Clinical Contributions

Evidence-Based Clinical Vignettes from the Care Management Institute:
Diabetes Mellitus
By Jill Bowman, BS; R James Dudl, MD

Introduction

Patients with diabetes mellitus comprise 7% of Kaiser Permanente (KP) nationwide membership.^1:p21 However, because complications accompany the disease, patients with diabetes account for a disproportionately increased share of medical expenditures. In the KP Northern California Region, patients with diabetes use 2.4 times more medical resources than patients without diabetes.² Cardiovascular complications of diabetes are particularly excessive and devastating. In the KP Northwest Region, macrovascular complications account for 62% to 89% of the cost associated with inpatient treatment of diabetes-related complications.³ KP members with diabetes are admitted to the hospital for myocardial infarction at a rate of 18.3 admissions per 1000 members^1:p21 compared with a rate of 6.6 admissions per 1000 members without diabetes.^4:p2 This difference between members with diabetes and members without diabetes has increased in the past two years.^1:p21

Historically, treatment of diabetes emphasized control of blood glucose level. However, recent studies have shown that glucose control alone does not have a statistically significant effect on preventing cardiovascular disease (CVD), although the trend for successful prevention of CVD is in a positive direction.^5,6

This article, part of a series highlighting key aspects of guidelines and care programs from the KP Care Management Institute (CMI), is an overview of part of the recently completed Evidence-based Guidelines and Technical Review for the Management of Diabetes Mellitus.⁷ Members of the committee that assembled these guidelines are listed in Table 1. One section of the guidelines is devoted to CVD prevention and discusses the evidence supporting seven interventions proven to decrease macrovascular complications of diabetes. The clinical practice guidelines are available through the CMI product line at 510-271-6426, CMIproducts@kp.org, or http://pkc.kp.org.

Case Study: Dan's Devastating News

During what he thought was to be a routine office visit, Dan learned he had diabetes. Dan was instantly devastated--after all, he was only 55 years old--but then recalled that his father was diagnosed with diabetes at age 52 years. His father's diagnosis was quickly followed by onset of hypertension, a heart attack, congestive heart failure, and, finally, death from a stroke (at age 58 years). Equally discomforting to Dan was the fact that three of his uncles had diabetes and that, despite good control of their blood glucose levels, all three died of similar complications before age 60 years.

Dan's doctor told him that his blood sugar was 300 mg/dL (16.65 mmol/L) and that he was overweight at 240 lb (108 kg). Dan also learned his blood pressure was elevated at 150/90 mmHg, his LDL cholesterol level was high at 160 mg/dL (4.14 mmol/L), and his HDL cholesterol level was low at 35 mg/dL (0.91 mmol/L). In addition, although he tried many times to quit, Dan still smoked. Dan's doctor told him that he had a high risk of having a heart attack, stroke, cardiac surgery, or hospitalization in the next ten years.

The doctor said other things, but Dan couldn't remember anything else. A feeling of hopelessness overwhelmed him. He felt that he would inevitably follow in his father's footsteps. What Dan did not yet know was that if he used an appropriate diet, exercise, and several commonly used medications, he could take control of his diabetes and would probably proceed down a markedly altered path from that of his father.

Calculating Dan's Risk for CVD Events: "High Risk" as Defined Using The Framingham and HOPE Data
Which patients with diabetes have the highest risk for heart disease? The CMI diabetes guidelines recognize that not every type of treatment for CVD reduction can be given to all patients with diabetes; treatment risks, side effects, compliance with medical follow-up and medication regimen, and resource limitations preclude such uniform treatment. However, assessing CVD risk in each patient with diabetes and targeting for treatment those patients at "high risk" (these patients stand to benefit the most from preventive therapy) constitutes a logical, practical approach to population-based diabetes care.

