Matters PRACTICE PRACTICE Matters

• About 1 in 8 patients seen in the VHA system has

diabetes.1

• In 1997, US health care costs for people with diabetes exceeded $77 billion dollars (8% of all health

care spending).2

• Veterans with diabetes account for more than

75,000 VHA hospital admissions and 3.8 million

outpatient clinic visits annually and for more than

25% of pharmacy expenditures.

• Cardiovascular disease (e.g., heart attacks, strokes,

and congestive heart failure) is the leading cause of

complications and death in people with diabetes,

and middle-aged diabetic patients have 2-4 times

higher risk of cardiovascular events and death

than age-sex matched controls.3-4

• Optimal risk factor management can substantially

reduce cardiovascular events and death in people

with diabetes.

• Strict attention to blood pressure control is the

single most important medical intervention to

prevent complications and premature death in the

typical patient with type 2 diabetes.

DIABETES

CARE

PRIORITIES:

PREVENTING

CARDIOVASCULAR

COMPLICATIONS

A publication of the Management Decision and Research Center

A program within the Department of Veterans Affairs Health Services Research and Development Service

MAY 2000 VOL. 5 ISSUE 1
2 PRACTICE Matters

BACKGROUND:

Providing optimal care to patients with diabetescan be a challenge. In addition to the long list

of recommended health maintenance interventions

and the ongoing task of managing blood glucose

levels, patients with diabetes often have many

symptomatic problems that must be addressed

during office visits. Although the average veteran

with diabetes has more than 10 office visits a year,

fewer than half of these are with their primary care

physician, allowing just 3-5 brief office visits to

manage this complex, multi-system disease. Perhaps due to the complexities of blood sugar control,

interventions to prevent cardiovascular complications are sometimes overlooked, although these

complications pose the greatest single threat to the

health of people with diabetes.3-4 As we strive to

meet all of the diabetes related guidelines and

performance measures,5 we should remain aware

that control of hypertension and hyperlipidemia are

those interventions which are most likely to impact

morbidity and mortality in the typical patient with

type 2 diabetes.

TREATMENT GOALS AND

THERAPIES:

Treatment goals are chiefly directed at preventing

strokes and heart attacks, but some treatments are

also directed at decreasing risk of peripheral vascular disease (and therefore amputations), congestive

heart failure, end-stage renal disease, and visual

impairment.

Blood Pressure Control

Most veterans with diabetes also have hyper–

tension and for most of these patients,

controlling their blood pressure is the single most

important medical intervention in improving their

health and prolonging their lives. Blood pressure

control has 1) twice the absolute benefit in diabetic

patients than it does in non-diabetic patients6

 and 2)

dramatically improves both cardiovascular and

microvascular (eye and kidney) outcomes.7-8 How

tightly must blood pressure be controlled? No one

knows for sure, but for diabetic patients 140/90 is

not a sufficient goal. The ADA recommends 130/

85 as the best target. Using a strictly evidencebased approach, updated VA guidelines recommend

140/85 as a minimum goal, but acknowledge that

there may be benefits to achieving even tighter

blood pressure control. 6-8

Patients with hypertension often receive suboptimal treatment for their blood pressure. Even in a

randomized controlled trial, it may be extremely

difficult to achieve tight blood pressure control.

Although the Hypertension Optimal Treatment

(HOT) trial strove to get the diastolic blood pressure in patients with hypertension decreased to <80

mmHg, the mean blood pressure was still 82-83

mmHg in the intensive treatment group.7 Studies

suggest that it is even more difficult to achieve

intensive control of systolic blood pressure. No

large randomized controlled trial of patients with

diabetes and hypertension has achieved a mean

blood pressure below 135 systolic, even with the use

of 3-4 anti-hypertensive agents. In contrast, using

3-4 anti-hypertensive medications is generally

successful in achieving blood pressures of 140/90 or

better.7 Therefore, common recommendations for

tight control (such as blood pressure <130/85) may

best be used as ideal goals that clinicians should try

to achieve, within reason. Considering achievement

of these strict goals as a quality or performance

standard, without allowing for the number of blood

pressure medications that the patient has been

prescribed, is probably not appropriate.

