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Reducing Cardiovascular Reducing Cardiovascular Disease in Type 2 DiabetesDisease in Type 2 Diabetes
Case 1Case 1
51yo Sri Lankan man51yo Sri Lankan man Does not see GP regularly Does not see GP regularly Presents with anterior AMIPresents with anterior AMI
SmokerSmoker FHx premature vascular diseaseFHx premature vascular disease No PHx of DM No PHx of DM Not on any medicationsNot on any medications
BSL of 17, HbA1C 9.0%BSL of 17, HbA1C 9.0% Creatinine 110Creatinine 110
Total CholesterolTotal Cholesterol 6.5 mmol/L6.5 mmol/L LDL LDL 4.2 mmol/L4.2 mmol/L HDLHDL 0.8 mmol/L0.8 mmol/L TriglyceridesTriglycerides 3.2 mmol/L 3.2 mmol/L
BP 140/85BP 140/85 BMI 27BMI 27
Abdominal distributionAbdominal distribution
No left ventricular failureNo left ventricular failure
BD insulin on wardBD insulin on ward Continued Novomix 30 on dischargeContinued Novomix 30 on discharge Intensive diabetes educationIntensive diabetes education Dietician reviewDietician review Medications on dischargeMedications on discharge
Novomix 22units/10units Novomix 22units/10units Aspirin 150mg dailyAspirin 150mg daily Ramipril 5mg dailyRamipril 5mg daily Metoprolol 25mg BDMetoprolol 25mg BD Atorvastatin 40mg dailyAtorvastatin 40mg daily
11stst review in clinic 14 days post review in clinic 14 days post dischargedischarge
No further chest painNo further chest pain BSLs under 12 (adjusted by diabetes educator)BSLs under 12 (adjusted by diabetes educator) Metformin commencedMetformin commenced BP 128/70 with no postural dropBP 128/70 with no postural drop Seen by endocrinologist, diabetic educator, Seen by endocrinologist, diabetic educator,
dietician dietician Quit smokingQuit smoking
22ndnd review 10 weeks post discharge review 10 weeks post discharge BSL all under 10; insulin had been weaned as an BSL all under 10; insulin had been weaned as an
outpatient-outpatient- On Metformin 1g BDOn Metformin 1g BD Diamicron MR 60mg maneDiamicron MR 60mg mane No hypoglycemiaNo hypoglycemia
HbA1C 7.3%HbA1C 7.3% Repeat lipidsRepeat lipids
TC 4.3TC 4.3 Triglycerides 1.8Triglycerides 1.8
Still not smokingStill not smoking
Follow up with local GPFollow up with local GP
Many patients like our case exampleMany patients like our case example
Need to optimise opportunity for CV/ Need to optimise opportunity for CV/ diabetes screening to minimise CV diabetes screening to minimise CV riskrisk
Assessment of RiskAssessment of Risk
New Zealand Cardiovascular Risk CalculatorNew Zealand Cardiovascular Risk Calculator Useful tool doctors and patientsUseful tool doctors and patients Who should be assessed?Who should be assessed?
