Pharmacologic Interventions for a Patient With Lipodystrophy
Pharmacologic Interventions for a Patient With Lipodystrophy
We have a 42-year-old man who has had AIDS for 10 years, with a CD4+ cell count of 300 cells/mcL and clinical lipodystrophy. He has multidrug-resistant HIV, but has undetectable viral load on emtricitabine, tenofovir, efavirenz, and atazanavir/ritonavir. He has consistently shown high glucose levels up to 170 mg/dL and hyperlipidemia (latest cholesterol 262 mg/dL and triglycerides 266 mg/dL). He currently receives pravastatin 40 mg once daily. Now his hemoglobin A1c (HbA1c) has come back at 6.7%, which is the highest level measured thus far. What is your opinion on using metformin for this patient?
This case raises several problems that are increasingly common in clinical practice: an individual with stigmatizing morphologic change, accompanied by metabolic disturbances that suggest the impending onset of diabetes mellitus. First, you should be congratulated on doing a great job in manipulating his treatment regimen to one that contains drugs least likely to contribute to these abnormalities and that maintain virologic control.
Protease inhibitors, in particular, have been associated with the risk of diabetes. Recent data on atazanavir, however, indicate that this agent alone does not trigger insulin resistance or reduced peripheral glucose disposal in healthy volunteers, in contrast to lopinavir/ritonavir or indinavir when tested in similar circumstances. Differences in the contribution of nucleoside analog combinations to dyslipidemia and insulin resistance, as well as to morphologic changes, have recently been reviewed. Tenofovir and emtricitabine appear to be lower-risk agents for the development of lipodystrophy and dyslipidemia. Indeed, individuals switched from stavudine to tenofovir may see improvements in both lipids and morphology. Problems with lipoatrophy may be very slow to recover, and beyond switching nucleoside analogs, no other agents have been shown to reliably improve peripheral fat mass.
I am not precisely sure what you mean in this circumstance by "lipodystrophy," but I will assume that the individual has a mixed picture of both lipoatrophy and central fat accumulation. I will also assume that he has had appropriate dietary and exercise advice. Increased waist circumference together with insulin resistance, dyslipidemia, and hypertension make up "the metabolic syndrome." One difficulty commonly encountered in clinical practice is that once the metabolic syndrome is established, it is a vicious cycle that feeds on itself. One can remove the antiretrovirals that originally contributed to or triggered the metabolic syndrome but this does not lead reliably to resolution of the syndrome. Several agents may be helpful in this regard. The insulin sensitizer metformin is the most well-studied choice. Clinical trials with metformin at doses as low as 500 mg twice daily have indicated reductions in weight, waist circumference, blood pressure, and trends to improvements in lipids. The majority of these benefits are observed within 3 months of initiation of therapy and are sustained with continued use. The potential downside of metformin is that lost weight may lead to worsening of the appearance of lipoatrophy. Thiazolidinedione drugs, such as rosiglitazone, appear to have more modest benefits in breaking the metabolic syndrome cycle in people with HIV infection, do not appear to lead to improvements in peripheral fat mass, and may be associated with worsening dyslipidemia. The other possible choice is recombinant human growth hormone. This agent may lead to improvements in visceral adiposity and dyslipidemia but is not well suited to your patient with hyperglycemia, as the use of growth hormone is likely to worsen insulin resistance, at least initially.
To summarize, metformin would be a reasonable choice at a starting dose of 500 mg twice daily. This may lead to improvements in abdominal contour, lipids, and glucose management. I would suggest doing a fasting oral glucose tolerance test and insulin prior to commencement of therapy and repeat these tests at 3 months together with regular monitoring of the HbA1c. At present the HbA1c level is approximately on target. I would also suggest that it would be reasonable to change the pravastatin to atorvastatin (commencing at 10 mg and increasing to 20 mg if non-LDL cholesterol is not satisfactory after 1 month). You may wish to make this change around 3 months after the initiation of metformin, as it is possible that the metformin intervention might be sufficient to improve the lipid profile to a satisfactory level.
