Study Design

1

Insulin Resistance Due to HIV Infection and Its
Therapies Drug, Host Response, or Restoration
to Health?
Carl Grunfeld, MD, PhDProfessor of
MedicineUniversity of California San Francisco
The International AIDS SocietyUSA
2
Introduction
Slide 2

• It is widely assumed that HIV PI induce a
  syndrome of insulin resistance accompanied by
  hyperlipidemia and fat redistribution that
  resembles Metabolic Syndromes with its increased
  risk of cardiovascular disease.
• Today I will discuss the following questions
• How do you diagnose insulin resistance?
• What are the implications of insulin resistance?
• What are the causes of insulin resistance?
• What are the experimental treatments for insulin
  resistance?

From C Grunfeld, MD, PhD, at 10th RW Program
Clinical Update, IASUSA.
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Diagnosis of Insulin ResistanceBad News
Slide 3

• Insulin resistance cannot be diagnosed accurately
  in the clinic.
• Clinical insulin assays are terrible.
• Research insulin assays may work.
• Insulin resistance HOMA gt 4.
• HOMA insulin (µU/mL) x glucose (mmol/L)/22.5
• Similar calculations from GTT.
• Gold Standards ITT and Clamp.
• Bottom Line We infer insulin resistance.

From C Grunfeld, MD, PhD, at 10th RW Program
Clinical Update, IASUSA.
4
Implications of Insulin ResistanceBad Future
Slide 4

• Insulin resistance is the first step on the way
  to diabetes.
• But you need genes that lead to decreased insulin
  secretion.
• Insulin resistance is part of the WHO definition
  of Metabolic Syndrome
• But that is why no one uses WHO.
• There is debate over whether Metabolic Syndrome
  is gt sum of parts.
• Insulin resistance is epidemiologically
  associated with CAD.
• There is debate over whether it is the prime
  causal factor

From C Grunfeld, MD, PhD, at 10th RW Program
Clinical Update, IASUSA.
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Factors Known to Cause Insulin Resistance in
HIV-Negative
Slide 5

• 20 of healthy thin subjects are insulin
  resistant.
• Obesity, especially visceral obesity.
• Inactivity.
• Drugs (e.g., glucocorticoids, niacin)
• Acute bacterial infection (with end-stage sepsis
  causing hypoglycemia)

From C Grunfeld, MD, PhD, at 10th RW Program
Clinical Update, IASUSA.
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Glucose Metabolism in Infection

• Studies of acute infection usually show insulin
  resistance and hyperglycemia (with hypoglycemia
  appearing during sepsis)
• Early studies of HIV infection were remarkable in
  that there was no insulin resistance or
  hyperglycemia
• Patients were thin, if not cachectic!

Increased Insulin Sensitivity in HIV
InfectionHommes et al. Metabolism 40651, 1991
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PI Therapy Increases Plasma Glucose and Insulin
in HIV-infected Subjects

• K. Mulligan et al  JAIDS 2335, 2000 Data
  obtained before after (ca. 3 mos) beginning
  ARV
• a PI
• ( IDV16, SQ 2, RTV2)
• 3TC, but no PI (N9)
• A control group (CON)
• on stable regimens that included neither PI
  or 3TC (N12)

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Independent effects on glucose and lipid
metabolism
Peripheral fat loss ARV Toxicity
Body composition changes
Protease inhibitors
Central fat gain Restoration to health vs. ARV
Toxicity
Insulin Resistance Dyslipidemia
Immune response to infection

HIV-associated factors
Response to HIV therapy Opportunistic infections
disappear. Immunosuppression improves. Some
hyperimmunity remains.
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HIV Load and CD4 Cells Improved, but NO Change in
Body Fat Mulligan et al  JAIDS 2335-43, 2000
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In HIV-seronegative subjectsIndinavir increases
fasting glucose insulin. Lopinavir/ritonavir
does not.
Noor et al. AIDS 2001. Lee et al.
AIDS 2004
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Indinavir Decreased Insulin Sensitivity Measured
by Insulin-mediated Glucose Disposal (M/I) on
Clamp
From C Grunfeld, MD, PhD, at 10th RW Program
Clinical Update, IASUSA.
12
Indinavir Increased 2-hr plasma glucose during
OGTT
From C Grunfeld, MD, PhD, at 10th RW Program
Clinical Update, IASUSA.
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IndinavirFree Fatty Acid (FFA) Levels are
Suppressed Normally During OGTT
Slide 13
Not Usual Insulin Resistance
Lopinavir/Ritonavir Increases FFA, but FFA
suppress on OGTT
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The Effect of PIs on Glucose Transport Murata,
Hruz Mueckler J. B. C. 27520251, 2000