Assess risk in asymptomatic men>45 yo (>35 if Assess risk in asymptomatic men>45 yo (>35 if risk factors)risk factors)
Assess women> 55 yo (45 if risk factors)Assess women> 55 yo (45 if risk factors)
Fasting lipids, glucose and 2 BP measurements Fasting lipids, glucose and 2 BP measurements good starting pointgood starting point
Who to risk assessWho to risk assessMenMen WomeWome
nn
Asymptomatic people, Asymptomatic people, without other known risk without other known risk factorsfactors
Age Age 4545
Age 55Age 55
Māori, Pacific people and Māori, Pacific people and people from the Indian sub-people from the Indian sub-continent continent
Age Age 3535
Age 45Age 45
Those with at higher risk of Those with at higher risk of CVD or developing diabetesCVD or developing diabetes
Age Age 3535
Age 45Age 45
People with diabetesPeople with diabetes At diagnosisAt diagnosis
High risk groups for High risk groups for CVD/diabetes screeningCVD/diabetes screening
Family history of premature CVD or diabetesFamily history of premature CVD or diabetes PHx gestational diabetes or polycystic ovary PHx gestational diabetes or polycystic ovary
syndromesyndrome Current smoking Current smoking Prior BP > 160/95 or TC:HDL ratio > 7Prior BP > 160/95 or TC:HDL ratio > 7 IGT or IFG IGT or IFG Obesity (BMI > 30)Obesity (BMI > 30) Truncal obesity Waist CircTruncal obesity Waist Circ > 100cm men > 100cm men
or > 90cm or > 90cm womenwomen
Absolute 5 yr RiskAbsolute 5 yr Risk
Very highVery high >20%>20% HighHigh >15%>15% ModerateModerate >10%>10% MildMild <10%<10%
The overall goal of therapy is to The overall goal of therapy is to achieve a 5 year cardiovascular risk of achieve a 5 year cardiovascular risk of <15%<15%
Very High Risk PatientsVery High Risk Patients
Clinically “very high risk”Clinically “very high risk” Risk assumed to be more than 20%Risk assumed to be more than 20%
Previous CV eventPrevious CV event AMI, angina, CABG, TIA, CVA, PVDAMI, angina, CABG, TIA, CVA, PVD
Genetic lipid disordersGenetic lipid disorders Diabetes with overt nephropathyDiabetes with overt nephropathy Diabetes with other renal diseaseDiabetes with other renal disease
Also move up one category ifAlso move up one category if FHx CVD male >55, female>65FHx CVD male >55, female>65 EthnicityEthnicity Diabetes and microalbuminuriaDiabetes and microalbuminuria Type 2 DM >10 yearsType 2 DM >10 years HbA1C >8.0%HbA1C >8.0% People with the metabolic syndromePeople with the metabolic syndrome
Significant improvements in long Significant improvements in long term prognosisterm prognosis Smoking cessationSmoking cessation Treatment of hypertensionTreatment of hypertension Improvement of lipid profileImprovement of lipid profile Addition of aspirinAddition of aspirin Weight lossWeight loss
In our patientIn our patient Very high risk-- >25% Very high risk-- >25%
Even without AMIEven without AMI Man>50Man>50 SmokerSmoker DiabeticDiabetic TC :HDL >8TC :HDL >8
Diabetes FactsDiabetes Facts
Diabetes increases risk of coronary disease Diabetes increases risk of coronary disease 2-fold in men and 4-fold in women 2-fold in men and 4-fold in women
65-80% of patients with diabetes die of 65-80% of patients with diabetes die of coronary heart diseasecoronary heart disease
Diabetes is the leading cause of kidney Diabetes is the leading cause of kidney failurefailure
15% of diabetics will experience foot ulcers15% of diabetics will experience foot ulcers Diabetes is the most common cause of Diabetes is the most common cause of
blindness under 60blindness under 60
A child born in the US in 2005 has a A child born in the US in 2005 has a 48.5% chance of developing diabetes 48.5% chance of developing diabetes during their lifetimeduring their lifetime
Classification of Glucose Classification of Glucose Tolerance StatusTolerance Status
Plasma glucose (mmol/l)Plasma glucose (mmol/l)
DiabetesDiabetes 7.0 7.0 oror 11.1 11.1
Impaired GlucoseImpaired GlucoseToleranceTolerance 7.0 7.0 && 7.8 - 11.07.8 - 11.0
Impaired FastingImpaired FastingGlucoseGlucose 6.1 - 6.96.1 - 6.9