The Southern California Permanente Medical Group guidelines use the classic Framingham formula to calculate risk of a CVD event (eg, heart attack, stroke, or hospitalization).⁸ At the time and place of the office visit, most KP clinicians already have the data needed to determine this risk (Table 2). These data are used in a formula to calculate risk (expressed as a percentage) of a CVD event occurring during the next ten years. Different methods are available for accessing tools to calculate this risk. One such method is to use the Intranet at the Web site http://kpnet.kp.org/california/scpmg/CPG/images/Dyslipidemia.pdf, where the formula to calculate this risk is available (Figure 1).⁹

The CMI diabetes guidelines define "high cardiovascular risk" as >20% ten-year risk of having a CVD event.^7:p53 Alternatively, high risk may be defined by the criteria used in the HOPE study:¹⁰ patients with known CVD or patients with diabetes aged 55 years who have one of the following additional CVD risk factors: hypertension; total cholesterol level of >200 mg/dL (>5.17 mmol/L) or LDL cholesterol >130 mg/dL (3.36 mmol/L); HDL cholesterol level <35 mg/dL (<0.91 mmol/L); or being a smoker.

To calculate Dan's ten-year risk for CVD by using the table shown in Figure 1, first scan the top rows of the table (choose the table for males) to find Dan's age (55 years), LDL cholesterol level (160 mg/dL [4.14 mmol/L]), and HDL cholesterol level (35 mgdL [0.91 mmol/L]). Next, using the risk factors in the left-hand column, find the cell that reflects a hypertensive smoker with diabetes; this cell is found at the bottom of that HDL column. The table shows that Dan's risk of having a CVD event in the next ten years is 36%. Dan would have reason to be depressed about such news if it were not for the powerful treatments is available that may literally make a life-or-death difference to him.

Preventing CVD is as Simple as AABBCC'S

A convenient way to recall seven types of CVD prevention treatment is to use a memory cue, the AABBCCs (Table 3): aspirin; angiotensin-converting enzyme inhibitors (ACE-I); blood pressure level; beta-adrenergic blocking drugs (beta blockers); treatment for cholesterol and dyslipidemia; glucose control with metformin; and smoking cessation.

A: Aspirin
The CMI diabetes guidelines state that patients with diabetes and a >10% ten-year risk of CVD events should be treated with >75 mg/dL of aspirin.⁷ For patients at lower CVD risk, the CMI diabetes guidelines workgroup decided that the potential risks for aspirin-induced bleeding outweighed the proven benefit of aspirin therapy for CVD.

Key support for this conclusion is provided by a meta-analysis¹¹ of "high-risk" patients with diabetes (most of whom have established CVD) treated with aspirin vs placebo: That analysis showed a decline of 16% in CVD events in the treated group (absolute risk reduction [ARR]^a12 = 2%, number needed to treat [NNT]¹² = 50). The appropriate age to start aspirin therapy is not established; however, the consensus recommendation of the guidelines workgroup is to start aspirin therapy in patients with diabetes excluding patients with low CVD risk (<10%).

A: ACE-I
The CMI diabetes guidelines state that ACE inhibitors should be prescribed to patients with diabetes aged >55 years who either have one or more additional factors predisposing to cardiovascular conditions^b or have a history of CVD (ie, coronary artery disease, stroke, or peripheral vascular disease). The single most convincing piece of evidence for use of ACE inhibitors in this group is the HOPE study,¹⁰ which evaluated more than 1800 patients with diabetes who were treated for nearly five years with an ACE inhibitor or placebo. The group treated with ACE inhibitors had 22% fewer heart attacks (ARR = 2.7%, NNT = 37), 33% fewer strokes (ARR = 1.9%, NNT = 53), 37% fewer deaths from CVD (ARR = 3.5%, NNT = 29), and a 25% overall mortality rate (ARR = 3.2%, NNT = 32) compared with the placebo group.¹⁰

B: Blood Pressure Control
The CMI diabetes guidelines recommend initiating antihypertensive therapy in patients with diabetes who have systolic blood pressure level >140 mmHg, diastolic blood pressure level 85-90 mmHg, or both.⁷ The target blood pressure level is 130/80 mmHg. ACE inhibitors are the recommended first-line antihypertensive therapy, but other antihypertensive medication may be needed for optimal control. A simple way to remember the types of blood pressure treatment documented as effective in CVD prevention is another ABC memory guide: ACE-I, Beta blocker, and hydrochlorothiazide (HCTZ).

