Steve V. Edelman, MD
Robert R. Henry, MD
The long-term, chronic complications of diabetes have the greatest impact on the health of individuals with diabetes as well as on the health care system. Diabetes and its associated vascular complications are the fourth leading cause of death in the United States….
Consequently, early detection and aggressive treatment of these complications are essential to reduce associated morbidity and mortality. Striving for tight metabolic control also has been proven to help delay the onset and prevent the development of microvascular complications (diabetic retinopathy, nephropathy, and neuropathy).
The DCCT, a multicenter, randomized clinical trial, investigated the effects of intensive therapy vs. traditional therapy on the development and progression of microvascular complications of Type 1 diabetes mellitus. The aim of intensive therapy was to achieve and maintain near-normal blood glucose values following a regimen of three or more daily insulin injections or treatment with an insulin pump. In contrast, only one or two insulin injections were used in conventional therapy. Patients were followed for a mean of 6.5 years and assessed regularly for the presence or progression of retinopathy, nephropathy, and neuropathy.
Intensive therapy proved to be highly effective in delaying the onset and slowing the progression of the long-term complications being evaluated in patients with Type 1 diabetes. Furthermore, similar benefits were observed in the UKPDS in Type 2 diabetes. In response to the DCCT and UKPDS findings, the ADA recommended striving for the best possible glycemic control in patients with Type 1 and Type 2 diabetes with the following goals:
- Fasting and preprandial blood glucose level 80 mg/dL to 120 mg/dL
- PPG level
- A1c 7% (normal reference range = 4% to 6%) or three standard deviations from the mean of the normal range.
Attempts to normalize glycemia and A1c should be balanced, however, with minimizing weight gain and hypoglycemia and maintaining an acceptable quality of life.
The incidence of the three major macrovascular diseases (coronary artery, cerebrovascular, and peripheral vascular) is greater in individuals with diabetes than in nondiabetic individuals, accounting for up to 80% of mortality in adults with diabetes. Atherosclerosis develops at an earlier age, accelerates more rapidly, and is more extensive in patients with diabetes than in nondiabetics matched by age, weight, and sex.
Type 2 diabetes is a risk factor for macrovascular disease, as are conditions that commonly coexist in patients with diabetes (hypertension, dyslipidemia, and central obesity). Smoking and lack of exercise contribute to an increased risk in both those with Type 2 diabetes and the nondiabetic population. In addition, renal insufficiency can increase the risk of and accelerate macrovascular disease in diabetic individuals with microalbuminuria or gross proteinuria.
Weight control and exercise are safe and effective methods for modifying macrovascular risk and should form the basis to which all other treatments are added. The following treatments for hypertension and dyslipidemia should be applied when appropriate.
Hypertension should be treated vigorously in all patients with diabetes to limit and/or prevent the development and progression of atherosclerosis, nephropathy, and retinopathy. Lowering elevated blood pressure is the most important and immediate consideration, with a therapeutic goal of <130/80 mm Hg if there is no evidence of protein in the urine. The goal for patients with isolated systolic hypertension (180 mm Hg) is 160 mm Hg; further reductions to 140 mm Hg are suggested if the treatment is well tolerated. The goal for patients with renal insufficiency should be <120/80 mm Hg with a mean blood pressure
Treatment should be initiated with a no-salt added diet and weight loss (for obese patients) combined with appropriate aerobic exercise. Because patients with diabetes can be uniquely impacted by certain side effects of antihypertensives, physicians must be familiar with the potential complications with the various classes of antihypertensive drugs (Table 15.1).
In general, reductions in systolic or diastolic blood pressure of 5% to 10% occur with most antihypertensives. The potential benefits of the commonly prescribed antihypertensives are shown in Table 15.2. Treatment guidelines include:
- One or more antihypertensive medications may be necessary to achieve satisfactory blood pressure control.
- Adding a second drug to small or moderate doses of the first drug often results in better control with fewer side effects than using full doses of the first agent.