NormalNormal 6.1 6.1 && 7.8 7.8
ClassificationClassification FastingFasting 2-hr2-hr
AusDiabAusDiab Study of 11,247 Australians over age 25 Study of 11,247 Australians over age 25
living in 42 randomly selected urban living in 42 randomly selected urban and rural areas and rural areas
Aims- Aims- Estimate prevalence of diabetes and abnormal GTEstimate prevalence of diabetes and abnormal GT Estimate prevalence of related conditions Estimate prevalence of related conditions
including obesity, HT, lipid abnormalitiesincluding obesity, HT, lipid abnormalities Assess trends in risk factor levelsAssess trends in risk factor levels
Estimated Diabetes Cases in Australia: Estimated Diabetes Cases in Australia: Number of PersonsNumber of Persons
ThousandsThousands
0
200
400
600
800
1000
1200
1400
1982 1986 1990 1994 1998 2202 2006 2010
YearYear
aa
bb
cc
dd
ee
a. Busselton, 1981 b. NHF, 1983 c. ABS, 1989-90 d. ABS, 1995 e. (Estimate)a. Busselton, 1981 b. NHF, 1983 c. ABS, 1989-90 d. ABS, 1995 e. (Estimate)
Weighted Prevalence (%) of Associated Weighted Prevalence (%) of Associated Conditions Stratified by Glucose Tolerance StatusConditions Stratified by Glucose Tolerance Status
Glucose tolerance statusGlucose tolerance status
Associated conditionAssociated condition DiabetesDiabetes IFGIFG IGTIGT NormalNormal
Hypertension*Hypertension* 69.369.3 43.543.5 50.150.1 21.121.1
Obesity (BMI Obesity (BMI 30 kg/m²) 30 kg/m²) 44.444.4 30.130.1 31.531.5 15.915.9
LDL (LDL ( 3.5 mmol/l) 3.5 mmol/l) 45.945.9 59.659.6 53.053.0 44.144.1
HDL (HDL (1.0 mmol/l)1.0 mmol/l) 23.123.1 16.816.8 11.611.6 10.610.6
Triglycerides (Triglycerides ( 2.0 mmol/l) 2.0 mmol/l) 42.942.9 31.431.4 31.131.1 16.016.0
* On treatment, or systolic pressure * On treatment, or systolic pressure 140 mm Hg, 140 mm Hg, or diastolic pressure or diastolic pressure 90 mm Hg 90 mm Hg
Control of Risk FactorsControl of Risk Factors
BP TargetsBP Targets
ConditionCondition Example BPExample BPPatients without clinical Patients without clinical CVDCVD
< 140 / 85< 140 / 85
Patients with diabetes or Patients with diabetes or CVDCVD
< 130 / 80< 130 / 80
Patients with diabetes Patients with diabetes and overt nephropathy and overt nephropathy or other renal diseaseor other renal disease
< 120 / 75< 120 / 75
United Kingdom Prospective United Kingdom Prospective Diabetes StudyDiabetes Study
Each 10mmHg decrease in mean systolic Each 10mmHg decrease in mean systolic blood pressure accompanied byblood pressure accompanied by 12% reduction in risk for any complication 12% reduction in risk for any complication
related to diabetesrelated to diabetes 15% reduction in deaths related to diabetes15% reduction in deaths related to diabetes 11% reduction in myocardial infarcts11% reduction in myocardial infarcts 13% reduction in microvascular 13% reduction in microvascular
complicationscomplications
Non-Pharmacological Non-Pharmacological TherapiesTherapies
Weight reduction reduces BP independent of Weight reduction reduces BP independent of sodium intake sodium intake
1 kg loss of weight, 1mmHg decrease in systolic 1 kg loss of weight, 1mmHg decrease in systolic BPBP
Na restriction not studied diabetics Na restriction not studied diabetics in essential hypertension, a moderate Na intake in essential hypertension, a moderate Na intake
restriction leads to a 5mmHg decrease in systolic BP and restriction leads to a 5mmHg decrease in systolic BP and 2-3mmHg decrease in diastolic BP2-3mmHg decrease in diastolic BP
30-45 minutes brisk walking most days of week 30-45 minutes brisk walking most days of week also shown to decrease BPalso shown to decrease BP
Pharmacological TherapyPharmacological Therapy Lots of studies, lots of drugsLots of studies, lots of drugs Many patients need 3+ drugsMany patients need 3+ drugs
ACE-inhibitors and ARBs retard development of diabetic ACE-inhibitors and ARBs retard development of diabetic nephropathynephropathy
B-blockers benefit in post-AMI patientsB-blockers benefit in post-AMI patients ACE-inhibitors favorable effect on cardiovascular outcomeACE-inhibitors favorable effect on cardiovascular outcome
