Diabetes Clinic, Part 2 - Clinically Effective Approaches to Meeting the American Diabetes Association's Guidelines: Blood Pressure Levels, Renal Evaluations, and Physical Examinations

Dr. Davidson is from the Clinical Center for Research Excellence, Charles R. Drew University, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Diabetes is a leading cause of blindness, dialysis for renal failure, and amputations for foot ulcers. These complications, however, are largely avoidable. Both microvascular and macrovascular disease could be sharply curtailed with appropriate glycemic control in addition to lipid and blood pressure management, smoking cessation, aspirin therapy, and vigilant physical examinations. In addition to promulgating standards of care regarding glycated hemoglobin (HbA1c) and low-density lipoprotein (LDL) cholesterol, which were discussed in part 1 of this series, the American Diabetes Association (ADA) has also outlined blood pressure goals. This report will review these blood pressure goals and discuss important components of the physical examination for diabetic patients, including eye and renal evaluations.

ADA blood pressure goals

There is a difference in the patterns of hypertension observed between type 1 and type 2 diabetic patients. In the former, hypertension usually only occurs after patients develop renal disease. In the latter, the incidence of hypertension is up to 3 times greater than in age- and sex-matched people without diabetes and is frequently present when type 2 diabetes is diagnosed. Although lowering blood pressure in hypertensive individuals is known to be beneficial in the general population,⁴⁸ what do the data in people with diabetes indicate?

Regarding cardiovascular disease (CVD) outcomes, 3 studies have compared intensive treatment of hypertension in diabetic patients with either placebo or usual care.^49-51 Blood pressure levels, not surprisingly, were significantly lower in the intensively treated groups. In 3 other studies,^52-54 subjects were randomly assigned to different blood pressure targets, allowing the impact of different blood pressure levels on CVD events to be evaluated.

In the HDFP (Hypertension Detection and Follow-up Program), patients were randomly assigned to intensive treatment versus referral to usual care.⁴⁹ Subjects receiving intensive treatment had 38% less cardiovascular morbidity and mortality. In the SHEP (Systolic Hypertension in the Elderly Program), patients were also randomly assigned to intensive treatment or usual care by primary care providers.⁵⁰ There was a 34% reduction in total cardiovascular events and a 26% decrease in total mortality in the intensively treated group. In the Syst-Eur (Systolic Hypertension in Europe) study, patients were randomly assigned to nitrendipine or placebo.⁵¹ There was a 70% reduction in cardiovascular mortality, a 65% reduction in all cardiovascular events, and after adjustment for confounders, a 55% reduction in overall mortality in those receiving nitrendipine.

In the HOT (Hypertension Optimal Treatment) study, patients were randomly assigned to target diastolic blood pressures of 90, 85, or 80 mm Hg.⁵² Achieved diastolic blood pressures were 85, 83, and 81 mm Hg. The groups assigned to a diastolic blood pressure of 80 mm Hg had a significant decrease in cardiovascular events of 51% and of total cardiovascular deaths of 44% compared with the group assigned to a blood pressure of 90 mm Hg. In the UKPDS (United Kingdom Prospective Diabetes Study), patients were randomized to a “tight” blood pressure group with a goal of less than150/85 mm Hg or a “less tight” blood pressure group of less than180/105 mm Hg;⁵³ the “less tight” goal is so high because the UKPDS was planned in the 1970s. The blood pressures actually achieved were 144/82 mm Hg and 154/87 mm Hg, respectively. There was a significant 34% reduction in total cardiovascular events and an 18% reduction in total mortality (the latter just missing significance) in the “tight” blood pressure group compared with the “less tight” group. Unlike the legacy effect noted in UKPDS with lowering glycemia,²⁰ there was none found with lowering blood pressure.⁵⁵ Between group differences in systolic and diastolic blood pressure were lost by year 1 and year 2, respectively. Significant differences in any diabetes-related end point, diabetes-related death, microvascular disease, and stroke seen during the active phase of the trial were not sustained during the follow-up observational phase.

In the ABCD (Appropriate Blood Pressure Control in Diabetes) trial,⁵⁴ patients were assigned to an intensive treatment group (target diastolic blood pressure of 75 mm Hg) or a moderate control group (target diastolic blood pressure of 80-89 mm Hg). Achieved blood pressures were 132/78 mm Hg and 138/86 mm Hg, respectively. Total mortality was significantly reduced by 49% in the intensively treated group compared with the moderate control group, but there was no difference in cardiovascular mortality to explain it.