One large study, the United Kingdom Prospective Diabetes Study (UKPDS),¹³ showed that people with diabetes who were treated with either an ACE inhibitor or beta blocker had a 44%decline in incidence of stroke (ARR= 3.7%, NNT= 27) and in incidence of myocardial infarction (ARR = 7%, NNT = 14) as well as a 24% decline in any diabetes endpoint (ie, stroke, myocardial infarction, sudden death, angina, heart failure, renal failure, amputation, eye disease, or peripheral vascular disease) (ARR = 1.65%, NNT = 60). This study also showed that 29% of the patients needed three or more medications to lower their blood pressure.¹³ Use of thiazide diuretic agents produced a 34% decline in CVD events (ARR = 10.1%, NNT¹² = 10) compared to placebo in the subpopulation of patients with diabetes described in the large Systolic Hypertension in the Elderly Population (SHEP) study.¹⁴

B: Beta Blocker
The CMI diabetes guidelines list use of beta blockers as an option for secondary prevention of CVD in patients with diabetes.⁷ The best evidence of benefit is shown for patients after myocardial infarction: in the Bezafibrate Infarction Prevention study,¹⁵ subgroup analyses of patients with diabetes receiving beta blockers during the study period showed that these patients had 44% fewer myocardial infarctions (ARR= 6.2%, NNT= 16) than did patients with diabetes who did not receive beta blockers. These study findings were supported in a retrospective review.¹⁶

How to use the drug treatment tables: Select the table corresponding to the person's sex. Find the columns corresponding to the person's age, LDL-C level, and HDL-C level. Find the row that matches the person's nonlipid risk factors: none, hypertension, diabetes, etc. The number in the intersecting "cell" is a person's percent risk of a CAD event in the next 10 years. If treatment is indicated, the LDL-C goal is <130 mg/dL

(Adapted and reproduced by permission of the publisher and author from: Southern California Permanente Medical Group. Technology Assessment and Guidelines Unit. Clinical practice guidelines handbook, 2000-2001. 5th ed. Hudson (OH): Lexi-Comp; 2001. p 114-21.⁹)

^a There is evidence that people with diabetes have a risk for a CAD event comparable to people who have already had an event. In addition, compared to people without diabetes, those with diabetes have increased morbidity and mortality when they do have a CAD event. As a result of this increased risk, though there is no direct evidence, many experts recommend treating all individuals with diabetes to an LDL-C <130 mg/dL and, if other risk factors are present, an LDL-C <100 mg/dL may be appropriate.

General notes:

1. The CAD Risk and Recommendations for Dyslipidemia Drug Treatment tables use the Framingham equations (1991) to estimate the ten-year
   risk of a CAD event in people who do not have atherosclerotic disease at baseline.
2. In deriving the treatment recommendations, weights were applied to predicted events to compensate for the longer life expectancy in younger age groups. The CAD event risk (%) in each cell is not weighted. For information on assumptions used in the model for the CAD Risk and Recommendations for Dyslipidemia Drug Treatment, go to the Clinical Practice Guidelines Intranet Web site at: http://kpnet.kp.org/california/scpmg/CPG.