Some studies have shown an excess of selected CV deaths in Some studies have shown an excess of selected CV deaths in dihydropyridine calcium channel blockers (DCCB) compared with dihydropyridine calcium channel blockers (DCCB) compared with ACE-inhibitorsACE-inhibitors Not evident when DCCB used in combination with ACE-inhibitors, Not evident when DCCB used in combination with ACE-inhibitors,
B-Blockers, diureticsB-Blockers, diuretics ACE-inhibitors and B-blockers superior to DCCB in preventing ACE-inhibitors and B-blockers superior to DCCB in preventing
CCF and AMICCF and AMI
Appropriate addition to but not instead of b-blockers or ACE-Appropriate addition to but not instead of b-blockers or ACE-inhibitorsinhibitors
Lipid TargetsLipid TargetsLipid fractionLipid fraction ValueValue
Total cholesterolTotal cholesterol < 4 mmol/L< 4 mmol/L
LDL-cholesterolLDL-cholesterol < 2.5 mmol/L< 2.5 mmol/L
HDL-cholesterolHDL-cholesterol > 1 mmol/L> 1 mmol/L
TC:HDL RatioTC:HDL Ratio < 4.5< 4.5
TriglyceridesTriglycerides < 1.7 mmol/L< 1.7 mmol/L
Lipids and DiabetesLipids and Diabetes
Most common pattern of Most common pattern of dyslipidemia is elevated triglycerides dyslipidemia is elevated triglycerides and reduced HDLand reduced HDL
Mean concentration of LDL no Mean concentration of LDL no different from non-diabeticsdifferent from non-diabetics
Qualitative differencesQualitative differences
Non-Pharmacological Non-Pharmacological TherapyTherapy
Weight loss and physical activity leads to Weight loss and physical activity leads to decreased triglycerides, increased HDL decreased triglycerides, increased HDL and modest reduction of LDLand modest reduction of LDL
Maximal medical nutritional activity Maximal medical nutritional activity typically reduces LDL cholesterol by 0.4 to typically reduces LDL cholesterol by 0.4 to 0.65mmol/L0.65mmol/L
Interventions to improve glycemia Interventions to improve glycemia typically lower triglyceridestypically lower triglycerides
Plant SterolsPlant Sterols Similar structure to cholesterolSimilar structure to cholesterol Reduce amount of dietary and biliary cholesterol absorbedReduce amount of dietary and biliary cholesterol absorbed 2g/day reduces LDL-C by 10-15%2g/day reduces LDL-C by 10-15% Additive to reductions seen through other dietary changes and Additive to reductions seen through other dietary changes and
statinsstatins No adverse effects seen in trials but long-term studies not No adverse effects seen in trials but long-term studies not
donedone Reduce gut caretenoid absorption- do not use in children or Reduce gut caretenoid absorption- do not use in children or
pregnancypregnancy
Fish oilsFish oils Decrease triglyceridesDecrease triglycerides Encourage fish meals twice a weekEncourage fish meals twice a week if supplements are used 2 g omega-3 PUFA recommendedif supplements are used 2 g omega-3 PUFA recommended
Characteristics of StatinsCharacteristics of Statins
SimvastatinSimvastatin Max dose 80mg dayMax dose 80mg day Max LDL-C reduction 47%Max LDL-C reduction 47% Typical LDL reduction 41%Typical LDL reduction 41% Trig reduction 18%Trig reduction 18% HDL increase 10%HDL increase 10%
AtorvastatinAtorvastatin Max dose 80mgMax dose 80mg Max LDL-C reduction 60%Max LDL-C reduction 60% Typical LDL reduction 50%Typical LDL reduction 50% Trig reduction 29%Trig reduction 29% HDL increase 6%HDL increase 6%
Heart Protection StudyHeart Protection Study 5963 patients over 40, with diabetes and 5963 patients over 40, with diabetes and
TC>3.5TC>3.5 Patients with diabetes assigned simvastatin Patients with diabetes assigned simvastatin
had a 22% reduction in the event rate for had a 22% reduction in the event rate for major CV eventsmajor CV events
Risk reduction similar across all LDL Risk reduction similar across all LDL categories examined, including patients with categories examined, including patients with lower LDL (<3.0) at entrylower LDL (<3.0) at entry
