CARDIOVASCULAR MANAGEMENT OF PATIENTS WITH DIABETES
From the Interstate Postgraduate Medical Association of North America’s Primary Care Update
Jan N. Basile, MD, Professor of Medicine, Division of General Internal Medicine/Geriatrics, Medical University of South
Carolina, and Director, Primary Care Service Line, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC
| Introduction: using diabetes as evidence-based approach to patients at very high risk; such patients often
overlooked until some underlying cardiovascular disease (CVD) appears
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| Obesity epidemic: 246 million cases worldwide, already surpassing estimate for 2010; for white men 70 yr
of age, cumulative risk for diabetes ≈22%, Hispanic men ≈35%, white women ≈25%, Hispanic women
≈41%
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| CVD in diabetes: main cause of death in men and women with diabetes, although diabetic women more
likely to die of CVD
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Hyperglycemia and Diabetes
| Glucose control: United Kingdom Prospective Diabetes Study (UKPDS) found 30% increase in retinopathy,
neuropathy, and nephropathy for each 1% increase in glycosylated hemoglobin (HbA1C ); each 1% drop
in HbA1C reduced microvascular end points linearly; suggestion but no clinical trial-based evidence that
same true for macrovascular end points, ie, stroke, CVD, transient ischemic attack (TIA)
|
| Action to Control Cardiovascular Risk in Diabetes (ACCORD): National Heart, Lung, Blood Institute
trial involving 10 291 participants with type 2 diabetes; intensive strategy arm aims for HbA1C <6%, standard
arm aims for HbA1C 7.0% to 7.9%; multiple end points being studied, eg, cognition, blindness, amputation
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Hypertension and Diabetes
| Results of UKPDS: in first strategy for blood pressure (BP) control, patients started with BPs ≈180/105 mm
Hg and ended at ≈154/87 mm Hg; group with second strategy ended with mean BP ≈144/82 mm Hg; 10
mm Hg higher systolic and 5 mm Hg higher diastolic BP translated to significant microvascular end points,
stroke, and other diabetes-related outcomes
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| Current situation: >70% of people with diabetes have BP above goal, ie, ≥130/80 mm/Hg (or take antihypertensives);
hypertension in diabetes associated with—2-fold increase in stroke or CVD risk; 5- to 6-fold increase
in risk for end-stage renal disease; increased risk for peripheral vascular disease, lower extremity
amputations, and retinopathy
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| American Diabetes Association (ADA) guidelines: patients with diabetes and hypertension should be
treated with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), using
whichever drug tolerated; if target BP <130/80 mm Hg not achieved, add diuretic; consider ACEI to reduce
cardiovascular (CV) risk in diabetics without hypertension but with other CV risk factors; comment—
ramipril, 10 mg, probably best evidence-based strategy
|
| Recommended BP goal: <130/80 mm Hg in all type 2 diabetics; evidence—<80 mm Hg based on Hypertension
Optimal Treatment (HOT) trial; showed small change in mm Hg yielded 51% difference in CV outcome;
<130 mm Hg systolic not evidence-based, although UKPDS found 10-mm Hg decline in systolic BP
and 5-mm Hg decline in diastolic improved all-cause mortality; ACCORD trial—intensive BP arm aims for
systolic <120 mm Hg and standard arm for <140 mm Hg (current evidence actually for <140/80 mm Hg);
seeks to determine if <120 mm Hg can be achieved and if lowering ≥13 mm Hg improves outcomes;
speaker’s ≈170 patients in intensive arm have mean systolic BPs of 100 mm Hg
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| Multiple agents: results of diabetic nephropathy trials “not even close to <130 mm Hg”; in ACCORD trial,
speaker using mean of 4.2 drugs to achieve mean systolic BP <100 mm Hg
|
 | Which drugs to use: Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment
of Hypertension (JNC 7)—unless diabetic has micro- or macroalbuminuria or chronic kidney disease
(CKD), no evidence for one drug over another, as long as BP reduced; ACEI or ARB recommended for
patients with diabetes and CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 or macroalbuminuria);
this differs from ADA guidelines; Heart Outcomes Prevention Evaluation (HOPE) trial—found all
outcomes benefited from ACEI; OnTarget trial—comparing ACEI to ARB and combination of ACEI and
ARB; ACE-intolerant subjects with cardiovascular disease (TRANSCEND) trial—investigating effectiveness of
ARB in ACEI-intolerant patients
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Lipids and Diabetes
