Reducing Cardiovascular Disease in Type 2 Diabetes

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Reducing Cardiovascular Disease in Type 2 Diabetes
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Case 1

• 51yo Sri Lankan man
• Does not see GP regularly
• Presents with anterior AMI
• Smoker
• FHx premature vascular disease
• No PHx of DM
• Not on any medications

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• BSL of 17, HbA1C 9.0
• Creatinine 110
• Total Cholesterol 6.5 mmol/L
• LDL 4.2 mmol/L
• HDL 0.8 mmol/L
• Triglycerides 3.2 mmol/L

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• BP 140/85
• BMI 27
• Abdominal distribution
• No left ventricular failure

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• BD insulin on ward
• Continued Novomix 30 on discharge
• Intensive diabetes education
• Dietician review
• Medications on discharge
• Novomix 22units/10units
• Aspirin 150mg daily
• Ramipril 5mg daily
• Metoprolol 25mg BD
• Atorvastatin 40mg daily

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• 1st review in clinic 14 days post discharge
• No further chest pain
• BSLs under 12 (adjusted by diabetes educator)
• Metformin commenced
• BP 128/70 with no postural drop
• Seen by endocrinologist, diabetic educator,
  dietician
• Quit smoking

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• 2nd review 10 weeks post discharge
• BSL all under 10 insulin had been weaned as an
  outpatient-
• On Metformin 1g BD
• Diamicron MR 60mg mane
• No hypoglycemia
• HbA1C 7.3
• Repeat lipids
• TC 4.3
• Triglycerides 1.8
• Still not smoking
• Follow up with local GP

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• Many patients like our case example
• Need to optimise opportunity for CV/ diabetes
  screening to minimise CV risk

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Assessment of Risk

• New Zealand Cardiovascular Risk Calculator
• Useful tool doctors and patients
• Who should be assessed?
• Assess risk in asymptomatic mengt45 yo (gt35 if
  risk factors)
• Assess womengt 55 yo (45 if risk factors)
• Fasting lipids, glucose and 2 BP measurements
  good starting point

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Who to risk assess
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High risk groups for CVD/diabetes screening

• Family history of premature CVD or diabetes
• PHx gestational diabetes or polycystic ovary
  syndrome
• Current smoking
• Prior BP gt 160/95 or TCHDL ratio gt 7
• IGT or IFG
• Obesity (BMI gt 30)
• Truncal obesity Waist Circ gt 100cm men
• or gt 90cm women

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Absolute 5 yr Risk

• Very high gt20
• High gt15
• Moderate gt10
• Mild lt10
• The overall goal of therapy is to achieve a 5
  year cardiovascular risk of lt15

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Very High Risk Patients

• Clinically very high risk
• Risk assumed to be more than 20
• Previous CV event
• AMI, angina, CABG, TIA, CVA, PVD
• Genetic lipid disorders
• Diabetes with overt nephropathy
• Diabetes with other renal disease

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• Also move up one category if
• FHx CVD male gt55, femalegt65
• Ethnicity
• Diabetes and microalbuminuria
• Type 2 DM gt10 years
• HbA1C gt8.0
• People with the metabolic syndrome

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• Significant improvements in long term prognosis
• Smoking cessation
• Treatment of hypertension
• Improvement of lipid profile
• Addition of aspirin
• Weight loss

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• In our patient
• Very high risk-- gt25
• Even without AMI
• Mangt50
• Smoker
• Diabetic
• TC HDL gt8

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Diabetes Facts

• Diabetes increases risk of coronary disease
  2-fold in men and 4-fold in women
• 65-80 of patients with diabetes die of coronary
  heart disease
• Diabetes is the leading cause of kidney failure
• 15 of diabetics will experience foot ulcers
• Diabetes is the most common cause of blindness
  under 60

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• A child born in the US in 2005 has a 48.5 chance
  of developing diabetes during their lifetime

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Classification of Glucose Tolerance Status

• Plasma glucose (mmol/l)

Classification Fasting 2-hr
Diabetes ? 7.0 or ? 11.1 Impaired
GlucoseTolerance ? 7.0 7.8 - 11.0 Impaired
FastingGlucose 6.1 - 6.9 Normal ? 6.1 ? 7.8
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AusDiab

• Study of 11,247 Australians over age 25 living in
  42 randomly selected urban and rural areas
• Aims-
• Estimate prevalence of diabetes and abnormal GT
• Estimate prevalence of related conditions
  including obesity, HT, lipid abnormalities
• Assess trends in risk factor levels

