Comprehensive cardiovascular risk reduction in diabetes mellitus

Multiple risk factor intervention

Although in the past the treatment of diabetes has focused on glycemic control, there is emerging evidence that therapy addressing the concurrent CV risk factors that frequently coexist in the diabetic patient is essential to provide comprehensive CV risk reduction. This approach has

o in

BP 1SS/9S mm Hg

BP 1SS/9S mm Hg Age SS years

BP 165/95 mm Hg

Age 56 years LDL-C 155 mg/dL

BP 165/95 mm Hg

Age 56 years LDL-C 155 mg/dL Smoker

BP 1SS/9S mm Hg

BP 1SS/9S mm Hg Age SS years

BP 165/95 mm Hg

Age 56 years LDL-C 155 mg/dL

BP 165/95 mm Hg

Age 56 years LDL-C 155 mg/dL Smoker

Fig. 6. Multiple risk factors: additive risk. The total severity of multiple low-level risks often exceeds that of a single severely elevated risk. (From Grundy SM, Pasternak R, Greenland P, et al. AHA/ACC scientific statement: Assessment of cardiovascular risk by use of multiple-risk-facfor assessment equations: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology. J Am Coll Cardiol 1999;34:1348-59; with permission.)

been strengthened by results from a number of randomized, controlled trials of intensive glycemic control that have failed to show a definite independent link between glycemic control and CV risk reduction. Because the risk of CV events is additive for various risk factors that are frequently present in diabetic patients (Fig. 6), treatment should address all of the CV risk factors in diabetic patients and should not be confined to glycemic control.

Interventions addressing individual CV risk factors in diabetic patients can result in a 15%

to 30% reduction in CV risk. The current stringent treatment targets for glycemic control, blood pressure, and lipid levels have been established as the result of these studies (Table 3).

Although addressing individual risk factors in the diabetic patient is a logical extension of the findings from currently available evidence, this approach has limited potential in achieving the maximal attainable benefit from reduction of CV risk. A more appropriate approach would be to address multiple risk factors concurrently with the hope of obtaining a comprehensive reduction in

Table 3

Goals for risk factor management in diabetes

Table 3

Goals for risk factor management in diabetes

Risk factor

Goal of therapy

Reference

Cigarette smoking

Complete cessation

47

Blood pressure

<130/80 mm Hg

46,47

(with proteinuria)

<125/75

46,47

LDL cholesterol

<100 mg/dL

47,52

<70 mg/dL in high riska

Triglycerides 200-499 mg/dL

Non-HDL cholesterol < 130 mg/dL

52

HDL cholesterol <40 mg/dL

Raise HDL

52

Prothrombotic state

Low-dose aspirin therapy

47

(patients with congestive heart

disease and other high-risk patients)

Glucose

Hemoglobin A1C < 7%

47

Overweight and obesity

Lose 10% of body weight in 1 year

28

(body mass index >25 kg/m2)

Physical inactivity

Exercise prescription dependent

47

on patient status

Adverse nutrition

Diets low in saturated fat and lower

47,53,28,52,51

glycemic index (when necessary

with caloric concentration)

risk. Although such a strategy would require considerable effort on the part of the physician and the patient, available data suggest that the approach of comprehensive risk reduction is beneficial in the management of the diabetic patient.

The Steno-2 Trial prospectively examined the benefits of multifactorial intervention in reducing CV disease in 160 patients with microalbuminuria [42]. One hundred sixty patients with type 2 diabetes and microalbuminuria were randomly assigned to receive either conventional care or intensive treatment. Eighty patients were randomly assigned to receive conventional treatment for multiple risk factors from their general practitioner, following the 1998 recommendations of the Danish Medical Association that were revised in 2000. The remaining 80 patients were randomly assigned to undergo intensive multifactorial intervention with strict treatment goals (Table 4) to be achieved through behavior modification and a stepwise introduction of pharmacologic therapy overseen by a project team consisting of a physician, nurse, and dietician. Therapy was intended to maintain glycosylated hemoglobin values below 6.5%, blood pressure below 130/80 mm Hg, cholesterol levels below 175 mg/dL, and triglyceride levels below 150 mg/dL. Intensive therapy involved clinic visits with the multidisciplinary diabetes team every 3 months. During these visits, patients received advice regarding lifestyle adjustment (eg, diet, exercise, smoking cessation courses), and medications were adjusted to achieve treatment targets for hypertension, dyslipidemia, microalbuminuria, and hyperglyce-mia along with aspirin for secondary prevention of CV disease. Dietary intervention was aimed at a total fat intake of less than 30% of daily energy intake and an intake of saturated fatty acids representing less than 10% of the daily energy intake. Light to moderate exercise for at least 30 minutes three to five times a week was recommended, and all smoking patients and their spouses were invited to participate in smoking-cessation courses. All patients were prescribed an ACE inhibitor in a dose equivalent to 50 mg of captopril two times/d or, if the ACE-inhibitor was contraindicated, an ARB in a dose equivalent to 50 mg of losartan two times/d, irrespective of blood pressure. After 2000, these medications were also routinely prescribed for patients in the conventional-therapy group (Table 5).