Reducing blood pressure also reduced the risk for stroke. In the UKPDS,⁵³ strokes were reduced by 44% in the “tight” control group compared with the “less tight” group, but these differences were not sustained when blood pressure differences disappeared.⁵⁵ There was a 20% reduction in strokes in the SHEP study.⁵⁰ The excess stroke risk associated with type 2 diabetes was abolished in the nitrendipine group in the Syst-Eur study.⁵¹ Blood pressures control had a striking beneficial effect on the microvascular complications of diabetic patients,⁵³ but this was not sustained unless blood pressure remained reduced.⁵⁵

In patients with renal insufficiency, controlling blood pressure is the most important factor in preserving renal function.⁵⁶ Based on these data, the ADA recommends a blood pressure goal of lower than 130/80 mm Hg.1 Few patients, however, are meeting that goal. For instance, 73% of diabetic patients had a blood pressure of higher than 140/90 mm Hg, a higher percentage than the 66% of nondiabetic patients.⁵⁷ For patients with renal insufficiency, the National Kidney Foundation recommends an even lower blood pressure goal of less than 125/75 mm Hg in patients with proteinuria exceeding 1 g per day.⁵⁸

Renal evaluations

Many studies have evaluated the effects of either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) on renal disease in diabetic patients. Studies on patients with clinical proteinuria (ie, albumin:creatinine ratios >300 µg/mg, 24 hour urinary albumin >300 mg, 24 hour urinary protein >500 mg), many of whom had renal insufficiency, used a primary end point of a doubling of serum creatinine levels and secondary end points of dialysis, renal transplant, or death. In randomized control trials, both an ACE inhibitor40 and an ARB^41,42 significantly reduced these end points compared with a placebo. Either blood pressures were kept the same in the 2 groups⁴⁰ or the benefits were independent of blood pressure changes.^41,42 Many smaller studies support these conclusions.⁴³

ACE inhibitors and ARBs also reduce the progression of microalbuminuria (30-300 µg albumin/mg creatinine) to clinical proteinuria (>300 µg/mg) and increase the return of microalbuminuria to normoalbuminuria.⁴³ These effects are independent of changes in blood pressure. Studies in normotensive type 144 and type 245 diabetic patients in whom an ACE inhibitor significantly decreased the development of clinical proteinuria from microalbuminuria prove this point. When the ACE inhibitor was discontinued (by patient choice), microalbuminuria returned.⁴⁶ This demonstrates that the improvement was not due to natural variability. A meta-regression analysis showed that although blood pressure lowering decreased proteinuria and increased glomerular filtration rate, ACE inhibitors had an additional beneficial effect independent of their effect on blood pressure.⁴⁷ Based on these data, the ADA1 recommends that patients with microalbuminuria or clinical proteinuria be given either an ACE inhibitor or an ARB as part of an antihypertensive treatment regimen, unless contraindicated.

Eye examination

Patients should be screened for diabetic retinopathy because the process prior to visual loss is asymptomatic and laser photocoagulation surgery, although effective in stabilizing vision, does not restore it. The National Institutes of Health sponsored 2 large randomized trials that firmly established beneficial effects of this treatment for severe diabetic retinopathy (but not for mild or moderate disease). In the Diabetic Retinopathy Study,⁵⁹ panretinal photocoagulation decreased the incidence of severe visual loss (best acuity of 5/200 or worse) by 50% during a 6 year follow-up, starting almost immediately.

