis. Current medications include metformin 500 milligrams twice a day. You make the following recommendation for this patient. A, start metroleptin. B, increase metformin to a thousand milligrams twice a day. C, start to samarelin. Or D, switch the antiretroviral regimen. So data show that there is a differential fat redistribution among persons with HIV, even at normal and overweight BMIs. So we should really be thinking about fat redistribution even apart from the obese phenotype. This is a key point that persons with HIV have significantly increased VAT and reduced SAT as shown here in the white bars when compared to persons without HIV as shown in the gray bars, who are well-matched based on age, race, and BMI. Again, highlighting that BMI is not always a good measure as we reviewed earlier. And again, to hit it home, beyond the total amount of VAT, it's really the distribution of VAT that contributes to the metabolic state. It has been shown that persons with HIV lipodystrophy are more likely to have impaired glucose tolerance, diabetes, hyperinsulinemia, hypertriglyceridemia, and decreased HTL than age and BMI-matched persons without HIV. These data are taken from the FRAM study. And after controlling for traditional risk factors as well as HIV-specific risk factors, increased VAT and more so those in the highest tertile were related to higher mortality. We do know that in the era of effective antiretroviral therapy, or ART, over half of persons with HIV will die of non-communicable diseases. In this regard, the excess VAT could be a driver of non-communicable disease. To that point, we know that VAT redistribution is an important contributor to cardiovascular or CBD risk in HIV. And actually, CBD is the number one cause of morbidity and mortality from non-communicable disease in HIV. Studies have consistently shown that the risk of coronary artery disease is approximately two-fold higher in persons with HIV compared to those without. We know that the VAT is positively associated with the presence of coronary plaque. And in addition, there's an inverse association between SAT and the extent of total plaque in HIV. Moreover, myocardial steatosis correlates with VAT and can lead to myocardial dysfunction in HIV. And with regards to diabetes, there's a four-fold increase in diabetes in persons with HIV receiving ART versus persons without HIV. In addition, abdominal fat gain over two to four years is associated with a three-fold increased risk of incident glucose disorders. So there are other potential hormone pathways for abdominal fat accumulation and fat redistribution in HIV aside from lipodystrophy. So hypogonadism or low testosterone is a well-recognized risk factor and can occur prematurely in HIV. With low testosterone, you are likely to lose muscle mass and may gain abdominal weight. Among women with HIV, the menopausal transition actually occurs earlier. Age-adjusted antemullarian hormone or AMH levels, which are a measure of reduced ovarian reserve, have been shown to be lower in women with HIV versus women without HIV. And again, it's well-known that women gain abdominal fat in the perimenopausal and menopausal state. Data have also shown that 30% of men with lipodystrophy in HIV are growth hormone deficient and body composition can be affected by growth hormone deficiency. And we'll discuss how targeting this unique growth hormone physiology has resulted in a therapeutic strategy for HIV in the coming slides. We'll also highlight the relevance of cortisol excess in the next couple of slides. So it would really be important to evaluate thoroughly for potential causes of body composition changes in HIV. So differentiating between Cushing syndrome and lipodystrophy in HIV is relevant. There may be overlapping features, including abdominal lipohypertrophy or dorsal cervical fullness. Though one differentiating feature may be that Cushing syndrome will present with moon faces and superclavicular fullness while we typically may see facial atrophy in HIV lipodystrophy. It's important to recognize exogenous glucocorticoids can be a lipodystrophy mimicker in the setting of ART interactions. Antiretrovirals ritonavir and covicastat are potent inhibitors of the cytochrome P450-CYP384 enzyme and prevents the breakdown of drugs metabolized via this route. This drug-drug interaction prevents the metabolism of exogenous glucocorticoids, which leads to iatrogenic Cushing's or cortisol excess. And this typically occurs with preparations other than the oral glucocorticoids such as the inhaled or intraarticular steroids, more so because these routes are lipophilic and typically have a longer half-life. Once the steroids have been discontinued, the Cushing's picture is typically irreversible, but you may need to replace with glucocorticoids as there can be transient secondary adrenal insufficiency. So on the right here, you'll see an example of a person with HIV on fluticasone interacting with the ART and following discontinuation of the fluticasone, the dorsal cervical and abdominal fat accumulation have reversed. Again, gleaning insights from other lipodystrophies, we do