Metabolic Syndrome

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Metabolic Syndrome

• Dianne Weyer, CFNP
• Clinical Coordinator/Clinical Instructor
• SEATEC/Emory University
• Atlanta, Georgia

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Disclosure of Financial Relationships

• This speaker has no significant financial
  relationships with commercial entities
• to disclose.

This slide set has been peer-reviewed to ensure
that there are no conflicts of interest
represented in the presentation.
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(No Transcript)
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Metabolic Syndrome

• The Metabolic Syndrome was defined by NCEP
  (ATP-III) criteria, which requires individuals to
  have at least three at the following
• abdominal obesity (defined by waist circumference
  measurement),
• triglycerides gt150mg/dl,
• blood pressure ( gt130mmHg systolic or gt85
  diastolic),
• fasting glucose gt110mg/dl,
• low HDL-cholesterol ( lt40mg/dl in men, lt50mg/dl
  in women).

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Case

• JM - 44 y/o WM dx with HIV/AIDS
• Diagnosed in Oct 1996 no medical care
• October 1997
• Cryptococcosis with meningitis
• Fluconazole for secondary prevention
• May 1998 started ART
• Nelfinavir, Stavudine, and Lamivudine
• CD4 168 and Viral load lt400 on ART
• March 1999 hypercholesterolemia and started on
  Mevacor
• February 2000 Mevacor changed to Pravastatin
  and Genfibrazole was added for elevated
  triglycerides

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Case continued

• Rapid accumulation of fat on chest, back and neck
• Marked loss of fat in the nasal labial folds
• 2002 enrolled in Human growth hormone study
• August of 2002 ART changed to
• Videx, Viread, and Efavirenz
• September 2004 lipids normalized and
  Pravastatin discontinued
• Current CD4 936 and VL - lt50

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Lipodystrophy Host Factors

• Older age
• Body Mass Index
• Duration of HIV infection
• Effectiveness of Viral Suppression
• Baseline degree of immunodeficiency
• Subsequent immunosuppression
• White Race
• Shambelan, M et al.
• JAIDS 31257-275

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Lipoatrophy Results of ACTG 5142

• Efavirenz based regimen revealed significant
  atrophy compared to boosted Lopinavir
• Some increase of lipoatrophy with
  Stavudine/Efavirenz vs Efavirenz/Zidovudine
• No difference in lipoatrophy for those taking
  boosted Lopinavir or Efavirenz if taking
  Tenofovir
• Adapted from Haubrich
• et al. CROI 2007
• Abstract 38 and oral presentation

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Treatment of Lipodystrophy

• Modification of Antiretrovirals
• Exercise/Diet
• Human Growth Hormone
• Thiazolidinediones
• Metformin
• Testosterone
• Plastic surgery

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Cardiovascular DiseaseMonitoring and Treatment

• Baseline fasting lipid profiles and monitored
  every 3-6 months if on treatment
• Smoking cessation
• HTN and DM control
• Exercise
• Treatment that follows the NCEP II guidelines but
  remembering the following
• Drug/Drug interactions with PI and statins
• Newer agents available but not widely utilized
• Ezetimibe
• Leptin

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Combination Antiretroviral Therapy

• Increase in cardiovascular risk
• Exposure to PI, not NNRTIs increase risk of MI
• Regimens with both PI and NNRTIs associated with
  highest prevalence of dyslipidemia
• Hypercholesterolemia associated with
• Higher CD4
• Lower viral load
• Clinical signs of lipodystrophy
• Older age

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Lipid-Lowering Agents and ARV TherapyPotentially
Dangerous Drug Interactions
Recommendation
Agent

• Pravastatin
• Atorvastatin
• Lovastatin
• Simvastatin
• Gemfibrozil
• Fenofibrate
• Niacin
• Bile sequestrants

No dose adjustment Dose titration Avoid Avoid No
dose adjustment No dose adjustment Associated
with insulin resistance Avoid