| ADA recommends: in patients >40 yr of age without overt CVD, statin therapy to reduce low-density lipoprotein
(LDL) 30% to 40% below baseline (or LDL <100 mg/dL, regardless of baseline); option—high-
dose statin to reach LDL <70 mg/dL in very high-risk group (ie, established CVD and major risk factors,
including diabetes); risk (not necessarily baseline) determines improved outcome with statins
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| Trial findings: Heart Protection Study (HPS)—high-risk patients; statin therapy reduced LDL 30% to 40%
from baseline; diabetic subgroup reached LDL <70 mg/dL; Anglo-Scandinavian Cardiovascular Outcomes Trial
(ASCOT)—lipid-lowering arm included patients with hypertension and 3 other major risk factors, eg, microalbuminuria,
smoking, family history of CVD or hypertension, TIA, diabetes; initial LDL average ≈130
mg/dL; statin therapy reduced LDL 30% to 40%
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| Non–high-density lipoprotein (HDL) cholesterol: triglycerides and very low-density lipoprotein (VLDL)
cholesterol; often overlooked after LDL reaches goal; in diabetes, triglycerides elevated and HDL reduced;
ADA secondary recommendation to lower triglycerides to <150 mg/dL and raise HDL to >40 mg/dL, >50
mg/dL in women (lacks good evidence); ACCORD trial—in setting of good glucose control and LDL <100
mg/dL, investigating whether lowering triglycerides and raising HDL improves outcome (and whether fibrate
and statin better than statin alone)
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Multifactorial Approach
| ADA recommendations for aspirin therapy: 75 mg to 162 mg/day (European recommendation; 81 mg to
162 mg/day in United States); as secondary therapy in patients with CVD; as primary therapy in all diabetic
patients without overt CVD but at increased risk; speaker recommends baby aspirin as part of therapy in all
diabetics ≥30 yr of age
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| Steno type 2 diabetes trial: from Steno Diabetes Center, Copenhagen; only trial looking at global risk reduction
in type 2 diabetics; involved 160 patients (mean 55 yr of age; 75% men) with type 2 diabetes and microalbuminuria;
followed for mean of 7.8 yr; results in intensive management group—greater reduction in
HbA1C , systolic and diastolic BP, total and LDL cholesterol, and triglycerides; modifications led to significant
improvement in first evidence of primary CV end point; demonstrated that reducing multiple risk factors
yields outcome improvement; ACCORD trial—will provide evidence for what exact goals of improvement
should be
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| Evidence-based therapy: for high-risk patients; metformin; baby aspirin; statin (reduce LDL ≥30%-40%
from baseline or ≤100 mg/dL, perhaps <70 mg/dL); ACEI; evidence may be forthcoming for ARB and
ACEI-ARB combination
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Diagnosing Diabetes
| Postprandial glucose: abnormality may not be detected on fasting glucose; HbA1C not sensitive enough to diagnose
diabetes (eg, in range of 5.0%-5.6%); obtain 2-hr postprandial glucose level in patient with glucose of
104 mg/dL; easy way to do it—glucola contains ≈75 g of glucose; have fasting patient drink 2 12-oz cans of
Coca Cola (≈80 g of glucose) in office; 2 hr later, measure glucose level (>200 mg/dL diagnostic for diabetes)
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| Metabolic syndrome: goals of therapy uncertain; focus on diagnosing diabetes; ≈85% of diabetics have
metabolic syndrome, but only ≈15% of patients with metabolic syndrome frankly diabetic
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| Delaying onset of diabetes: be careful of measures taken in patients with metabolic syndrome; lifestyle
modification evidence-based; metformin evidence-based but its use not approved by Food and Drug Administration;
observational data—for delaying onset, perhaps by β-cell preservation, eg, with thiazolidinediones
or metformin; inform patient that drugs being used off-label and document in chart; risks
low, but speaker does not use drugs in his practice; cost-effectiveness unclear
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| Proteinuria: extremely unusual when risk factors well controlled; smoking major risk factor for proteinuria;
approach to reducing proteinuria—when patient at goal for lipids, BP, HbA1C , and not smoking; if on ACEI,
add ARB; if on ARB, add ACEI; rather than first using combined ACEI and ARB, use ACEI plus diuretic,
or ACEI plus calcium channel blocker (CCB), or ARB plus diuretic or ARB plus CCB; ARB-CCB combinations
available—olmesartan and amlodipine (Azor); valsartan and amlodipine (Exforge); main point—BP