know that adipocyte dysfunction can occur anywhere along the pathway from the development, differentiation, or death of the adipocyte. And if we were to pick out potential factors specific to HIV that may be implicated, we're gonna think about ART, direct viral effects, the adipose depots of viral reservoir and gut barrier disruption. We'll touch upon ART and viral effects in the following slides. So this is a nice summary table describing the effect of ART classes on the adipose depot. Across the board, these are generally known to impair adipogenesis and differentiation. We've known the NRTIs to cause limb and facial atrophy, especially with the thymidine analogs, stavidine and zaduvidine. And this is mainly due to mitochondrial dysfunction. The more contemporary ART, tenofovir-L-ephanide, has been associated with generalized weight gain. It's less common to see body composition changes with the NNRTIs, though they do also present with an adverse metabolic profile. With regards to the protease inhibitors, or PIs, these are known to cause visceral or dorsal cervical lipohypertrophy. PIs also inhibit glute board translocation, and therefore cause insulin resistance, and have been related to defects in lamin, a gene that's critical to lipodystrophies. While NSTs were initially thought to spare the adipocyte, emerging data suggests otherwise, and this is certainly not the case. We see generalized weight gain with the NSTs, and they've also been linked to insulin resistance. One side note is that with integrase inhibitors, there's a drug-drug reaction with metformin, and this will typically increase plasma levels of the metformin, so you may need to exercise caution in dosing of the metformin. The first-line regimen for ARTs these days includes the integrase inhibitor plus two NRTIs, but you may see patients on other ARTs, such as the protease inhibitors and NRTIs, due to drug resistance profiles and access to care. So we may think further about how starting or changing ART regimens may impact body composition. We know that switching off thymidine analogs demonstrates improvement in lipoatrophy, though patients are rarely on this regimen current day. Overall, initiation of NRTI, PI, and NST-based ART is generally associated with SAT and VAT gain, and in general, VAT increases by about 25 to 35% after the initial two years of start. Randomized switch studies have not shown a benefit of switching from a protease inhibitor, and the bottom line is really that ART switches do not generally work, and the priority is to maintain a regimen that will provide adequate viral suppression for the patient. So viral protein R, or VPR, is an HIV accessory protein secreted in the bloodstream that can have broad systemic effects, and in this way, we actually may think of VPR as a hormone. The key point here is that even in persons with undetectable viral loads on ART well-treated may still have measurable VPR in the serum. Studies have shown that VPR is a co-repressor of the PPAR-gamma-mediated transcription and a co-activator of glucocorticoid receptor. In this regard, it's no wonder that individuals with HIV lipodystrophy have a pushinoid-type appearance, and it may be that they secrete a hormone that mimics glucocorticoid activity if we think about the VPR this way. Preclinical models of VPR overexpression resemble the metabolic phenotype of HIV lipodystrophy in VAT. This also may explain why we see metabolic disease despite adequate suppression of the virus, and this may be independent of antiretroviral therapy effects. So back to leptin. So as expected here on the left, we see that leptin is proportional to the amount of VAT regardless of whether it is subcutaneous or visceral in HIV. This is a similar principle in non-HIV. We also see that there are differential leptin levels based on HIV lipodystrophy subtype, which mirrors and correlates generally with the amount of VAT. We see that leptin levels are normal in those with lipohypertrophy, lower but still remaining in the lower range for those with mixed lipohypertrophy and lipoatrophy, and finally lowest among those with lipoatrophy, which makes sense because this is, again, correlated with the amount of VAT. So because leptin levels are generally normal in lipodystrophy, use of leptin replacement has not been beneficial, which is not different from really thinking about other partial lipodystrophies. To summarize here, some familiar treatment strategies that have been tested in HIV lipodystrophy. Leptin has been shown to decrease VAT with no effect on SAT. It improves the metabolic profile as well. Overall, leptin may be beneficial in HIV lipodystrophy among those who may present with significant lipoatrophy and low leptin levels less than four. A limitation of the strategy is that most patients with HIV lipodystrophy, as we just spoke about, do not fit into this category of leptin deficiency, and leptin is not approved for use in HIV lipodystrophy. Glitazones have shown no effect on VAT, but may modestly increase SAT in the limbs and improve insulin resistance, potentially in a subset of those with preexisting insulin resistance. Of