Cardiovascular disease with diabetes or the metabolic syndrome should statins or fibrates be first l

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Cardiovascular disease with diabetes or the
metabolic syndrome should statins or fibrates be
first line lipid therapy

• Current Opinion in Lipidology 2003, 14575-583
• By ???

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Introduction

• Statin therapy for pt with high LDL convincingly
• DM or metabolic syndrome is the high risk for CHD
  events but with low-to-moderate level LDL? far
  less convincing than for a high LDL
• Review data are all individuals with DM or
  metabolic syndrome ?insulin resistance, abdominal
  obesity , HTN , low level HDL, high TG and
  abnormalities in glucose metabolism

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Coronary heart disease reduction in diabetes in
large lipid trials

• Early trials? chiefly niacin, the fibrate with
  clofibrate and bile acid-binding resin with
  cholestyramine? exclude DM Hx or treated DM
• Last 2 decades ?9 statin trials and 3 fibrate
  trials ? include DM
• But 4 of these trials ?exclude the
  insulin-dependent DM ?BIP, HPS, ALLHAT and ASCOT

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Coronary heart disease reduction in diabetes in
large lipid trials
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Coronary heart disease reduction in diabetes in
large lipid trials

• 4S?high LDL with or without DM ?statin therapy
  will result in a profound reduction in the MI and
  CHD death
• But low LDL ?with modest reduction in CHD event
  with Tx
• Argue for short period study with PROSPER and
  ASCOT?3.2 yrs and 3.3 yrs respectively follow up
  less than other 5 yrs trials

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Coronary heart disease reduction in diabetes in
large lipid trials

• HPS ?27 reduction in CHD with simvastatin in DM
  and equivalent to non DM
• HPS ?67 of DM without CHD Hx
• ?37 relative risk reduction in DM without CHD
  VS 19 RRR in DM with prior CHD

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Coronary heart disease reduction in diabetes in
large lipid trials

• HHS ?3.3 of total numbers was DM
• ?not significant of Tx
• VA-HIT?30 DM with gemfibrozil
• ? significantly reduced the CHD
• death or MI or stroke
• ? reduction more than twice with
  statins in pt with a low to average LDL

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Coronary heart disease reduction in diabetes in
large lipid trials
3.2yrs
3.3yrs
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Coronary heart disease reduction in diabetes in
large lipid trials
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Coronary heart disease death and other
cardiovascular events as a combined endpoint in
diabetes

• CHD death during a 5 yrs period ?more frequent in
  placebo groups with DM
• Only HPS reported a reduction in CHD death with
  statin Tx
• CHD death reduced by pravastatin in CARE and
  LIPID trial without DM Pt and only 3 reduction
  in DM Pt
• VA-HIT ? gemfibrozil reduce CHD death in DM by
  39 but in non DM,gemfibrozil did not reduce CHD
  death

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Coronary heart disease death and other
cardiovascular events as a combined endpoint in
diabetes
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Coronary heart disease events with insulin
resistance and the result of lipid therapy

• Cause of type 2 DM ?insulin resistance
  ?frequently with abd obesity
• Insulin resistance is strongly correlated with
  high fasting blood insulin levels ?even without
  DM, hyperinsulinemia associated with increased in
  major CHD events

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Coronary heart disease events with insulin
resistance and the result of lipid therapy

• In VA-HIT
• ?fasting insulin levels were linearly related to
  both body weight and waist circumference
• ?cardiovascular events more than non insulin
  resistance and significantly reduced with
  gemfibrozil even in non DM

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Coronary heart disease events with insulin
resistance and the result of lipid therapy

• In HHS
• ?gemfibrozil greater CHD reduction at BMI gt26
• ?high BMI, high level TG and low level HDL,
  response to fibrate was greater
• ?same in BIP trial with bezafibrate Tx

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Coronary heart disease events with insulin
resistance and the result of lipid therapy

• CARE and LIPID ? in low LDL , there was no
  significant difference in the reduction of CHD
  events with pravastatin below and above BMI 27
• HPS ?no preferential reduction in CV events with
  simvastatin in those with DM or obesity

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Coronary heart disease events with insulin
resistance and the result of lipid therapy
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Coronary heart disease events with insulin
resistance and the result of lipid therapy

• In 4S study
• ?statin might be beneficial in the Pt with
  metabolic syndrome ?only with high LDL
  irrespective of BMI and HDL level or TG level
• In ASCOT study with CV events
• ?9.9 in metabolic syndrome VS 9.1 in non
  metabolic syndrome (by NCEP criteria )

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Lipid changes with statins and fibrates in
diabetes and insulin resistance

• In type2 DM and underlying insulin resistance
  ?mod elevation in total cholesterol and LDL but
  high in TG and HDL in a low range
• Statins predominantly result in lowering LDL
  level
• Fibrates produce less LDL lowering but ordinarily
  greater reduction in TG and increase in HDL

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Lipid changes with statins and fibrates in
diabetes and insulin resistance

• In VA-HIT study
• ?gemfibrozil did significantly predict a
  reduction in CV events if increase in HDL level,
  except the insulin resistance

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Diabetes, insulin resistance and cardiovascular
disease as a vascular inflammatory process

• Atherosclerosis and CHD with DM are in large part
  the result of a vascular inflammatory process
  ?key cytokines in adipose tissue ?IL-6 and
  TNF-aincreasing with obesity and insulin
  resistance
• Increases in CRP levels in response to increase
  IL-6 and TNF-ain DM , metabolic syndrome and new
  CV events
• Statin and fibrate could low CRP and reduce CV
  events but there is no prospective clinical trial
  evidence to show a reduction of CRP by lipid Tx
  will independently predict a reduction in CV
  events

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Summary of lipid trial results with statins or
fibrates in individuals with diabetes or the
metabolic syndrome

• Va-HIT
• ?significant reduction in CHD death reduction in
  DM and a reduction in major CV events with
  insulin resistance in the absence of DM
• HPSonly one showed the reduce CV events in the
  low to moderate LDL level

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Conclusions

• ADA and NCEP suggestions
• ?to reduce LDL to less than 100mg/DL
• ?statins are the drugs of choice
• In VA-HIT
• ?pt with a modest increase in LDL level with DM
  or metabolic syndrome might be likely to achieve
  more substantial CV benefit from fibrate than
  from statins Tx

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Conclusionsfrom Diabetes Care, Vol27 supplement
1 Jan 2004

• Primary Tx should be directed first at lowering
  LDL level (lt100 mg/dl)
• Initial drugs are statins
• If HDL lt 40 mg/dl , fibric acid like fenofibrate
  or niacin might be used with LDL between 100 to
  129 mg/dl

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Conclusionsfrom Diabetes Care, Vol27 supplement
1 Jan 2004

• The initial Tx for hypertriglycerdemia is
  improved glycemic control and lifestyle
  intervention
• Or with fibric acid derivatives ( gemfibrozil or
  fenofibrate) or niacin
• If high LDL and high TG ?high dose of statins may
  be used

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Conclusionsfrom Diabetes Care, Vol27 supplement
1 Jan 2004