ACE inhibitors and now the ARBs commonly are the first choices for therapy because they are effective and have a low incidence of side effects. They are useful in diabetic patients with and without nephropathy. In the UKPDS, the ACE inhibitor captopril was equally efficacious as the beta-blocker atenolol in reducing microvascular and CV complications of Type 2 diabetes. They have no negative impact on carbohydrate or lipid metabolism, can slow the rate of progression of proteinuria in diabetic nephropathy, reduce the decline in renal function, and prevent progression of retinopathy. Caution should be used in patients with peripheral occlusive disease because renal artery stenosis may be present, which could lead to renal decline with ACE inhibitors.
ACE inhibitors have now been shown to be cardioprotective in addition to having beneficial effects on the diabetic kidney. The Heart Outcomes Prevention Evaluation (HOPE) trial studied more than 3500 subjects with diabetes who had documentation of previous CV events and were over 55 years of age. Subjects were randomized to either ramipril (10 mg/day) or placebo and vitamin E or placebo. Within 4.5 years, the ramipril-treated group experienced a 22% reduction in MI, a 33% reduction in stroke, a 37% reduction in any CV event, and a 24% reduction in the development of overt nephropathy when compared with the placebo group. These benefits occurred despite minor reductions in blood pressure, raising the possibility that ACE inhibitors have benefits for diabetic patients independent of blood pressure lowering. In summary, the HOPE study is a landmark study confirming the results of multiple smaller and less-powered studies demonstrating the cardiac and renal protective effects of ACE inhibitors in subjects with diabetes. Based on the results of these studies, ACE inhibitors should be considered as first-line therapy in diabetics with mild to-moderate hypertension and/or microalbuminuria or macroalbuminuria.
Serum potassium should be monitored during therapy with ACE inhibitors in patients with suspected hyporeninemic hypoaldosteronism (Type IV renal tubular acidosis) to prevent severe hyperkalemia.
Like the ACE inhibitors, ARBs have been shown to slow the progression of albuminuria and to be protective in diabetic nephropathy. There is some evidence from the Candesartan and Lisinopril Microalbuminuria study that combining an ACE inhibitor and an ARB reduces blood pressure and urinary albumin levels more than either agent alone.
β-Blockers are being used more frequently as antihypertensive agents following the beneficial effects reported with atenolol in the UKPDS. Besides equal efficacy to the ACE inhibitor captopril, atenolol did not cause an increased incidence of hypoglycemic episodes. However, it is probably prudent to avoid β-blockers in patients with a history of severe hypoglycemia or hypoglycemic unawareness. The potential to blunt counterregulatory responses or prolong hypoglycemia needs to be weighed against the clear-cut benefits of β-blockers to reduce mortality in diabetic patients with recent MI. Selective β-blockers may be more beneficial than the nonselective β-blockers and have a lower incidence of side effects.
Adrenergic blockers have been associated with improved insulin sensitivity and modest decreases in LDL cholesterol, but no long-term randomized studies have been conducted examining renal or CV outcomes. Orthostatic hypotension can occur, so caution should be used in patients with diabetic autonomic neuropathy.
There are three subclasses of CCBs: the dihydropyridine group (DCCBs) and the benzothiazepines and phenylalkylamines (NDCCBs). The DCCBs are a heterogenous class of compounds with significant pharmacologic differences and a primary vasodilatory effect. Due to conflicting evidence, it is unclear whether the DCCBs reduce CV events or progression of nephropathy. They may protect against stroke but appear to be less effective than ACE inhibitors in reducing CV events. An increase in CV mortality has been reported with the short-acting DCCB nifedipine. Short-acting DCCBs are not approved for and should not be used to treat hypertension in diabetic patients.
Use of the NDCCBs has been associated with decreased proteinuria in short-term studies of patients with overt diabetic nephropathy.
Next Week: Use of Diuretics and Dyslipidemia
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© Copyright 2010. Steven V. Edelman, MD, Robert R. Henry, MD, Professional Communications, Inc. All rights reserved.