course, we know that this has to be weighed against potential side effects that we would worry about the glitazones, such as bone and CBD side effects, and they may also increase total cholesterol. Metformin may decrease VAT. Those significant effects have not been demonstrated. Metformin reduces SAT actually, but may not be beneficial to those with lipoatrophy. So overall, metformin may help reduce insulin resistance in HIV lipodystrophy patients with glucose intolerance, and in general, these medications are not truly a comprehensive treatment strategy for HIV lipodystrophy. So from there, it was noted that the phenotype of HIV lipodystrophy closely resembled that of patients seen with growth hormone deficiency. Therefore, the question was posed as to whether individuals with HIV lipodystrophy may also have relative growth hormone deficiency. In these case studies, it was shown that increased VAT was associated with the lowest mean growth hormone levels as measured by frequent overnight sampling. It was also found that individuals with HIV lipodystrophy, as shown in the black bars, were more likely to fail a GHRH arginine stimulation test as compared to those without HIV, as shown in the white bars. So it could be hypothesized that relative growth hormone deficiency may be exacerbating the phenotype observed in HIV lipodystrophy, and that leveraging this unique growth hormone physiology may be a beneficial treatment strategy to restore the growth hormone access. When you look at growth hormone secretion profiles among individuals with HIV lipodystrophy and those without HIV, there's an important distinction. Individuals with HIV lipodystrophy have intact growth hormone pulsatility, but the GH pulse amplitude is reduced. The mechanism for this phenomenon was thought to be twofold. One, individuals with HIV lipodystrophy have increased somatostatin tone in part due to increased free fatty acids, and this may inhibit growth hormone. And two, individuals with lipodystrophy have lower ghrelin levels, which otherwise typically would augment growth hormone-releasing hormone and growth hormone directly. So we know that growth hormone is important to metabolic homeostasis, even as adults. Growth hormone is lipolytic, with its primary effect to reduce fat and spare the SAT. Growth hormone inhibits de novo lipogenesis, which may have important implications for triglyceride homeostasis. Growth hormone reduces inflammation as well. Overnight frequent sampling demonstrated that mean overnight growth hormone levels are reduced approximately 50% in men with HIV with fat redistribution, compared to weight-matched groups without HIV. And again, there were reductions in the pulse amplitude, pulse width, and trough levels without any significant changes in the pulse frequency. So this randomized double-blind placebo-controlled trial of persons with HIV tested growth hormone as a treatment strategy. Persons with HIV were required to have abdominal fat accumulation and reduced growth hormones secretion, and low-dose physiologic growth hormone was tested over 18 months. Those on growth hormone had significantly reduced visceral fat and truncal obesity, reduced triglycerides, as well as diastolic blood pressure. However, the two-hour glucose levels on glucose tolerance testing was significantly increased. So here we can add growth hormone to our treatment studies. And we know that physiologic growth hormone, as I've just shown you, may selectively reduce fat, triglycerides, and blood pressure. However, a significant limitation is that it worsens glucose tolerance. This may pose a challenge, as we know, as there's always already an increased risk of dysglycemia and HIV lipodystrophy. And with this, growth hormone is not currently approved for use in HIV lipodystrophy. So continuing along this trajectory of studies, the growth hormone-releasing hormone analog to samarelin was tested as a novel strategy to augment the growth hormone IGF-1 access in HIV. Again, to remind ourselves, persons with HIV lipodystrophy have intact pulsatility, but the pulse amplitude is reduced. To samarelin takes advantage of the patient's intact hypothalamus and pituitary to increase endogenous growth hormone secretion, rather to administer growth hormone itself exogenously. By doing so, the pulsatility of growth hormone can be maintained, which would not be the case with exogenous administration. And in addition, endogenous GH secretion is subject to normal negative feedback mechanisms by IGF-1 so that the GH-IGF-1 access are more likely to stay in a physiologic range. In the randomized control trial, it was shown that to samarelin reduced VAT by approximately 15% compared to placebo. Interestingly, samarelin spared any SAT loss as shown on the left portion of the graph. This is an extremely useful clinical strategy in HIV lipodystrophy where there may be increased VAT but decreased SAT as well. Moreover, there was metabolic benefit to reduce triglycerides. And on the right in crossover studies, however, it may suggest that when to samarelin is stopped, there may be reaccumulation of visceral adiposity to baseline. So neither fasting glucose nor insulin-stimulated glucose uptake was significantly affected by to samarelin in this short-term study. Effects are usually greatest at the beginning of treatment with growth hormone on the glucose and whose use we know can be limited by hyperglycemia, but no such perturbations were seen here with growth hormone-releasing hormone administration. So additional studies performed have shown that to samarelin led to a significant reduction in liver fat and HIV as shown in the top left with a relative change of 37%. 