C: Cholesterol
The CMI diabetes guidelines recommend treating patients with diabetes and dyslipidemia for secondary prevention of cardiovascular events.⁷ It also recommends treating patients with diabetes for primary prevention of CVD if they have an LDL cholesterol level of 130 mg/dL (3.36 mmol/L), or if they have a ten-year CVD event risk of 20% or higher. The guidelines recommend an LDL cholesterol treatment goal of less than 100 mg/dL in CVD patients and 100 to 130 mg/dL (2.59-3.36 mmol/L) in primary prevention of CVD. The most supportive data come from the Heart Protection Study (HPS), which treated almost 6000 patients with diabetes between ages 40 and 80 years for five years.¹⁷ Allowing for noncompliance, the program found that use of 40 mg/dL simvastatin produced a reduction of about 33% in major vascular events among patients with diabetes (ARR and NNT not determined from data provided). For patients with diabetes who did not have established CVD at entry into the study, these results represent avoidance of about seven major cardiovascular events per 100 patients treated for five years.¹⁸

Although not reported for the subset of patients with diabetes, the Heart Protection Study showed no statistically significant excess liver disease or rhabdomyolysis in the treated group compared with the control group.¹⁹ Moreover, in regard to secondary prevention, the Scandinavian Simvastatin Survival Study trial found that patients with diabetes who were treated with statins for secondary prevention of CVD events had a 42% reduced risk of major coronary events (ARR = 13.8%, NNT = 7), a finding
that confirmed the benefit found in the Heart Protection Study.²⁰

C: Glucose Control Using Metformin
The CMI diabetes guidelines recommend metformin (Glucophage, Bristol Myers-Squibb, Princeton, New Jersey) for use as the first line drug in obese, middle-aged patients with type 2 diabetes.⁷ The best evidence supporting this recommendation is derived from the UKPDS study of type 2 diabetes,²¹ which showed that patients with diabetes who were treated with metformin had a 36% lower mortality rate from all causes (ARR = 7.1%, NNT¹² = 14) than did patients with diabetes treated con
ventionally. In addition, patients with diabetes who were treated with metformin had a 32% risk reduction (ARR = 13.5% NNT¹² = 7-8) of diabetes-related endpoints (ie, sudden death; hyperglycemia; hypoglycemia; fatal or nonfatal myocardial infarction; angina; congestive heart failure; stroke; renal failure; amputation; vitreous hemorrhage; retinopathy; blindness in one eye; or cataract extraction), and had fewer strokes (ARR = 2.2%, NNT¹² = 48),²¹ and fewer MIs (ARR = 7%, NNT = 16).

S: Smoking Cessation
The CMI Diabetes Guidelines workgroup did not formally review the literature on smoking cessation in patients with diabetes; instead, the committee accepted the conclusions in the British Medical Journal's Clinical Evidence:²² "People with diabetes are likely to benefit from smoking cessation at least as much as people who do not have diabetes but have other risk factors for cardiovascular events." Although little new or diabetes-specific data on smoking cessation exist, many data conclude that the subgroup with diabetes is likely to benefit from smoking cessation and that this group should therefore be advised to stop smoking.

Implementing Treatment Protective Against CVD: Impact on Dan's CVD Risk

On the basis of the large studies cited here, the additive relative risk reduction for a CVD event exceeds 50% for aspirin, ACE inhibitors, statins, metformin, and smoking cessation. However, not all benefits are certain to accrue by simple addition. Nonetheless, some evidence exists that the benefits may be cumulative. For example, in regard to the combined effect of taking ACE inhibitors, the HOPE study showed that benefits of this therapy occurred in patients who were already taking aspirin, lipid-lowering drugs, and beta blockers.²³ Therefore, a reasonable plan would be to tell Dan that he will probably reduce his risk substantially by starting the recommended treatment.

What Dan's Doctor Should Recommend

A: Aspirin
Dan is at "high CVD risk" because he has a 36% risk of having a CVD event in the next ten years. Starting 81 mg/dL or 325 mg/dL of aspirin is recommended.

A: ACE-I
Dan meets the HOPE criteria for ACE inhibitor use: He is a 55-year-old hypertensive smoker with diabetes and an LDL cholesterol level >130 mg/dL (>3.36 mmol/L) and HDL cholesterol level of 35 mg/dL (0.91 mmol/L). The recommendation is to start lisinopril at 10 to 20 mg daily, and to check Dan's potassium and creatinine levels in two weeks.