We have a 42-year-old man who has had AIDS for 10 years, with a CD4+ cell count of 300 cells/mcL and clinical lipodystrophy. He has multidrug-resistant HIV, but has undetectable viral load on emtricitabine, tenofovir, efavirenz, and atazanavir/ritonavir. He has consistently shown high glucose levels up to 170 mg/dL and hyperlipidemia (latest cholesterol 262 mg/dL and triglycerides 266 mg/dL). He currently receives pravastatin 40 mg once daily. Now his hemoglobin A1c (HbA1c) has come back at 6.7%, which is the highest level measured thus far. What is your opinion on using metformin for this patient?
This case raises several problems that are increasingly common in clinical practice: an individual with stigmatizing morphologic change, accompanied by metabolic disturbances that suggest the impending onset of diabetes mellitus. First, you should be congratulated on doing a great job in manipulating his treatment regimen to one that contains drugs least likely to contribute to these abnormalities and that maintain virologic control.
Protease inhibitors, in particular, have been associated with the risk of diabetes. Recent data on atazanavir, however, indicate that this agent alone does not trigger insulin resistance or reduced peripheral glucose disposal in healthy volunteers, in contrast to lopinavir/ritonavir or indinavir when tested in similar circumstances. Differences in the contribution of nucleoside analog combinations to dyslipidemia and insulin resistance, as well as to morphologic changes, have recently been reviewed. Tenofovir and emtricitabine appear to be lower-risk agents for the development of lipodystrophy and dyslipidemia. Indeed, individuals switched from stavudine to tenofovir may see improvements in both lipids and morphology. Problems with lipoatrophy may be very slow to recover, and beyond switching nucleoside analogs, no other agents have been shown to reliably improve peripheral fat mass.
I am not precisely sure what you mean in this circumstance by "lipodystrophy," but I will assume that the individual has a mixed picture of both lipoatrophy and central fat accumulation. I will also assume that he has had appropriate dietary and exercise advice. Increased waist circumference together with insulin resistance, dyslipidemia, and hypertension make up "the metabolic syndrome." One difficulty commonly encountered in clinical practice is that once the metabolic syndrome is established, it is a vicious cycle that feeds on itself. One can remove the antiretrovirals that originally contributed to or triggered the metabolic syndrome but this does not lead reliably to resolution of the syndrome. Several agents may be helpful in this regard. The insulin sensitizer metformin is the most well-studied choice. Clinical trials with metformin at doses as low as 500 mg twice daily have indicated reductions in weight, waist circumference, blood pressure, and trends to improvements in lipids. The majority of these benefits are observed within 3 months of initiation of therapy and are sustained with continued use. The potential downside of metformin is that lost weight may lead to worsening of the appearance of lipoatrophy. Thiazolidinedione drugs, such as rosiglitazone, appear to have more modest benefits in breaking the metabolic syndrome cycle in people with HIV infection, do not appear to lead to improvements in peripheral fat mass, and may be associated with worsening dyslipidemia. The other possible choice is recombinant human growth hormone. This agent may lead to improvements in visceral adiposity and dyslipidemia but is not well suited to your patient with hyperglycemia, as the use of growth hormone is likely to worsen insulin resistance, at least initially.
To summarize, metformin would be a reasonable choice at a starting dose of 500 mg twice daily. This may lead to improvements in abdominal contour, lipids, and glucose management. I would suggest doing a fasting oral glucose tolerance test and insulin prior to commencement of therapy and repeat these tests at 3 months together with regular monitoring of the HbA1c. At present the HbA1c level is approximately on target. I would also suggest that it would be reasonable to change the pravastatin to atorvastatin (commencing at 10 mg and increasing to 20 mg if non-LDL cholesterol is not satisfactory after 1 month). You may wish to make this change around 3 months after the initiation of metformin, as it is possible that the metformin intervention might be sufficient to improve the lipid profile to a satisfactory level.
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