Anti-Hypertensive Agents

• Angiotensin converting enzyme (ACE) inhibitors:

ACE inhibitors have generally been considered

the preferred first choice agent in most patients

with diabetes because of possible advantages over

other anti-hypertensive medications in preventing renal insufficiency.3

 However . . .

• Beta-Blockers: The recently completed United

Kingdom Prospective Diabetes Study (UKPDS),

a large randomized trial, found no overall benefit

of using an ACE inhibitor versus a beta-blocker

as a first choice agent in treatment of hypertension. Indeed, there was a non-statistically significant trend for patients treated with beta-blockers

having better overall outcomes.10
PRACTICE Matters 3

• Calcium channel blockers: In contrast, two studies

found that calcium channel blockers may not be

ideal as a first line choice for treatment of hypertension for those with diabetes. These two

studies suggest that when used as a first choice

agent, calcium channel blockers are less effective

than other agents in preventing important

cardiovascular outcomes.11-12 This has led some

to recommend that calcium channel blockers,

given their greater expense and possible lower

efficacy, be reserved as a third or fourth choice

agent.

In the past there were some concerns about using

beta-blockers and thiazide diuretics for treatment of

hypertension in diabetic patients. However, recent

evidence suggests that these medications are effective, safe and relatively inexpensive treatments for

controlling blood pressure and preventing adverse

cardiovascular events, especially when used in low

or moderate doses.6, 10, 13 Often other conditions,

such as angina or benign prostatic hypertrophy, will

guide the choice of anti-hypertensive agent so that

two conditions can be treated with a single medication. In general, the medication used is less important than the commitment to use up to 3-4 antihypertensive agents, as necessary, in an attempt to

achieve strict blood pressure control.6-8

Treatment of High Cholesterol

Hyperlipidemia is common in patients withtype 2 diabetes. While any pattern of hyperlipidemia can be seen in diabetes, common findings

include elevations in serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol,

and triglycerides, often associated with low levels of

high-density lipoprotein (HDL) cholesterol.4

 Each

of these has been found to be an independent

predictor of coronary artery disease in observational

studies, but only treatment of elevated LDL cholesterol with HMG-CoA reductase inhibitors

(“statins”) has been shown to reduce mortality in

randomized controlled trials. Treating patients who

have high LDL cholesterol levels with statins

reduces cardiovascular risk.3-4 Given the high risk

of cardiovascular complications in type 2 diabetes

there is general agreement that LDL cholesterol

should be treated aggressively.3-5, 9 Yet, because

there are no studies of primary prevention specifically in patients with diabetes, the optimal treatment goal for diabetic patients is not known and is

therefore somewhat controversial.

The National Cholesterol Education Program

advocates that LDL cholesterol should be treated to

<100 mg/dl in all diabetic patients, since their risk

of cardiovascular complications are similar to those

with known coronary artery disease. However,

except for patients with post coronary-artery bypass

surgery, there are no studies indicating that there is

a reduction in cardiovascular events by decreasing

LDL cholesterol from 130 mg/dl to 100 mg/dl,

although several trials are in progress.9

 The VA

guidelines suggest that lipids should be measured

annually for veterans with diabetes, with an LDL

cholesterol target level of less than 130 and a

triglyceride target level of 400 mg/dl; individual

clinicians and patients may wish to try for even

tighter control.5

A recent VA study demonstrated that treatment

with gemfibrozil in patients with low HDL cholesterol levels (< 45 mg/dl) but normal LDL cholesterol levels is effective in reducing cardiovascular

events, but not total mortality.14 The absolute

benefit of treating these patients is smaller than

treating elevated LDL cholesterol, and because the

evidence is recent, there are no current recommendations from any major guideline group suggesting

that patients with isolated low HDL cholesterol

levels should receive drug therapy.