B: Blood Pressure
Dan's systolic blood pressure level was 150 mm Hg. Use of an ACE inhibitor is already recommended; however, because Dan's systolic blood pressure is >15 mm Hg above the target level, one could consider simultaneously starting hydrochlorothiazide at 12.5 mg to 25 mg daily. Dan's blood pressure should be checked after three weeks, and the medication dose should be titrated to achieve the target blood pressure level, 130/80 mmHg.

B: Beta-Blocker
Dan does not have known CVD and thus does not meet the guideline's criteria for treatment. However, because many hypertensive patients with diabetes eventually need three antihypertensive agents, use of a beta blocker (ie, atenolol, 25-50 mg daily) would be reasonable if other antihypertension treatment
fails to achieve the target pressure level of 130/80 mm Hg.

C: Cholesterol Treatment
Dan's baseline LDL is >150 mg/dL and his ten-year risk for CVD is >20% indicating initiation of lipid-lowering therapy. The recommended action is to start drug therapy with 40 mg lovastatin daily, confirm normal kidney and liver function when starting the medication (to assure safety), and check lipid panel results and alanine aminotransferase (ALT) level after two months.

C: Glucose Control with Metformin
Dan meets the criteria of being a middle-aged, obese patient with type 2 diabetes. The recommendation is therefore to prescribe 500 mg/day metformin for glycemic control initially and then titrate the dosage to achieve a usual glucose target.

S: Smoking Cessation
Dan should be advised to stop smoking. Use of a KP regional smoking cessation program is suggested.

When Dan and his physician had a talk, the doctor noted Dan's disheartened look and asked about the cause. Dan admitted he was depressed because he felt that he was inevitably progressing to a heart attack, stroke, or early death. Dan's doctor presented to Dan facts that encouraged him to actively change his path. Using these facts, Dan should be able to reduce his risk of myocardial infarction and stroke by stopping smoking, improving his diet, exercising, and taking a few pills each day. Dan became energized; knowing that he could take achievable steps to prevent a death similar to his father's was "just what the doctor ordered." Dan knew it would not be easy to change his path, but he now had the hope that by getting involved and taking charge of his health-related behavior, he could change his own future.

Table 4 presents a practical summary of the CMI diabetes guide lines for CVD prevention.

Summary

Providing population-based care to patients with diabetes requires stratification of patients according to their risk for CVD. On the basis of this risk profile, patients with diabetes at high risk for CVD should receive evidence-based forms of intervention proven to reduce CVD risk and, in some cases, to decrease mortality. Although not included in the CMI diabetes guidelines for CVD prevention, specific medications and dosages are suggested.

 

^a Here and throughout, unless otherwise referenced, AAR and NNT calculated by author JB.

^b Total cholesterol level >200 mg/dL (>5.17 mmol/L) (or LDL cholesterol level >130 mg/dL [>3.36 mmol/L]), HDL cholesterol level <35 mg/dL (<0.91 mmol/L).

Acknowledgments
The authors wish to recognize the contributions of William M Caplan, MD, Director of Clinical Development, Care Management Institute, both for ongoing support and for intellectual contributions.