• PIs decrease insulin-stimulated glucose transport
  in fat cells, but do not inhibit
  insulin-stimulated translocation of GLUT4
• No blockade of any aspect of insulin activation
  (e.g., phosphorylation, lipids)
• PIs block glucose transport in cells transfected
  with GLUT4 (but not with GLUT1) supporting a
  direct GLUT4 block
• Most important, the effects of PIs were
  immediate- within minutes

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IndinavirA single dose acutely decreased
Glucose Disposal Rate per unit of insulin
(M/I).Effect was seen within 30 min. on clamp.
16
Single Dose Ritonavir but not Amprenavir acutely
decreases M/I
P0.007
N.S.
8.5 1.2
8.4 0.9
9.4 /- 0.7
8.0 /- 0.7
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Effects of PIs on Insulin ResistanceIn
HIV-Negative Subjects
Adapted from Lee, Rao, and Grunfeld. Curr.
HIV/AIDS Rep. 239-50, 2005.
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Indinavir-induced insulin resistance is worse in
HIV than HIV-

• IDV HIV- PI HIV
• Noor et al Mulligan et al
• 4 weeks 3 months
• Glucose 105 111
• Insulin 134 195
• I/G 126 159
• HOMA 147 249
• Resistance induced before any change in fat

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Insulin Levels in the FIRST Study (µ/mL) Shlay et
al JAIDS 2005, 2007
PI vs. NNRTI vs. PINNRTI PI Slight early
increaseAll Increase later
ddID4T vs. ABC3TC ddId4T is worse
Mean Change from Baseline
16
0
4
8
12
20
28
32
24
Months
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Effect of Metformin or Rosiglitazone in HIV
Lipodystrophy with Insulin ResistanceAdapted
from Hadigan JAMA 2000 and Annals 2004
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Diabetes Prevention Program

• Studied subjects with impaired fasting glucose or
  impaired glucose tolerance.
• Lifestyle changes reduced incidence of diabetes
  diagnosis by 68.
• Metformin reduced incidence of diabetes by 31.
• Trolgitazone was discontinued, but reduced
  incidence of diabetes similar to lifestyle
  changes at early time points.
• No hard outcomes. Cannot tell if better than
  treating early diabetes.

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To treat or not to treat?That is the question.

• Treatment before diabetes is off-label.
• Another study showed thiazolidenediones are
  better at preventing diabetes1.
• A meta-analysis found rosiglitazone associated
  with OR of 1.43 for MI.
• More fractures (2-3x) found in women in a
  rosiglitazone treatment arm2.
• Rosiglitazone and pioglitazone linked to lower
  BMD3.
• 1S.E. Kahn. NEJM 355 2427, 2006. 2S.E. Nissen.
  NEJM 356 2007.
• 3A. Schwartz JCEM 91 3349, 2006. A. Grey. JCEM
  92 2007.

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Question for the Audience 1

• You have a 46 yo HIV-infected Caucasian male,
  normal weight, exercises, on LPVr/TDF/EMC,
  fasting glucose 89 mg/dl, HOMA 6. Would
  you treat?
• 1) Yes
• 2) No

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Treatment Options 1

• Metformin
• Pioglitazone
• Insulin

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Question for the Audience 2

• You have a 60 yo HIV-infected Caucasian male, big
  belly, no longer exercises, on EFV/TDF/EMC,
  fasting glucose 109 mg/dl. Would you treat?
• 1) Yes
• 2) No

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Treatment Options 2

• Diet and Exercise
• Metformin
• Pioglitazone
• Insulin

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Conclusions

• These data demonstrate that the causes of insulin
  resistance in HIV infection are multifactorial
  Restoration to Health, PI, NRTI, VAT, Age
  Inactivity etc.
• Insulin resistance is hard to diagnose, but can
  be inferred.
• Treatment of insulin resistance is similar in
  HIV-infected and control subjects, but the long
  term value of treating before the development of
  diabetes is unknown.

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Effects of ARV on Lipids
Adapted from Lee, Rao, and Grunfeld. Curr.
HIV/AIDS Rep. 239-50, 2005.
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A Few Words About Fat Redistribution

• Many papers report identical lipodystrophy in
  HIV on NRTI Rx without PIs.
• Other data implicate duration of HIV, change in
  CD4 cell count and age in lipodystrophy.
• Data from the FRAM study have refuted the link
  between loss of peripheral fat and gain of
  central fat, requiring redefinition of the
  lipodsytrophy syndrome as lipoatrophy.