HMG-CoA Reductase Inhibitors

1

JS Currier, MD, June 2001
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Metabolic Complications

• One syndrome or several?
• One etiology or multifactorial?

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Morphologic Changes Definitions

• Fat Accumulation (lipohypertrophy)
• Dorsocervical fat
• Visceral adiposity
• Breast enlargement
• Fat Loss (lipoatrophy)
• Facial fat loss
• Subcutaneous fat loss of extremities

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Morphologic Changes Predictors-The HIV
Outpatient Study (HOPS)

• Predictors Odds Ratio
• Age gt 40 years 2.5
• Years since HIV diagnosis 1.4
• Months since nadir CD4 2.0
• NRTI use gt 6 months 3.0
• Protease inhibitor use gt 2 years 2.1
• Nadir CD4 1.7
• Body Mass Index loss gt 1.0 kg/m2 1.7

Adapted from Lichtenstein K et al. 7th CROI, San
Francisco, CA, 2000. Abstract 23.
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Morphologic Changes Management Approaches

• Antiretroviral therapy switches
• Exercise and diet
• Anabolic steroids
• Recombinant human growth hormone (rhGH)
• Testosterone
• Metformin
• Thiazolidinediones
• Plastic surgery

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Morphologic Changes Summary and Conclusions

• Lack of a standard case definition complicates
  characterization, diagnosis, and tracking
• Morphologic changes have a substantial impact on
  quality of life
• Etiology remains unknown appears to be
  multifactorial and influenced by ARV use and host
  factors
• All management strategies remain unproven

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Lipid AbnormalitiesRecommended Evaluations

• Obtain baseline fasting cholesterol
• Total HDL
• LDL Triglycerides
• Assess cardiovascular risk and lifestyle factors
• Family History Exercise
• Diabetes Smoking
• Obesity Alcohol use
• Identify comorbidities
• Prior pancreatitis

Adapted from Dube MP et al. Clin Infect Dis. 2000
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Dyslipidemia Management Approaches

• Assessment of cardiovascular risk
• Dietary and lifestyle changes
• Lipid-lowering agents (statins, fibrates)
• Modify antiretroviral therapy
• Substitute NNRTIs for PIs
• Substitute abacavir for PIs

Adapted from Dube MP et al. Clin Infect Dis. 2000
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Indications for Intervention -Hypercholesterolemi
a(National Cholesterol Education Program1)
Risk factors include age (men ? 45 years, women
? 55 years or premature menopause without
estrogen replacement therapy), family history of
CHD (first-degree male relative with CHD before
55 years of age or first-degree female relative
before 65 years of age), current cigarette
smoking, hypertension, low HDL cholesterol (lt 35
mg/dL), diabetes mellitus. In the presence of
high HDL cholesterol (gt 60 mg/dL), subtract one
risk factor. 1. NCEP.Circulation.1994891329-144
5.
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Indications for Intervention Hypertriglyceridemi
a

• Base initial management on lifestyle and dietary
  modification
• Consider lipid-lowering agents (gt 1000 mg/dL) in
  absence of other risk factors
• Consider lipid-lowering agents at lower levels (gt
  500 mg/dL) if other risks are present
• Beware of drug-drug interactions!

Adapted from Dube MP et al. Clin Infect Dis. 2000
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Drug Therapy for Lipid Abnormalities
Adapted from Dube MP et al. Clin Infect Dis.
2000.
12
HMG-CoA Reductase Inhibitors (statins) and PI
Interactions
Adapted from Dube MP et al. Clin Infect Dis.
2000.
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DyslipidemiaSummary and Conclusions

• Dyslipidemia is frequent and varies by drug
• Initial management approach should be lifestyle
  modification (diet, exercise)
• Lipid-lowering agents can be added as necessary,
  but beware of drug-drug interactions and
  toxicities
• Switching to non-PI regimens may be most
  effective for triglyceride elevations, but
  long-term efficacy is unclear
• Cardiovascular sequelae are minimal short-term
  long-term outcome is unknown

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Glucose MetabolismEmerging Questions

• Do PIs have a direct effect on glucose
  metabolism?
• Is this drug specific?
• Is this distinct from impact on lipids?
• Do changes in glucose metabolism precede body
  shape changes?
• If so is this limited to increases in visceral
  fat?
• Does reversing insulin resistance reduce visceral
  fat?