Dube MP et al. Clin Infect Dis 2000311216-24.
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Cardiovascular Risks - Summary

• Really a summation of multiple risk factors that
  lead to coronary artery disease
• Along with increases in cholesterol seen with PIs
  there can also be an increase with both NRTI and
  NNRTIs
• DAD study Smoking, DM, HTN and altered body
  composition combined with PI/NNRTI use associated
  with accelerated course for atherosclerosis
• Smoking has greater impact contributing to CV
  risk in HIV versus HIV- individuals

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American Diabetic Association Definitions
Kimberly Smith, MD Ryan White Conference June
2005
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Insulin Resistance is characterized to the
reduced ability of insulin to inhibit hepatic
gluconeogenesis and muscle uptake of
glucose.Exact mechanism in HIV disease and
treatment with HAART speculated to be a result of
an impairment in cellular uptake or by indirect
mechanisms related to body fat changes, including
central obesity and or peripheral lipoatrophy.
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Insulin Resistance

• Impaired glucose tolerance and DM uncommon in HIV
  prior to HAART
• Co-morbidity usually associated with specific
  interaction such as the use of Pentamidine or
  Megace
• Patients on a PI regimen can have a 40 increase
  in impaired glucose tolerance
• AIDS 1998, 12 1167-1173

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Insulin Resistance and PIs

• PIs may have an early effect inducing insulin
  resistance by inhibiting the glucose transporter
  leading to peripheral insulin resistance and
  impaired glucose tolerance.
• J. Acquired Immune Def Syndrome 2000 25 312-21

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Glucose Monitoring/Treatment

• Baseline fasting glucose
• Every 3-6 months while on HAART
• Oral glucose tolerance tests might be indicated
  to identify individuals with impaired glucose
  intolerance
• Treatment follow established guidelines for
  treating DM in general population
• Diet
• Exercise
• Weight loss if appropriate
• Use of insulin sensitizing agents Metformin or
  Thiazolidinediones

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Conclusions

• HAART-treated patients are at increased risk of
  insulin resistance, prediabetes, and diabetes
  mellitus fasting blood sugar levels should be
  monitored before and during treatment (3-6 months
  after starting and annually thereafter).
• Risk factors for insulin resistance and type 2
  diabetes in HIV-infected patients include the
  classic risk factors, such as diet, obesity,
  physical inactivity, and genetic background
  (family history, race/ethnicity), plus certain
  HIV-associated risks of PI use, lipodystrophy,
  and hepatitis C infection.

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Conclusions-Contd

• The presence of any of these risk factors,
  particularly when severe lipodystrophy is
  present, should prompt the clinician to consider
  further evaluation including performing a 2-hour
  OGTT.
• Diet and exercise are preferred over drug
  interventions for treatment and prevention of
  diabetes although certain drug interventions may
  be appropriate in the setting of established
  lipodystrophy.

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Lactic Acidosis

• Lactic Acidosis-elevated venous lactate level of
  gt2 mmol/L and a low arterial pH
• Lactic Acidemia an elevated venous lactate
  level and normal arterial pH
• Associated with NRTI and nucleotide reverse
  transcriptase inhibitors and has a mitochondrial
  pathogenesis
• Predisposing risk factors
• Women
• Pregnancy
• Increased BMI
• Greater than 6 months treatment with NRTI

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Lactic Acidosis

• Clinical features
• Fatigue
• Weight loss
• Myalgias
• n/v
• Abdominal distension
• Pain
• Dyspnea
• Cardiac arrhythmia
• Overall mortality 80 in HIV related lactic
  acidemia of gt10 mmol/L
• CID 2002 34838-46

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Risk Factors for the Development of Lactic
Acidemia in Persons Taking NRTIs
0
Most cases have involved stavudineEspecially
with the use of stavudine plus didanosine
Source HIV Web Study (www.hivwebstudy.org)
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Recommendations for the Management of Lactic
Acidemia
0
Source HIV Web Study (www.hivwebstudy.org) Carr
A. Clin Infect Dis 200336 (Suppl 2)S96-100.
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Osteopenia/Bone Disease