reduction key to minimizing proteinuria
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| How much to lower LDL: no LDL level too low; questionable benefit—of additional lowering after reducing
LDL 30% to 40%; cost-effectiveness—avoid unnecessary expense for questionable benefit; ezetimibe (Zetia)
5 mg and 10 mg provide similar reduction in LDL (≈14.7% vs 15.9%); speaker splits tablets; trial
evidence—Treating to New Targets (TNT) found no more side effects, or liver function or muscle abnormalities
at LDL <40 mg/dL than at higher levels (but no evidence that <40 mg/dL better)
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Patient Compliance
| Patient BP still uncontrolled: after treatment with 3 drugs (including thiazide diuretic); schedule office visit—
ask patient to withhold taking medications until arrival and be prepared to stay all day; nurse takes BP at 2-
hr intervals; BP often nicely controlled by 4 Pm
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| Truly resistant patient: one who adheres to medication regimen but whose BP remains uncontrolled; treatment
strategies—ACEI-diuretic; ARB-CCB; add reserpine (0.05-0.10 mg at bedtime; add spironolactone 25
mg (patients often have reactive hyperaldosteronism); vasodilating β-blocker nebivolol; carvedilol (now generic);
chlorthalidone 12.5 mg (added to ACEI-diuretic) produces good response; avoid clonidine (side effects;
requires high dose); α-blockers useful as adjunctive therapy in patients with benign prostatic
hyperplasia
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Suggested Reading
Basile JN et al: Increased calcium intake doe.not suppress circulating 1,25-dihydroxyvitamin D in normocalcemic
patients with sarcoidosis. J Clin Invest 91:1396, 1993; Kharlip J et al: Screening for silent coronary
heart disease in type 2 diabetes: clinical application of American Diabetes Association guidelines.
Diabetes Care 29:692, 2006; Ogrin C et al: Heart protection study: a focus on diabetic patients. Curr Diab Rep
4:185, 2004; Plankey MW et al: Stability of basal metabolic rate over selected days of the menstrual cycle.
Obes Res 3:301, 1995; Poulter NR et al: Role of blood pressure and other variables in the differential cardiovascular
event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm
(ASCOT-BPLA). Lancet 366:907, 2005; Riddle MC: The Treat-to-Target Trial and related studies. Endocr
Pract 12 Suppl 1:71, 2006; Sever PS et al: Reduction in cardiovascular events with atorvastatin in 2,532 patients
with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial--lipid-lowering arm (ASCOT-
LLA). Diabetes Care 28:1151, 2005; Sleight P: The HOPE Study (Heart Outcomes Prevention Evaluation). J
Renin Angiotensin Aldosterone Syst 1:18, 2000; Tseng KH: Reduction in cardiovascular events with atorvastatin
in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm
(ASCOT-LLA): response to Server et al. Diabetes Care 28:2595; author reply 2595, 2005.
Educational Objectives
| The goal of this program is to improve management of cardiovascular disease (CVD) in patients with diabetes.
After hearing and assimilating this program, the clinician will be better able to:
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| Manage hyperglycemia in patients with diabetes and CVD.
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| Control blood pressure in patients with diabetes and CVD.
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| Treat lipid abnormalities in patients with diabetes and CVD.
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| Diagnose diabetes in patients whose fasting blood glucose is within normal range.
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| Adopt a multifactorial approach in managing patients with diabetes and CVD.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning
committee members to disclose relevant financial relationships within the past 12 months that might create any
personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes
quality in health care and not a proprietary business or commercial interest. For this program, the following
has been disclosed: grant/research support—National Heart and Blood Institute (ACCORD); Boehringer
Ingelheim (ONTARGET); Novartis (ACCOMPLISH); Speakers’ Bureaus—Abbott Laboratories; AstraZeneca;
Boehringer Ingelheim; Forest; GSK; Merck; Novartis; Pfizer; Daiischi-Sankyo
Acknowledgements
Dr. Basile was recorded at Primary Care Update, sponsored by the Interstate Postgraduate Medical Association
of North America, November 4-7, 2007, in Savannah, GA. The Audio-Digest Foundation thanks Dr. Basile
and the sponsor for their cooperation in the production of this program.
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