The results of focal photocoagulation for macular edema (the most common retinal cause for visual loss in type 2 diabetic patients) in the ETDRS (Early Treatment Diabetic Retinopathy Study)⁶⁰ were similar. The end point was a 50% deterioration in vision evaluated by an acuity chart (eg, 20/40 to 20/80). After 3 years, 12% of the treated eyes compared with 24% of the untreated eyes had deteriorated to that extent. Further analysis revealed that only eyes with “clinically significant macular edema” needed to be treated because the rate of visual loss was very low in eyes with milder macular changes and there was no evidence of benefit from treatment of this earlier process. Retinal thickening that occurs at or near the center of the macula is the hallmark of clinically significant macular edema. Unfortunately, this can only be assessed by stereo contact lens biomicroscopy and stereo photography, procedures not available to nonophthalmologists; however, exudates in the macular area almost always predict retinal thickening. To complicate matters further, initial visual acuity does not help select patients for further investigation. Even patients with normal visual acuity, but with clinically significant macular edema, were helped by focal macular photocoagulation. Because of this, yearly eye examinations are extremely important for detecting macular edema that would benefit from laser photocoagulation surgery, and clinicians should recommend annual eye examinations to their patients.

Foot examination Of lower extremity amputations in diabetic patients, most are for foot ulcers, which are largely preventable. Identification of the early signs of foot pathology is essential to spare limbs, and physicians should routinely check for areas of erythema, warmth, or calluses, which reflect increased pressure. Not taking the time to examine patients’ feet will result in early lesions being missed and going untreated. Prompt treatment is essential to prevent further damage and possible amputations.

Aspirin therapyA meta-analysis of 145 prospective controlled trials of antiplatelet therapy for secondary prevention of myocardial infarctions (MIs), strokes, or transient ischemic attacks revealed an approximate 25% reduction in recurrences in each of these outcomes.⁶¹ Diabetic patients had similar relative risk reductions but higher absolute reductions in these events because of their increased risk for such events. There were 2 randomized controlled studies of primary prevention that included diabetic patients that also showed a beneficial effect of aspirin. The US Physicians’ Health Study⁶² demonstrated a 44% reduction in MIs in those receiving aspirin, with a 61% reduction in the diabetic subgroup. In the HOT study,⁵² which was also discussed in the hypertension section of this report, the diabetic hypertensive patients were also randomized to receive 75 mg of aspirin or placebo. Aspirin significantly reduced cardiovascular events by 15% and MIs by 36%. In the ETDRS,⁶⁰ also discussed in the eye examination section, the comparator group to photocoagulation was aspirin. Since 48% of these patients had a history of CVD, this was a mixed primary and secondary prevention trial. The relative risk for MI in the first 5 years of the study was lowered by 28% in those receiving aspirin.⁶³

An ADA study showed an approximate 60% increase in the relative risk of major gastrointestinal bleeding with aspirin, which was not reduced by enteric-coated aspirin.⁶⁴ There was also a moderately increased risk in hemorrhagic stroke in patients taking aspirin, regardless of the dose. The absolute risk, however, was approximately 1 event per 1,000 users over 3 years to 5 years. Aspirin does not appear to increase retinal or vitreous hemorrhage.⁶³

Contraindications to aspirin use include allergy to aspirin, a bleeding tendency, anticoagulant therapy, recent gastrointestinal bleeding, and clinically active hepatitis. Because clopidogrel (Plavix) has been shown to reduce CVD events in diabetic patients,⁶⁵ it should be considered as alternative therapy for patients with aspirin allergies. Clopidrogel as adjunctive therapy with aspirin in very high risk patients also has been suggested.¹

Unfortunately, less than half of diabetic patients take aspirin, about 75% of those with CVD, but only one-third of those do not have a history of MI, angina, or a stroke.⁶⁶ Aspirin use is also significantly lower in diabetic women than in diabetic men.

Smoking cessation

Evidence from a variety of epidemiological, case-control, and cohort studies irrefutably document the causal relationship between smoking and health risks.⁶⁷ Smoking also increases the risk of microvascular complications in diabetic patients. Extensive public health efforts were associated with substantial reductions in smoking up to about 1990, after which about 25% of American adults, including people with diabetes, continued to smoke.⁶⁸ Although behavioral counseling and various drugs have been clearly shown to reduce smoking, only about half of smokers with diabetes have been advised to quit smoking by their health care providers.⁶⁷

Effective clinical protocols to achieve ADA goals

A clinical approach that was extremely successful in an inner city, minority population included a specially trained registered nurse, who followed detailed treatment algorithms and was supervised by an endocrinologist (mostly by phone). Nurse-directed care for 1 year resulted in mean HbA1c levels of 7.0%, with 60% meeting the ADA goal of less than 7.0% and 82% meeting the LDL cholesterol goal of less than100 mg/dL.⁶⁹ There was a 70% reduction in urgent care and emergency department visits and hospitalizations due to metabolic and infectious causes during the year spent under nurse-directed care compared with the previous year for the same patients under usual care.⁷⁰ The medications were restricted to those on the Los Angeles County formulary. The hypertension protocol was instituted after the research project ended, so no formal analysis of blood pressures is available from that study; however, during a follow-up quality improvement project, which also used the hypertension protocol, ADA systolic and diastolic blood pressure target levels were met 60% and 83% of the time, respectively.⁷¹

Disclosure: Dr Davidson was supported by NIH grant #U54-RR014616.