• Defined as a decrease in bone mineral density
• Rarely recognized prior to the use of ART
• Patients on PIs
• Osteopenia rates 22-55
• Osteoporosis 3-24
• Mechanism is unknown and fractures are rare
• Risk Factors
• ?PI use
• Longer duration of HIV infection
• Decreased bodyweight
• Before ARV an increased viral load
• Annapooma et al. Int J Med Sci 2004, 1
  (3)152-164

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Risk Factors for Osteopenia

• Non-HIV related
• Older age
• Female sex/menopause
• Ethnicity (Asian, Hispanic)
• Family history
• Smoking
• Alcohol use
• Estrogen/testosterone
• Weight loss/low BMI
• Physical inactivity
• Pancreatitis
• SLE/vasculitides
• Medications
• (steroids, benzodiazepine, anticonvulsants,
  heparin, vitamin A)

• HIV related
• HIV infection
• Steroid use (PCP Rx)
• Wasting
• Nadir CD4 count
• HAART use?
• Protease inhibitor use?
• Nucleoside analogues?
• Tenofovir?
• Lipid lowering agents?

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Assessment/Monitoring/Treatment

• As per general population
• DEXA screening
• Treatment
• Calcium/Vitamin D supplements
• Weight bearing exercises
• Pain control
• Resection and/or replacement of the involved
  bone/joint

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Metabolic Complications of HIV

• Summary Conclusions

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Lipodystrophy

• Lipoatrophy more common in HIV infected
  individuals and has been linked to markers of HIV
  disease severity and to d4T
• Switching out the offending agent appears to
  improve lipoatrophy, but very slowly
• Buffalo humps may be no more common in
  HIV-infected patients, but may be larger when
  they do occur
• Central fat deposition less common in
  HIV-infected individuals
• Diet, exercise are the most effective treatments
  for central fat accumulation
• Plastic surgery short-term benefit long term - ?

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Insulin Resistance

• Linked to many protease inhibitors, Efavirenz,
  and possibly some NRTIs
• Also linked to presence of lipodystrophy
• Progression to frank diabetes mellitus possible
• Monitor with fasting glucose values
• Improvement may or may not be seen with switching
  out of the offending agents

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Dyslipidemia ART

• Many antiretrovirals, especially protease
  inhibitors, associated with dyslipidemia
• ART-induced dyslipidemia may contribute to risk
  of coronary artery disease, though short-term
  absolute risk appears to be small
• Discontinuation of dyslipidemia-inducing agents
  will generally improve lipid profile
• ART-induced dyslipidemia can be treated with
  fibrates and/or statins, but response is often
  sub-optimal and potential drug interactions need
  to be considered carefully

C. Behrens, MD-NW AETC
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Hyperlactatemia/Lactic Acidosis

• Potentially fatal syndrome linked to prolonged
  NRTI use, especially ddI, d4T
• Signs and symptoms often subtle, nonspecific
• Venous lactate level useful in diagnosis
• Discontinuation of ART indicated for symptomatic
  hyperlactatemia/lactic acidosis
• Resumption of ART that includes NRTIs is
  controversial

C. Behrens, MD-NW AETC
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HIV Bone Disease

• Patients with HIV infection, especially Caucasian
  men, appear to be at increased risk of osteopenia
• Etiology not known at this time
• Role of ART overall and of individual ARV agents
  is unclear
• Routine screening not recommended
• Intervention warranted for modifiable risk
  factors such as smoking, alcohol, steroid use,
  hyperlipidemia, wasting, sedentary lifestyle, low
  calcium intake
• HIV-infected patients also at ? risk of
  osteonecrosis
• Consider diagnosis of osteonecrosis in patients
  with unexplained shoulder/hip/groin pain

C. Behrens, MD-NW AETC