References

1. Kaiser Permanente Medical Care Program. Care Management Institute. Kaiser Permanente diabetes outcomes report. Fifth annual report, data from 2000. [Oakland (CA)]: Care Management Institute, Kaiser Permanente Medical Care Program; 2001. Available on the World Wide Web (accessed June 11, 2002): http://pkc.kp.org/national/cmi/programs/diabetes/IDC_DOR_2001.pdf .
2. Selby JV, Ray GT, Zhang D, Colby CJ. Excess costs of medical care for patients with diabetes in a managed care population. Diabetes Care 1997 Sep;20(9):1396-402.
3. Brown JB, Nichols GA, Glauber HS, Bakst AW, Schaeffer M, Kelleher CC. Health care costs associated with escalation of drug treatment in type 2 diabetes mellitus. Am J Health Syst Pharm 2001 Jan 15;58(2):151-7.
4. Kaiser Permanente Medical Care Program. Care Management Institute. Kaiser Permanente cardiovascular outcomes report. Fourth annual report, data from 2000. [Oakland (CA)]: Care Management Institute, Kaiser Permanente Medical Care Program; 2002. Available on the World Wide Web (accessed June 11, 2002): http://pkc.kp.org/national/cmi/programs/cad/reports/COR_IV.pdf .
5. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993 Sep 30;329(14):977-86.
6. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998 Sep 12;352(9131):837-53.
7. Kaiser Permanente Medical Care Program. Care Management Institute. Evidence-based guidelines and technical review of management of diabetes mellitus. [Oakland (CA)]: Care Management Institute, Kaiser Permanente Medical Care Program; 2002. Available on the World Wide Web (accessed June 11, 2002): http://pkc.kp.org/national/cmi/programs/diabetes/diabetes_mellitus_guidelines2002.pdf .
8. Anderson KM, Odell PM, Wilson PW, Kannel WB. Cardiovascular disease risk profiles. Am Heart J 1991 Jan;121(1 Pt 2):293-8.
9. Southern California Permanente Medical Group. Technology Assessment and Guidelines Unit. Clinical practice guidelines handbook, 2000-2001. 5th ed. Hudson (OH): Lexi-Corp; 2001.
   p 115-21. Also available on the World Wide Web (accessed June 25, 2002): http://kpnet.kp.org/california/scpmg/CPG.
10. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart
    Outcomes Prevention Evaluation Study Investigators. Lancet 2000 Jan 22;355(9200):253-9.
11. 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. Antiplatelet Trialists' Collaboration. BMJ 1994 Jan 8;308(6921):81-106.
12. Sigal R, Meggison H, Malcolm J. Endocrine disorders: cardiovascular disease in diabetes. Table 2. Secondary prevention of cardio-vascular events in people with diabetes. Clinical Evidence 2002;(7). Available on the World Wide Web (accessed June 14, 2002):
    www.clinicalevidence.com/ Click on "Endocrine disorders"; click on "Cardiovascular disease in diabetes"; click on "Table 2."
13. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998 Sep 12;317(7160):703-13.
14. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA 1996 Dec 18;276(23):1886-92.
15. Jonas M, Reicher-Reiss H, Boyko V, et al. Usefulness of beta-blocker therapy in patients with non-insulin-dependent diabetes mellitus and coronary artery disease. Bezafibrate Infarction Prevention (BIP) Study Group. Am J Cardiol 1996 Jun 15;77(15):1273-7.
16. Malmberg K, Herlitz J, Hjalmarson A, Ryden L. Effects of metoprolol on mortality and late infarction in diabetics with suspected acute myocardial infarction. Retrospective data from two large studies. Eur Heart J 1989 May;10(5):423-8.
17. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J 1999 May;20(10):725-41.
18. MCR/BHF Heart Protection Study. Press release: Life-saver: world's largest cholesterol-lowering trial reveals massive benefits for high-risk patients [Web site]. Available on the World Wide Web (accessed June 13, 2002): www.ctsu.ox.ac.uk/~hps/ Click on "Press Material"; click on "Press Release."
19. MRC/BHF Heart Protection Study. Preliminary results slideshow, 13 November 2001 [Web site]. Available on the World Wide Web (accessed June 11, 2002): www.ctsu.ox.ac.uk/~hps/ Click on "Results"; click on "Slideshows"; click on "Results."
20. Haffner M, Alexander CM, Cook TJ, et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1999 Dec 13-27;159(22):2661-7.
21. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998 Sep 12;352(9131): 854-65.
22. Sigal R, Meggison H, Malcolm J. Endocrine disorders: cardiovascular disease in diabetes. Question: What are the effects of promoting smoking cessation in people with diabetes? Clinical Evidence 2002;(7). Available on the World Wide Web (accessed June 11, 2002): www.clinicalevidence.com/ Click on "Endocrine disorders"; click on "Cardiovascular disease in diabetes"; click on "Promoting smoking cessation."
23. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000 Jan 20;342(3):145-53.