HYPERTENSION PROTOCOL

Treatment Plan

1. Initial hypertension treatment for blood pressure (BP)<160/100 mm Hg is medical nutritional therapy and life-style modification.

2. Pharmacological therapy is initiated, on any patient who does not meet goal of ≤130/80 mm Hg and has failed medical nutritional therapy and life style modification for approximately 4-8 weeks or if initial BP is confirmed to exceed 160/100 mm Hg.

3. Principles of treatment to achieve the BP goal of ≤130/80 mm Hg:

a) To determine the effect of starting or changing the dose

of an anti-hypertensive medication, measure the BP approximately 4 weeks after initiating or changing the dose.

b) If BP goal of ≤130/80 mm Hg is not reached at the maximal (tolerated) dose of a class of drugs, add the drug from the next class.

Algorithm for the treatment of hypertension in patients enrolled in the DMP

A. Non-pharmacological therapy (lifestyle change)

• Weight reduction toward desirable body weight of at least 5%-10% of initial weight

• Salt restriction to as close to 2 g/day as possible utilizing the DASH diet

• Smoking cessation

• Limit daily alcohol intake to <2 oz per day

• Exercise (walking, swimming, etc, 30-45 minutes 3-4 x week)

• Caffeine cessation

• Stress reduction

• If BP is controlled at ≤130/80 mm Hg, continue with non-pharmacological program

• Life Style Modification for 8 weeks. If BP goal of ≤130/80 mm Hg not met, go to B

B. First Line Drug(s) for Pharmacologic Treatment: (ACE-I or ARB)

Start patient on 10 mg once daily of benazepril (Lotensin), an angiotensin converting enzyme inhibitor (ACE-I)

1. Start patient on benazepril 10 mg once daily.

2. Measure K+ 2 weeks after each change of benazepril dose.

3. If K+ above the upper limit of normal, decrease to previous dose.

4. Increase benazepril to 20 mg if BP goal not met at 4 week follow up.

5. Measure K+ 2 weeks after dose increase. If above the upper limit of normal, decrease to previous dose.

6. Increase benazepril to 40 mg once daily, if BP goal not met at 4 week follow-up.

7. Measure K+ 2 weeks after dose increase. If above the upper limit of normal, decrease to previous dose.

8. If patient complains of a cough or angioneurotic edema (two other side effects in addition to hyperkalemia), discontinue benazepril and start losartan (Cozaar), an angiotensin receptor blocker (ARB) using a dose equivalency from the table.

9. (Since ARB’s also raise K+ levels, they can not be substituted for an ACE-I if the latter causes hyperkalemia.)

Dose Equivalency ACE-I ARB

Benazepril 10 mg Losartan 20 mg

Benazepril 20 mg Losartan 50 mg

Benazepril 40 mg Losartan 100 mg

10. If BP goal of ≤130/80 mm Hg not met at 4 week follow-up visit after maximal dose of an ACE-I or ARB is

prescribed, go to Second Line Drug

C. Second Line Drug (Diuretic): Hydrochlorothiazide (if serum creatinine is ≤1.8 mg/dl) or indapamide (Lozol) (if serum creatinine is ≥1.9 mg/dL, see #4 below).

To be used if BP goal of ≤130/80 is not achieved with a maximal (tolerated) dose of an ACE-I or ARB.

1. Add hydrochlorothiazide 12.5 mg, once daily.

2. If BP goal of ≤130/80 mm Hg not met at 4 week follow-up visit, increase hydrochlorothiazide to 25 mg once daily (maximal dose).