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Estimated Diabetes Cases in Australia Number of
Persons
Thousands
1400
e
1200
1000
d
800
c
600
b
a
400
200
0
1982
1986
1990
1994
1998
2202
2006
2010
Year
a. Busselton, 1981 b. NHF, 1983 c. ABS,
1989-90 d. ABS, 1995 e. (Estimate)
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Weighted Prevalence () of Associated Conditions
Stratified by Glucose Tolerance Status

• Glucose tolerance status

Associated condition Diabetes IFG IGT Normal
Hypertension 69.3 43.5 50.1 21.1 Obesity (BMI ?
30 kg/m²) 44.4 30.1 31.5 15.9 LDL (? 3.5
mmol/l) 45.9 59.6 53.0 44.1 HDL (?1.0
mmol/l) 23.1 16.8 11.6 10.6 Triglycerides (? 2.0
mmol/l) 42.9 31.4 31.1 16.0
On treatment, or systolic pressure ? 140 mm
Hg, or diastolic pressure ? 90 mm Hg
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Control of Risk Factors
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BP Targets
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United Kingdom Prospective Diabetes Study

• Each 10mmHg decrease in mean systolic blood
  pressure accompanied by
• 12 reduction in risk for any complication
  related to diabetes
• 15 reduction in deaths related to diabetes
• 11 reduction in myocardial infarcts
• 13 reduction in microvascular complications

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Non-Pharmacological Therapies

• Weight reduction reduces BP independent of sodium
  intake
• ?1 kg loss of weight, 1mmHg decrease in systolic
  BP
• Na restriction not studied diabetics
• in essential hypertension, a moderate Na intake
  restriction leads to a 5mmHg decrease in systolic
  BP and 2-3mmHg decrease in diastolic BP
• 30-45 minutes brisk walking most days of week
  also shown to decrease BP

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Pharmacological Therapy

• Lots of studies, lots of drugs
• Many patients need 3 drugs
• ACE-inhibitors and ARBs retard development of
  diabetic nephropathy
• B-blockers benefit in post-AMI patients
• ACE-inhibitors favorable effect on cardiovascular
  outcome
• Some studies have shown an excess of selected CV
  deaths in dihydropyridine calcium channel
  blockers (DCCB) compared with ACE-inhibitors
• Not evident when DCCB used in combination with
  ACE-inhibitors, B-Blockers, diuretics
• ACE-inhibitors and B-blockers superior to DCCB in
  preventing CCF and AMI
• Appropriate addition to but not instead of
  b-blockers or ACE-inhibitors

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Lipid Targets
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Lipids and Diabetes

• Most common pattern of dyslipidemia is elevated
  triglycerides and reduced HDL
• Mean concentration of LDL no different from
  non-diabetics
• Qualitative differences

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Non-Pharmacological Therapy

• Weight loss and physical activity leads to
  decreased triglycerides, increased HDL and modest
  reduction of LDL
• Maximal medical nutritional activity typically
  reduces LDL cholesterol by 0.4 to 0.65mmol/L
• Interventions to improve glycemia typically lower
  triglycerides

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• Plant Sterols
• Similar structure to cholesterol
• Reduce amount of dietary and biliary cholesterol
  absorbed
• 2g/day reduces LDL-C by 10-15
• Additive to reductions seen through other dietary
  changes and statins
• No adverse effects seen in trials but long-term
  studies not done
• Reduce gut caretenoid absorption- do not use in
  children or pregnancy
• Fish oils
• Decrease triglycerides
• Encourage fish meals twice a week
• if supplements are used 2 g omega-3 PUFA
  recommended

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Characteristics of Statins

• Simvastatin
• Max dose 80mg day
• Max LDL-C reduction 47
• Typical LDL reduction 41
• Trig reduction 18
• HDL increase 10

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• Atorvastatin
• Max dose 80mg
• Max LDL-C reduction 60
• Typical LDL reduction 50
• Trig reduction 29
• HDL increase 6

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• Heart Protection Study
• 5963 patients over 40, with diabetes and TCgt3.5
• Patients with diabetes assigned simvastatin had a
  22 reduction in the event rate for major CV
  events
• Risk reduction similar across all LDL categories
  examined, including patients with lower LDL
  (lt3.0) at entry

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• Intensive Vs Moderate Lipid Lowering After Acute
  Coronary Syndromes
• Cannon et al, NEJM, 2004
• 4000 patients
• Hospitalised for ACS preceding 10 days
• Compared 40mg pravastatin (moderate Rx) to 80mg
  atorvastatin (intensive Rx)
• End-point death from any cause, AMI, stroke,
  angina needing hospitalisation
• Follow up 24 months