Daily Aspirin

nately

Daily aspirin use is a simple, effective and

inexpensive medical intervention. Unfortu-

, it is often forgotten among the complexities

of diabetes care. Subgroup analyses of randomized

controlled trials suggests that a low daily dose of

aspirin may lower cardiovascular risk twice as much

in patients with diabetes as it does in those without

diabetes.15-16 Given the high risk of cardiovascular

disease in diabetes, unless aspirin therapy is contraindicated due to drug intolerance or bleeding

risk, this simple inexpensive intervention is an

absolute must.

Continued on page 5
4 PRACTICE Matters

EXPERT OPINION

There has been an explosion of information onthe value of lowering blood pressure in diabetic individuals with hypertension. ACE-inhibitor

therapy is beneficial in diabetic subjects with high

cardiovascular risk. Lowering of LDL cholesterol

by statin therapy is clearly beneficial in diabetes.

The VA-HIT study provides strong support for

therapy with gemfibrozil for diabetic dyslipidemia.

Aspirin reduced cardiovascular risk by 15% over

that provided by antihypertensive therapy in the

HOPE Trial. C-reactive protein (CRP) is a new

cardiovascular risk factor, and aspirin therapy

reduced cardiovascular risk in CRP positive men in

the U.S. Physicians’ Health Study.

There are other new cardiovascular risk markers.

Fibrinolysis is activated by tissue plasminogen

activator (tPA) and is inhibited by plasminogen

activator inhibitor-1 (PAI-1). Studies have shown

elevated PAI-1 levels in type 2 diabetes, and PAI-1

is a predictor of future cardiovascular events. PAI-1

levels in diabetes are lowered by metformin and

troglitazone. Large scale trials are needed.

What about intensive blood glucose management? The Department of Veterans Affairs, the

National Heart, Lung, and Blood Institute, and

NIH, are sponsoring long-term trials to address this

important issue. Presently, it is prudent to take a

multifactorial approach to prevention of cardiovascular disease in diabetes which includes aggressive

antihypertensive and lipid-treatment strategies as

well as low dose aspirin as top priorities. Glycemic

regulation will slow progression of microvascular

disease, and may eventually be shown to be beneficial in preventing progression of macrovascular

disease.

John A. Colwell, MD, PhD, MACP

Professor of Medicine

Director, Diabetes Center

Medical University of South Carolina

Charleston, SC

RECOMMENDATIONS

• Up to 3-4 anti-hypertensive agents should be

used, as needed, in an attempt to achieve strict

blood pressure control in patients with diabetes

(<140/85 mmHg at minimum and even lower

blood pressures may be desirable).

• Choice of specific anti-hypertensive agent is less

important than level of blood pressure achieved.

However, due to higher costs, and possibly lower

effectiveness in preventing cardiovascular complications, calcium channel blockers should usually

be reserved as a third or fourth choice agent.

• LDL-cholesterol should be treated with statins as

the first choice agent, to achieve levels of at least

<130 mg/dl, and lower levels may be beneficial.

• Unless aspirin use is contraindicated, patients

with type 2 diabetes should take a low dose of

aspirin each day.

• Smoking cessation counseling is a high priority

for all patients who smoke, and this is particularly

true for those with diabetes.

VA Practice Matters is a publication for VA decision makers and practitioners that summarizes the results of important research to help

inform policy and to promote the application

of research for improved health care delivery

and decision making within VA. It is produced

by HSR&D’s Information Dissemination Program in collaboration with topic experts in the

field. For more information or to provide us

with your suggestions, please contact:

Information Dissemination Program

Management Decision and Research Center (152-M)

150 South Huntington Avenue

Boston, MA 02130

Phone: (617) 278-4433

FAX: (617) 278-4438

Email: geraldine.mcglynn@med.va.gov

VA Practice Matters is also available on the VA R&D

internet at www.va.gov/resdev/prt, and on our Fax on

Demand system by dialling (617) 278-4492 and For VA Diabetes Practice Guidelines visit the web following the voice prompts.

at http://www.va.gov/health/diabetes/default.htm

PRACTICE Matters 4
PRACTICE Matters 5

TREATMENT GOALS AND THERAPIES

Continued from page 3

Smoking cessation counseling

As a cost-effective behavioral intervention,counseling and support for smoking cessation

is a priority for all patients who smoke. Given the

high overall cardiovascular risk associated with type

2 diabetes, 3, 17 this is especially crucial for diabetes

care.