Intensive Vs Moderate Lipid Lowering After Intensive Vs Moderate Lipid Lowering After Acute Coronary SyndromesAcute Coronary Syndromes Cannon et al, NEJM, 2004Cannon et al, NEJM, 2004 4000 patients4000 patients Hospitalised for ACS preceding 10 daysHospitalised for ACS preceding 10 days Compared 40mg pravastatin (moderate Rx) to Compared 40mg pravastatin (moderate Rx) to
80mg atorvastatin (intensive Rx)80mg atorvastatin (intensive Rx) End-point death from any cause, AMI, stroke, End-point death from any cause, AMI, stroke,
angina needing hospitalisationangina needing hospitalisation Follow up 24 monthsFollow up 24 months
Median LDL achieved with pravastatin Median LDL achieved with pravastatin 2.5mmol/L2.5mmol/L
Median LDL with atorvastatin 1.6mmol/LMedian LDL with atorvastatin 1.6mmol/L Rates primary endpoints at 2 years 26.3% Rates primary endpoints at 2 years 26.3%
in pravastatin groupin pravastatin group Rates primary endpoints at 2 years 22.4% Rates primary endpoints at 2 years 22.4%
in atorvastatin groupin atorvastatin group 16% reduction in hazard ratio in favour of 16% reduction in hazard ratio in favour of
atorvastatinatorvastatin
Elevated TriglyceridesElevated Triglycerides
Improve glycaemic control aggressivelyImprove glycaemic control aggressively Above 4.5mmol/l strong consideration of Above 4.5mmol/l strong consideration of
pharmacological therapy to prevent pharmacological therapy to prevent pancreatitispancreatitis
Pharmacotherapy at clinicians judgement with Pharmacotherapy at clinicians judgement with triglycerides between 2.3mmol/l and 4.5mmol/ltriglycerides between 2.3mmol/l and 4.5mmol/l
Higher dose statins moderately effective at Higher dose statins moderately effective at reducing triglyceridesreducing triglycerides
Consider addition of fibric acid derivativeConsider addition of fibric acid derivative
HDLHDL Powerful predictor of CV disease in diabeticsPowerful predictor of CV disease in diabetics Difficult to raise HDL without pharmacological Difficult to raise HDL without pharmacological
interventionintervention Weight loss, smoking cessationWeight loss, smoking cessation Nicotinic acid and fibratesNicotinic acid and fibrates
Use nicotinic acid with caution in diabeticsUse nicotinic acid with caution in diabetics Effect on glycaemic controlEffect on glycaemic control
Statins and fibrates/nicotinic acid- Statins and fibrates/nicotinic acid- increase risk of myositisincrease risk of myositis Not evaluated in outcome studies for event reductionNot evaluated in outcome studies for event reduction
FibratesFibrates Veteran Affairs High Density Lipoprotein Veteran Affairs High Density Lipoprotein
Cholesterol Intervention TrialCholesterol Intervention Trial Gemfibrozil associated with 24% Gemfibrozil associated with 24%
decrease in cardiovascular events in decrease in cardiovascular events in diabetics with prior CV disease, low HDL diabetics with prior CV disease, low HDL and modestly elevated triglyceridesand modestly elevated triglycerides
Changes to therapy should be based Changes to therapy should be based on lab follow-up 4-12 weeks after on lab follow-up 4-12 weeks after initiating therapyinitiating therapy
Once goals achieved follow up 6-12 Once goals achieved follow up 6-12 monthsmonths
EzetimibeEzetimibe
Selectively inhibits the absorption of cholesterol Selectively inhibits the absorption of cholesterol at the brush border membrane in the intestinal at the brush border membrane in the intestinal lumenlumen
Available on authority if HMG CoA reductase Available on authority if HMG CoA reductase inhibitor contraindicated or adverse effectinhibitor contraindicated or adverse effect Severe myalgia, myositis (CK 2x ULN) or ALT 3x ULNSevere myalgia, myositis (CK 2x ULN) or ALT 3x ULN
Co-administration with a statin if lipid targets not Co-administration with a statin if lipid targets not metmet
Appears safeAppears safe No long term dataNo long term data
United Kingdom Prospective United Kingdom Prospective Diabetes Study IDiabetes Study I
10 yr follow-up of 3867 newly diagnosed 10 yr follow-up of 3867 newly diagnosed NIDDMNIDDM