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• Median LDL achieved with pravastatin 2.5mmol/L
• Median LDL with atorvastatin 1.6mmol/L
• Rates primary endpoints at 2 years 26.3 in
  pravastatin group
• Rates primary endpoints at 2 years 22.4 in
  atorvastatin group
• 16 reduction in hazard ratio in favour of
  atorvastatin

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Elevated Triglycerides

• Improve glycaemic control aggressively
• Above 4.5mmol/l strong consideration of
  pharmacological therapy to prevent pancreatitis
• Pharmacotherapy at clinicians judgement with
  triglycerides between 2.3mmol/l and 4.5mmol/l
• Higher dose statins moderately effective at
  reducing triglycerides
• Consider addition of fibric acid derivative

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HDL

• Powerful predictor of CV disease in diabetics
• Difficult to raise HDL without pharmacological
  intervention
• Weight loss, smoking cessation
• Nicotinic acid and fibrates
• Use nicotinic acid with caution in diabetics
• Effect on glycaemic control
• Statins and fibrates/nicotinic acid-
• increase risk of myositis
• Not evaluated in outcome studies for event
  reduction

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• Fibrates
• Veteran Affairs High Density Lipoprotein
  Cholesterol Intervention Trial
• Gemfibrozil associated with 24 decrease in
  cardiovascular events in diabetics with prior CV
  disease, low HDL and modestly elevated
  triglycerides

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• Changes to therapy should be based on lab
  follow-up 4-12 weeks after initiating therapy
• Once goals achieved follow up 6-12 months

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Ezetimibe

• Selectively inhibits the absorption of
  cholesterol at the brush border membrane in the
  intestinal lumen
• Available on authority if HMG CoA reductase
  inhibitor contraindicated or adverse effect
• Severe myalgia, myositis (CK 2x ULN) or ALT 3x
  ULN
• Co-administration with a statin if lipid targets
  not met
• Appears safe
• No long term data

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United Kingdom Prospective Diabetes Study I

• 10 yr follow-up of 3867 newly diagnosed NIDDM
• HbA1c 7.0 compared to 7.9
• 25 reduction in microvascular end-points

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Type 2 DM

• Preprandial BSL of lt5.5-6.0
• 2 hour postprandial BSL of lt7.8
• HbA1C lt7.0

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Type 2 DM

• These recommendations from 3 landmark studies-
• Diabetes Control and Complications Trial
• Kumamoto Study
• UKPDS
• These have shown unequivocally that maintaining
  BSL as close to normal as possible in type 1 and
  2 DM decreases microvascular complications

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Type 2 DM

• Diet, exercise and weight loss- the centre of any
  therapeutic program

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Sulphonylureas

• Available since 1954
• Compared to placebo- decrease HbA1C of 1-2
• Of practical concern-
• Weight gain- 2-5 kg
• Hypoglycaemia- especially in elderly, impaired
  renal function, irregular eating habits
• Optimal dosing of each member of this class
  varies
• AS A GENERAL RULE GLUCOSE LOWERING EFFECT
  PLATEAUS AFTER HALF THE MAXIMUM DOSE IS REACHED
• Most agents are metabolised by the liver and
  cleared by the kidney so use with caution in
  patients with renal and hepatic disease

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Metformin

• Ability to lower HbA1C similar to SU- 1-2
• Associated with weight neutrality and much less
  hypoglycaemia
• GIT complaints in up to 50
• Minimised with slow dose titration
• Optimal dose in most patients is 2000mg/day
• Risk of lactic acidosis is 1/30,000 patient-years
• Therefore avoid if abnormal Creatinine
• Avoid if severe hepatic dysfunction, CCF,
  dehydration, alcoholism
• With-hold in virtually any acute illness

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Thiazolidinediones

• Pioglitazone (ACTOS) and Rosiglitazone (AVANDIA)
• Pharmacological ligands for nuclear receptor-
  peroxisome-proliferator-activated receptor gamma
• Prominent effect is insulin-stimulated glucose
  uptake in skeletal muscle
• Like metformin, does not cause pancreatic beta
  cells to produce more insulin
• Decreases in HbA1C similar to SU and metformin

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TZD

• Actions-
• Decrease insulin levels
• Increase HDL, decrease triglycerides
• Adverse effects-
• weight gain
• usually peripheral subcutaneous sites, with
  reduction in visceral fat depots
• Oedema
• Patients with advanced CCF should not receive TZD

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• Individualise therapy
• Lifestyle advice
• Call if concerns

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