Diabetes care can be complex and difficult.

ttempts to improve glycemic control, foot care

nd early identification and treatment of microvasular complications are other very important

nterventions, especially for those with early onset

iabetes and those with poor glycemic control. 18

owever, we must not allow these other aspects of

are to distract us from the major killer of people

ith diabetes — cardiovascular disease. The above

reatment goals, directed at prevention of cardiovasular complications, may garner more benefit than

ll other aspects of diabetes care combined.

A

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d

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c

a

Evidence Chart for Diabetes Interventions

Major Blood Pressure Trials

Study Participants Intervention Outcome

SHEP (JAMA N=583 pts with Chlorthalidone plus atenolol or reserpine 34% (95% CI, 6%-54%) risk reduction

1996; 276:1886-92) T2DM and as needed (RR) in major cardiovascular events

isolated systolic

HTN

HOT (Lancet N=1501 pts with Randomized to target DBP of ≤90, ≤85, For DBP target of ≤90 vs ≤80; RR major

1998; 351:1755-62) T2DM and HTN or ≤80 using stepped protocol CVD events = 2.1 (1.2 – 3.4) RR CV

mortality = 3.0 (1.3 – 7.1) RR total

mortality = 1.8 (0.98– 3.2)

UKPDS (BMJ N=1148 pts with Randomized to “tight” (target BP <150/ For tight control vs. less tight control:

1998; 317:703-13) T2DM and HTN 85) vs “less tight” (target BP <180/105) RR any DM end pt = 0.76 (0.62-0.92) RR

control using stepped protocol total mortality = 0.82 (0.63-1.08) RR

microvascular disease = 0.63 (0.44-0.89)

ABCD (N Engl J N=470 pts with Comparison of enalapril and nisoldipine RR of MI in nisoldipine group = 9.5 (2.3-

Med 1998; T2DM and HTN for treatment of HTN for 5 years 21.4)

338:645-52)

FACET (Diabetes N=300 pts with Comparison of fosinopril and amlodipine For fosinopril vs. amlodipine: RR major

Care 1998; 21:597- T2DM and HTN for treatment of HTN for 2.5-3.5 years. cardiovascular events = 0.49 (0.26-0.95)

603)

Major Asprin Trials

Study Participants Intervention Outcome

Antiplatelets Collabora- Meta-analysis of RCTs: N=1300 ASA vs. placebo Odds reduction of major CVD events =

tion (BMJ 1994; 308:81- pts with T2DM 25% (non-significant trend)

106)

ETDRS (JAMA 1992; N=3711 pts with type 1 and 2 DM ASA vs. placebo RR MI = 0.83 (99% CI = 0.66-1.04) No

268: 1292-9) harmful effects; note use of 99% rather

than 95% CI.
Diabetes Care Priorities

REFERENCES:

1. Pogach LM, Hawley G, Weinstock R, et al. Diabetes

prevalence and hospital and pharmacy use in the Veterans

Health Administration (1994). Diabetes Care 1998;

21(3):368-373.

2. American Diabetes Association (ADA). Economic consequences of diabetes mellitus in the U.S. in 1997. Diabetes

Care 1998; 21(2):296-309.

3. Vijan S, Stevens DL, Herman WH, Funnell MM,

Standiford CJ. Screening, prevention, counseling and

treatment for the complications of type II diabetes mellitus:

putting evidence into practice. Journal of General Internal

Medicine 1997; 12(9):567-580.

4. Haffner SM. Diabetes, hyperlipidemia, and coronary

artery disease. American Journal of Cardiology 1999;

83(9B):17F-21F.

5. The Diabetes Mellitus Working Group. Veterans Health

Administration Clinical Guideline for Management of Diabetes

Mellitus. Version 1.0 ed. Washington, DC: 1997.