HbA1c 7.0% compared to 7.9%HbA1c 7.0% compared to 7.9%
25% reduction in microvascular end-25% reduction in microvascular end-pointspoints
Type 2 DMType 2 DM
Preprandial BSL of <5.5-6.0Preprandial BSL of <5.5-6.0
2 hour postprandial BSL of <7.82 hour postprandial BSL of <7.8
HbA1C <7.0%HbA1C <7.0%
Type 2 DMType 2 DM
These recommendations from 3 These recommendations from 3 landmark studies-landmark studies-
Diabetes Control and Complications TrialDiabetes Control and Complications Trial Kumamoto StudyKumamoto Study UKPDSUKPDS
These have shown unequivocally that These have shown unequivocally that maintaining BSL as close to normal as maintaining BSL as close to normal as possible in type 1 and 2 DM decreases possible in type 1 and 2 DM decreases microvascular complicationsmicrovascular complications
Type 2 DMType 2 DM
Diet, exercise and weight loss- the Diet, exercise and weight loss- the centre of any therapeutic programcentre of any therapeutic program
SulphonylureasSulphonylureas
Available since 1954Available since 1954 Compared to placebo- decrease HbA1C of 1-2%Compared to placebo- decrease HbA1C of 1-2%
Of practical concern-Of practical concern- Weight gain- 2-5 kgWeight gain- 2-5 kg
Hypoglycaemia- especially in elderly, impaired renal function, Hypoglycaemia- especially in elderly, impaired renal function, irregular eating habitsirregular eating habits
Optimal dosing of each member of this class variesOptimal dosing of each member of this class varies AS A GENERAL RULE GLUCOSE LOWERING EFFECT AS A GENERAL RULE GLUCOSE LOWERING EFFECT
PLATEAUS AFTER HALF THE MAXIMUM DOSE IS PLATEAUS AFTER HALF THE MAXIMUM DOSE IS REACHEDREACHED
Most agents are metabolised by the liver and cleared Most agents are metabolised by the liver and cleared by the kidney so use with caution in patients with by the kidney so use with caution in patients with renal and hepatic diseaserenal and hepatic disease
MetforminMetformin
Ability to lower HbA1C similar to SU- 1-2%Ability to lower HbA1C similar to SU- 1-2% Associated with weight neutrality and much less Associated with weight neutrality and much less
hypoglycaemiahypoglycaemia GIT complaints in up to 50%GIT complaints in up to 50% Minimised with slow dose titrationMinimised with slow dose titration Optimal dose in most patients is 2000mg/dayOptimal dose in most patients is 2000mg/day
Risk of lactic acidosis is 1/30,000 patient-yearsRisk of lactic acidosis is 1/30,000 patient-years Therefore avoid if abnormal Creatinine Therefore avoid if abnormal Creatinine Avoid if severe hepatic dysfunction, CCF, dehydration, Avoid if severe hepatic dysfunction, CCF, dehydration,
alcoholismalcoholism With-hold in virtually any acute illnessWith-hold in virtually any acute illness
ThiazolidinedionesThiazolidinediones Pioglitazone (ACTOS) and Rosiglitazone (AVANDIA)Pioglitazone (ACTOS) and Rosiglitazone (AVANDIA) Pharmacological ligands for nuclear receptor- Pharmacological ligands for nuclear receptor-
peroxisome-proliferator-activated receptor gammaperoxisome-proliferator-activated receptor gamma
Prominent effect is insulin-stimulated glucose Prominent effect is insulin-stimulated glucose uptake in skeletal muscleuptake in skeletal muscle
Like metformin, does not cause pancreatic beta Like metformin, does not cause pancreatic beta cells to produce more insulincells to produce more insulin
Decreases in HbA1C similar to SU and metforminDecreases in HbA1C similar to SU and metformin
TZDTZD
Actions-Actions- Decrease insulin levelsDecrease insulin levels Increase HDL, decrease triglyceridesIncrease HDL, decrease triglycerides
Adverse effects-Adverse effects- weight gainweight gain
usually peripheral subcutaneous sites, with reduction in usually peripheral subcutaneous sites, with reduction in visceral fat depots visceral fat depots
OedemaOedema Patients with advanced CCF should not receive TZDPatients with advanced CCF should not receive TZD
Individualise therapyIndividualise therapy
Lifestyle adviceLifestyle advice
Call if concernsCall if concerns