35% of participants had resolution of non-alcoholic fatty liver disease at 12 months compared to 4% in the placebo in the top right. And participants treated with to samarelin had significantly reduced progression of fibrosis compared to placebo-treated patients as shown in the bottom graph. So given these data, to samarelin is currently the only FDA-approved treatment for HIV lipodystrophy to reduce abdominal fat accumulation. It can be taken as a daily subcutaneous injection, is administered at one dose of 1.4 milligrams. We do not expect the IGF-1 to be low in all patients with HIV lipodystrophy, and it is okay to initiate to samarelin with a normal IGF-1 as endogenous feedback is maintained. IGF-1 and A1C levels are typically monitored for safety. It is acceptable to treat to a Z-score of three. It's use should be avoided in uncontrolled diabetes out of caution. There's a contraindication to active malignancy and potential side effects include injection site reactions, arthralgias, peripheral edema, and transient glucose elevation upon the start of therapy. But overall, it is generally well-tolerated. At this time, additional studies are really needed to assess whether there is mortality benefit to samarelin. So adding to our table of treatment strategies tested, we have to samarelin, which has been shown to decrease fat and hepatic fat while sparing SAT. It also reduces triglycerides. Importantly, there are neutral effects most likely on glucose homeostasis, though we still need to exercise caution in those with uncontrolled sugars. A potential limitation is that there may be rebound fat accumulation when stopped. So we can circle back to our pre-test question three. This individual has HIV lipodystrophy with notable lipohypertrophy and minimal lipoatrophy. Given the lipohypertrophy, his leptin is probably not low, and therefore he would not likely benefit from leptin, nor would it be approved for use. Given the drug-drug interaction of Bictegravir with metformin, maximizing the metformin dose may have adverse effects. And as we discussed, the ART switch regimens generally do not provide benefit. In this case, the patient may benefit from to samarelin to reduce fat, hepatic fat, and triglycerides. So to review and synthesize, despite effective ART strategies, there remains increased morbidity and mortality attributed to noncommunicable disease. Persons with HIV, both untreated and treated, are at risk for fat redistribution, secondary to viral effects or ART. The visceral depot is associated with cardiometabolic disease and inflammation, and current treatment strategies for HIV lipodystrophy are limited. To samarelin is the only FDA-approved medication for fat reduction and has additional benefits on the liver depot, as well as triglycerides. We do need to acknowledge that the spectrum of fat redistribution and dysfunction HIV is involving to include generalized obesity, especially given more contemporary ART, such as the use of TAP and INSTEA-containing regimens, which may predispose to weight gain in general. And with that, I would like to thank you for listening, and I'm happy to take any questions. Thank you. So in the question we have, with respect to metroleptin therapy and generalized lipodystrophy, what is the mechanism by which metroleptin decreases triglycerides? Is it the appetite effect so that there are fewer substrates coming in? It doesn't seem that leptin solves a central issue of having nowhere to store energy excess. So with regards to the leptin, potential mechanisms have been studied. So it seems that leptin's mechanism is actually independent of the effect of caloric intake. So there seems to be something other than leptin, replacing leptin, suppressing the appetite itself. There were mechanistic studies that looked at this, and it was thought perhaps that leptin may also play a role in reducing de novo lipogenesis. So the combination of those potentially may be why we're seeing a beneficial effect of the leptin. Okay, so TZDs increase subcutaneous adiposity while decreasing visceral. Any literature or other info on its use in lipodystrophies, especially associated with HIV treatment? So the, yeah, so that is correct, that when the TZDs, the glitazones, were evaluated in HIV lipodystrophies, it was potentially seen that they could increase limb fat. And it was seen mainly in those that were not on thymidine analogs. And in addition, these, because they may only work in a subset of patients with insulin resistance, there's really a specific subtype that you may want to use these in. Now, I know there have been