The primary endpoint of this open, parallel trial was a composite of death from CV causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation. After a mean follow-up period of 7.8 years, the declines in glycosylated hemoglobin values, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels, and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group. There was also significant reduction of CV disease, nephropathy, retinopathy, and autonomic neuropathy. The groups did not differ significantly in the number of patients who reported at least one minor episode of

Table 4

Treatment goals for the conventional therapy group and the intensive therapy group

Table 4

Treatment goals for the conventional therapy group and the intensive therapy group

Variable

Conventional therapy 1993-1999 2000-2001

Intensive therapy 1993-1999 2000-2001

Systolic blood pressure (mm Hg)

<160

<135

<140

<130

Diastolic blood pressure (mm Hg)

<95

<85

<85

<80

Glycosylated hemoglobin (%)

<7.5

<6.5

<6.5

<6.5

Fasting serum total cholesterol (mg/dL)a

<250

<190

<190

<175

Fasting serum triglycerides (mg/dL)b

<195

<180

<150

<150

Treatment with ACE-I irrespective of blood pressure

No

Yes

Yes

Yes

Aspirin therapy

For patients with known ischemia

Yes

Yes

Yes

Yes

For patients with peripheral vascular disease

No

No

Yes

Yes

For patients without coronary heart disease or

No

No

No

Yes

peripheral vascular disease a To convert values for cholesterol to millimoles per liter, multiply by 0.02586. b To convert values for triglycerides to millimoles per liter, multiply by 0.01129.

Data from Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93. Copyright © 2003 Massachusetts Medical Society.

peripheral vascular disease a To convert values for cholesterol to millimoles per liter, multiply by 0.02586. b To convert values for triglycerides to millimoles per liter, multiply by 0.01129.

Data from Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93. Copyright © 2003 Massachusetts Medical Society.

Table 5

Treatment in patients with type 2 diabetes and microalbuminuria in Steno-2

Treatment in patients with type 2 diabetes and microalbuminuria in Steno-2

Table 5

Start of study period

End of study period

Conventional

Intensive

Conventional

Intensive

therapy

therapy

therapy

therapy

Variable

(N = 80)

(N = 80)

(N = 63)

(N = 67)

P value

Glucose-lowering treatment

Diet alone (no. of patients)

21

28

4

1

0.15

Oral hypoglycemic agent

48

47

38

50

0.14

(no. of patients)

Insulin (no. of patients)

11

5

34

38

0.91

Both agents (no. of patients)

1

0

13

22

0.14

Insulin dose (IU)

0.91

Median

30

42

64

62

Range

14-142

10-52

12-360

12-260

Antihypertensive treatment

(no. of patients)

ACE-I

16

15

32

53

0.002

Angiotensin II-receptor antagonist

0

0

12

31

0.002

Both

0

0

0

19

<0.001

Diuretic

17

22

39

38

0.42

Calcium-channel blocker

5

11

18

24

0.45

Beta-blocker

8

1

13

10

0.35

Other

1

1

4

3

0.61

Any

33

33

52

66

0.009

Lipid-lowering treatment

(no. of patients)

Statin

0

2

14

57

<0.001

Fibrate

1

1

3

1

0.27

Both

0

0

0

1

1.00

Aspirin (no. of patients)

11

10

35

58

<0.001

Vitamin-mineral supplement

0

0

0

42

<0.001

(no. of patients)

Hormone replacement

3

2

2

1

0.61

(no. of patients)

P values are for the difference between the groups at the end of the study.

Data from Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93. Copyright © 2003 Massachusetts Medical Society.

P values are for the difference between the groups at the end of the study.

Data from Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93. Copyright © 2003 Massachusetts Medical Society.

hypoglycemia at the 4- or 8-year examination. The reduction in macrovascular events was 53% in the intensive-treatment group. The benefits of intensive treatment were evident at 1 year in the intensive-treatment group. This study indicates that five patients need to be treated intensively over 7 years to prevent one event (Figs. 7, 8). The treatment targets in the intensively treated group were rather liberal compared with current guidelines (see Table 3). It is conceivable that the reduction of events in the intensively treated group would have been more substantial if treatment targets had been set to current guidelines. Although the results of this study are exciting, more data are needed. Large, randomized, controlled trials in a wide variety of diabetic patients with various risk stratifications are needed to verify and reproduce similar results. Additionally trials need to be conducted using the newer pharmacologic agents, specially the TZDs, which were not used in the Steno-2 trial. Any such trial should also make a concerted effort to attain current recommended treatment goals regarding glycemic control, lipid levels, and blood pressure control. Although data from future trials might be useful in building the evidence base, feasibility could be an issue because current guidelines might make less intensive treatment ethically questionable. The results of ongoing trials such as Action Control CV Risk in Diabetes and Bypass Angioplasty Revascularization Investigation conducted by the National Institutes of Health should provide with useful data in this regard, however.

Fig. 7. Kaplan-Meier estimates of the composite endpoint of death from CV causes, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, nonfatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease in the conventional therapy group and the intensive therapy group. (From Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93; with permission. Copyright © 2003 Massachusetts Medical Society.)

Fig. 7. Kaplan-Meier estimates of the composite endpoint of death from CV causes, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, nonfatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease in the conventional therapy group and the intensive therapy group. (From Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93; with permission. Copyright © 2003 Massachusetts Medical Society.)

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