3. If BP goal of ≤130/80 mm Hg not met at 4 week follow-up visit, go to #6 or #7 below.

4. If the serum creatinine is ≥1.9 mg/dL, start indapamide 1.25 mg once daily.

5. If BP goal of ≤130/80 mm Hg not met at 4 week follow-up visit, increase indapamide dose to 2.5 mg once daily (maximal dose).

6. If BP goal of ≤130/80 mm Hg not met at 4 week follow-up visit and pulse rate is ≥70 beat per minutes, go to Third Line Drug.

7. If BP goal of ≤130/80 mm Hg not met at 4 week follow-up visit and pulse rate <70 beats per minute, go to Fourth Line Drug.

D. Third Line Drug (Beta blocker): Atenolol (Tenormin)

To be used if BP goal of ≤130/80 mm Hg is not achieved with combination of first and second line drugs and pulse rate is ≥70 beats per minute.

1. Add atenolol 25 mg once daily.

2. If BP goal of ≤130/80 mm Hg not met at 4 week follow-up visit, increase atenolol to 50 mg once daily.

3. If BP goal of ≤130/80 mm Hg not met at 4 weeks follow-up visit, increase atenolol to 100 mg once daily.

4. If BP goal of ≤130/80mm Hg not met at 4 weeks and patient at maximum doses of combination of first, second and third line drugs, go to Fourth Line Drug.

E. Fourth Line Drug (Calcium channel blocker): Felodipine (Plendil)

To be used if BP goal of ≤130/80 mm Hg is not achieved with either a combination of first, second and third line drugs or a combination of first and second line drugs and pulse rate is <70 beats per minute.

1. Add felodipine 5 mg once daily (unless patient has hepatic dysfunction; then start with 2.5 mg and increase to 5 mg and then 10 mg as necessary).

2. If BP goal of ≤ 130/80 mm Hg not met at 4 week follow-up visit, increase felodipine to 10 mg once daily.

3. If BP goal of ≤130/80 mm Hg not met at 4 weeks follow-up visit and patient is taking maximal doses of 4 classes of drugs (ACE-I or ARB, diuretic, beta-blocker and calcium channel blocker), CONSULT MD.

4. If BP goal of ≤ 130/80 mm Hg not met at 4 week follow-up visit and patient is taking maximal doses of 3 classes of drugs (ACE-I or ARB, diuretic, calcium channel blocker) and pulse rate is <70 beats per minute, CONSULT MD.

MICROALBUMINURIA PROTOCOL

A. Subjective Data:The following history is suggested (the patient is usually asymptomatic):

1. Diabetes mellitus, duration of disease

2. Hypertension

3. Kidney disease, proteinuria

4. Medications, prescribed and nonprescription

5. Smoking

B. Objective Data:

1. In an early morning urine sample, measure a dipstick protein.

2. If it is 1+ or greater (and infection and hematuria are ruled out), the patient has clinical proteinuria.

3. If it is negative or trace, measure an albumin/creatinine ratio; if it is >300 µg albumin/mg creatinine, the patient has clinical proteinuria.

4. If it is <30 µg albumin/mg creatinine, it is normal and should be repeated in 1 year.

5. If it is between 30 and 300 µg albumin/mg creatinine, it is in the microalbuminuric range; 2 such values within 6 months establishes the diagnosis of microalbuminuria.

C. Assessment:1. Clinical proteinuria - ≥1+ dipstick protein or an albumin/creatinine ratio ≥300 µg/mg.

2. Microalbuminuria -two albumin/creatinine ratios within 6 months between 30 and 300 µg/mg.

3. Normal — an albumin/creatinine ratio <30 µg/mg.

D. Treatment PlanIf patient is not already on an ACE inhibitor or an ARB, and has clinical proteinuria or microalbuminuria, treat with 10 mg of

benazepril once daily. If patient develops a cough or angioneurotic edema, switch to 25 mg of losarten, once daily. Measure a serum creatinine and K+ in approximately 2 weeks after starting an ACE inhibitor or an ARB. BP and ensure the BP meets goal if possible (<130/80 mm Hg) and that systolic pressure is >90 mm Hg.

The ADA has recommended a number of guidelines for diabetes care. The evidence for each was summarized above. Effective clinical protocols are provided to help physicians meet these guidelines and markedly reduce the potential devastating complications of diabetes.

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