studies where potentially, I did show you that growth hormone itself, when you give that exogenously, does perhaps cause hyperglycemia. The glitazones have been tested in conjunction with growth hormone treatment, not growth hormone releasing hormone, but growth hormone itself with the glitazones. And it has shown that perhaps the combination could suppress the hyperglycemia. And with regards to the glitazones in just generalized lipodystrophies, they could potentially be used for dysglycemia, insulin resistance. However, you want to be cautious of using those in the general lipodystrophies. Is there a role for tisamorol in treatment in patients without HIV, but NAFLD? Great question. So there were very early preliminary studies that may have showed that there may be a benefit in obesity, but there are currently ongoing studies right now that are focused just on that question to understand whether tisamorol may have more wide benefit for NAFLD, perhaps in generalized obesity. And again, this may leverage the fact that there is unique growth hormone physiology in obesity as well. As to samorelin, sorry, I thought the TZD effect was by increasing subcutaneous fat diverting from visceral. So typically, I think if you have more, if you have the subcutaneous fat is the metabolically protective fat. So in that case, when you are, and again, the increase in subcutaneous fat with the TZDs is actually thought to be quite minimal. So it won't have a large benefit, but the thought is that if you have a subcutaneous depot to store lipid properly, then perhaps that may lead to less deposition in the other visceral depots. But again, the glitozones haven't necessarily shown a benefit on fat in the studies per se. Has to samorelin been evaluated in patients with generalized or partial lipodystrophy as well as those with HIV lipodystrophy? So to my knowledge, there hasn't been any studies of to samorelin in the generalized or partial lipodystrophies. And this is really taking advantage of, again, this strategy was first thought of in HIV just because of the unique growth hormone physiology. Is there a generally accepted standardized metric for lipodystrophy diagnosis? So again, this is a great question. It would be nice to have more objective sort of criteria for lipodystrophy, as that would make it easier for diagnosis. But as of now, because we don't have, again, leptin may not be quite comprehensive in terms of thinking about the lipodystrophies. We don't really have a biomarker or such or an objective measure. So it's really based on sort of the clinical suspicion, putting together history, exam, and metabolic sort of abnormalities together and ruling out anything else that may have a picture that's consistent like this, consistent with lipodystrophy. So what is the role of Cobb's index in the clinical evaluation of lipodystrophy and its typing? So I'm not sure if I'm familiar with the Cobb's index. I don't know if you're referring to Coberlin's or as part of the familial partial lipodystrophies, but if you want to expand further, I can comment on that. And then in your practice, do you see a great overlap with patients who have lipodystrophy and get acute pancreatitis from the hypertriglyceridemia? So in general, I think similar to, I sort of showed you some natural history data in terms of thinking about the abnormalities that we may see. And typically you may see more liver or heart abnormalities, but just in sort of as with the presentation in patients that you may expect hypertriglyceridemia such as diabetes, these patients can get acute pancreatitis from high levels of triglycerides. This is a potential presentation. And then can you comment on the role of GLP-1 receptor agonists on partial lipodystrophy? Thank you. Okay, great. So of course, GLP-1 RAs are a hot topic right now, and these are being widely used in diabetes as well as for generalized obesity. In terms of like the data that we know on GLP-1 RAs in lipodystrophy, I shouldn't say in lipodystrophy, what we know of the studies is that, as I showed you before to samarelin is a strategy that reduces VAT but spares the SAT. We know that perhaps from the data, GLP-1 RAs actually reduce both VAT and SAT. So I think this would, we need to exercise caution in using GLP-1s in patients with severe forms of lipodystrophy because it may actually have a negative effect on the lipoatrophy. But I do, studies are needed to sort of understand this further. There's just sort of case reports and such in HIV lipodystrophy and others that speak about this, but in HIV lipodystrophy, we tend to see more lipohypertrophy and less lipoatrophy current day. And so it's possible that these may have benefits metabolically, but again, I would just exercise caution when there is severe presentation of lipoatrophy. Okay. Thank you very much for your presentation. It was excellent. And thank everyone for attending. Have a wonderful day, y'all. Thank you, everyone. Take care. Bye-bye.

Lipodystrophy

Fat

HIV-associated lipodystrophy

Metropolitane

Tisamorelin

Adipose tissue

Diagnosis

Leptin replacement therapy

Insulin resistance

Treatment options