6. Curb JD, Pressel SL, Cutler JA, et al. Effect of diureticbased anti-hypertensive treatment on cardiovascular disease

risk in older diabetic patients with isolated systolic hypertension. JAMA 1996; 276(23):1886-1892.

7. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of

intensive blood-pressure lowering and low-dose aspirin in

patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial.

Lancet 1998; 351(9118):1755-62.

8. UK Prospective Diabetes Study Group. Tight blood

pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ

1998; 317:703-713.

9. American Diabetes Association. Clinical Practice Recommendations 1999. Diabetes Care 1999; 22(Suppl 1):S1-S114.

10. UK Prospective Diabetes Study Group. Efficacy of

atenolol and captopril in reducing risk of macrovascular and

microvascular complications in type 2 diabetes: UKPDS 39.

BMJ 1998; 317(7160):713-720.

11. Extacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford

N, Schrier RW. The effect of nisoldipine as compared with

enalapril on cardiovascular outcomes in patients with noninsulin-dependent diabetes and hypertension. New England

Journal of Medicine 1998; 338(10):645-52.

12. Tatti P, Pahor M, Byington RP, DiMauro P, Guarisco R,

Strollo G., Strollo F. Outcome results of the fosinopril

versus amlodipine cardiovascular events randomized trial

(FACET) in patients with hypertension and NIDDM.

Diabetes Care 1998; 21(4):597-603.

13. Goldberg AL, Dunlay MC, Sweet CS. Safety and tolerability of losartan potassium, an angiotensin II receptor

antagonist, compared with hydrochlorothiazide, atenolol,

felodipine ER, and angiotensin-converting enzyme

inhibitors for the treatment of systemic hypertension.

American Journal of Cardiology 1995; 75(12):793-795.

14. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for

the secondary prevention of coronary heart disease in men

with low levels of high density lipoprotein cholesterol. New

England Journal of Medicine 1999; 341(6):410-418.

15. Steering Committee of the Physicians’ Health Study

Research Group. Final report on the aspirin component of

the ongoing Physicians’ Health Study. New England Journal

of Medicine 1989; 321(3):129-135.

16. Antiplatelet Trialists’ Collaboration. Collaborative

overview of randomized trials of antiplatelet therapy. I:

prevention of death, myocardial infarction, and stroke by

prolonged antiplatelet therapy in various categories of

patients. BMJ 1994; 308(6921):81-106.

17. Suarez L, Barrett-Conner E. Interaction between cigarette

smoking and diabetes mellitus in the prediction of death

attributed to cardiovascular disease. American Journal of

Epidemiology 1984; 120(5):670-675.

18. Vijan S, Hofer TP, and Hayward RA. Estimated benefits of

glycemic control in microvascular complications in type 2

diabetes. Annals of Internal Medicine 1997; 127(9):788-795.

PRACTICE Matters

Acknowledgements

This issue of VA Practice Matters on Diabetes Care Priorities: Preventing Cardiovascular Complications,

was written by Rodney A. Hayward, MD, Director of HSR&D Center for Practice Management and

Outcomes Research, VAMC Ann Arbor, MI and co-chair of the Quality Enhancement Research Initiative Diabetes Mellitus Group. Expert Opinion column was contributed by John A. Colwell, MD, PhD,

MACP, Medical University of South Carolina, Charleston, SC. Other contributors/reviewers were: Carlos

Abraira, MD, Co-Chairman of VA Cooperative Study on Glycemic Control and Complications in type 2

Diabetes; John G. Demakis, MD, Director, VA HSR&D; David Edelman, MD, Center for Health Services Research in Primary Care, VAMC Durham, NC; Karen Flynn, DDS, Manager, Technology Assessment Program; Shirley Meehan, PhD, Deputy Director, VA HSR&D; Thakor G. Patel, MD, Acute

Care Strategic Health Care Group; and Leonard Pogach, MD Chief of Endocrinology, VA New Jersey

Health Care System. The issue was edited by Geraldine McGlynn, MEd, Manager, Information Dissemination Program, Management Decision and Research Center.