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Evidence of PI Effects on Glucose Metabolism in
HIV Infection
Cross-sectional studies Abnormal insulin
sensitivity in 63 of patients on
PIs1 Patients on PIs had higher 2-h insulin,
glucose AUC2 Longitudinal studies Increases
in fasting glucose, insulin, TG, total and LDL
cholesterol after initiating PI therapy (no
evidence of fat redistribution)3 Improvements
in fasting glucose, insulin, TG, cholesterol with
substitution of nevirapine for PI4
Adapted from 1) Walli, AIDS 12F67, 1998 2)
Behrens, AIDS 13F63, 1999 3) Mulligan, JAIDS 4)
Martinez, AIDS 13805, 1999
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Glucose MetabolismEvaluation and Diagnosis

• Few clinical manifestations have been noted
• Frank diabetes mellitus is uncommon
• Fasting glucose levels are generally normal
• Syndrome is characterized by fasting
  hyperinsulinemia
• Two-hour glucose and insulin AUC levels are
  significantly abnormal following glucose challenge

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Glucose MetabolismManagement Strategies

• Diet, exercise, and weight reduction (if needed)
• Same treatment as for HIV-negative patients
• Optimal management of impaired glucose tolerance
  
• (2-hour glu gt 140 and lt 200 mg/dL) is not known
• Switch ARV regimen
• Insulin sensitizing agents
• Biguanides
• Glitazones
• No role for sulfonylureas and similar agents

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Glucose MetabolismSummary and Conclusions

• Abnormalities of glucose homeostasis (primarily
  insulin resistance) are common in patients on
  HAART
• Higher incidence is in patients receiving PIs
• Mechanisms remain unclear at this time
• Treatment with insulin-sensitizing agents may be
  beneficial

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Lactic AcidosisSymptoms and Laboratory Findings

• Symptoms
• Nausea and vomiting
• Abdominal pain
• Weight loss
• Malaise
• Dyspnea/tachypnea

• Laboratory Findings
• Increased anion gap
• Increased lactic acid levels
• Increased lactate/pyruvate

Adapted from Boxwell DE, Styrt BA. 39th ICAAC,
San Francisco, CA, 1999. Abstract 1284.
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Lactic acidemia vs acidosisDefining the
Syndrome

• Metabolic acidosis (pH lt 7.25) needs to be
  distinguished from elevated lactate levels
  without acidosis
• Lactic acidosis is a rare, often fatal syndrome
• Asymptomatic lactic acidemia has been reported in
  8-21 of asymptomatic NRTI treated patients
• This does not appear to herald the onset of
  acidosis
• Routine monitoring of asymptomatic patients is
  not currently recommended

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Lactic AcidosisFrequency

• 107 cases reported to FDA through June 30, 1998
• 46 cases on NRTI monotherapy
• 61 cases on dual NRTI therapy
• Majority (36) of monotherapy cases occurred with
  ZDV prior to 1995
• Majority (46) of dual therapy cases occurred with
  d4T after 1995 36 of 46 on d4T/3TC

Adapted from Boxwell DE, Styrt BA. 39th ICAAC,
San Francisco, CA, 1999. Abstract 1284.
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Lactic AcidosisSummary and Conclusions

• Lactic acidosis is a rare life-threatening
  complication of antiretroviral therapy
• Nucleoside analogue therapy-induced mitochondrial
  toxicity appears to be the cause of this syndrome
• Diagnosis is difficult because symptoms are vague
  and non-specific
• Routine monitoring of lactate levels is not
  recommended in asymptomatic patientshowever
  lactate should be measured in patients with
  unexplained weight loss, nausea or abdominal pain
• Treatment includes discontinuing NRTIs, followed
  by supportive care measures

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Clinical Issues-Definitions

• Osteopenia decreased bone density
• Osteoporosis decreased bone mass in combination
  with disruption in bone architecture
• Primary-progressive loss with age
• Secondary -due to underlying medial disease or
  drugs
• Osteomalacia disorder of mineralization of newly
  formed organic matrix. Caused by Vit D
  deficiency, hypophosphatemia, inhibitors of
  mineralization
• Diagnosis requires bone biopsy

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Bone DisordersAvascular Necrosis (osteonecrosis)

• Etiology
• Caused by death of cellular elements of bone,
  often secondary to impairment in blood supply
• Risk Factors
• Glucocorticoid treatment, connective tissue
  disease, embolization, alcohol use
• Common Sites
• Femoral and humeral heads, femoral condyles,
  proximal tibia hip disease is bilateral in 50
  of cases

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Bone DisordersSummary and Conclusions

• Osteopenia, osteoporosis, and avascular necrosis
  are being reported in patients with HIV infection
• An association has been made with PI-containing
  HAART regimens
• Various risk factors may contribute to their
  development in these patients
• Clinicians need to be aware of this potential
  complication and treat early
• Further study is needed on
• Etiology of loss of bone mineral density
• Identification of risk factors
• Appropriate prevention strategies