Pharmacy Times

Diabetic Complications: Are Your Patients at Risk?

Author: Tara Lyn Muzyk, PharmD

Diabetes is the most significant metabolic disorder facing the United States and the world today. In fact, by the year 2025, it is estimated that >250 million persons throughout the world will have diabetes.1 In the United States, the increase has been at a rate of >30% in the past 10 years.2 Such an increase is alarming, considering that it signals a simultaneous rise in the complications associated with diabetes. Most patients newly diagnosed with diabetes have had the disease for an average of 5 years before an official diagnosis was made. The complications associated with diabetes also have been developing for 5 years on average.

Diabetes contributes to a higher rate of morbidity and mortality through a variety of concomitant complications. Individuals with diabetes are at higher risk for heart disease, blindness, kidney failure, extremity amputations, and other chronic conditions. In 2002, the direct and indirect medical expenditures attributable to diabetes were estimated at $132 billion, with $24.6 billion alone spent on associated chronic complications.3 The systemic complications that follow the onset of diabetes are the result of both macrovascular and microvascular changes in the body. Macrovascular changes affect the large blood vessels and result in complications involving the coronary arteries, the cerebral vasculature, and the blood supply to the lower extremities. Microvascular changes affect the small vessels and result in complications such as those involving the retina.

A triad of care—comprised of glycemic regulation, hypertension control, and lipid management—is the key to reducing complications related to diabetes. A team of health care professionals is needed to manage these complications, as well as strict compliance on the part of the patient.

Glycemic Control

Complications associated with diabetes typically start from poor glycemic control. Therefore, strict glycemic control is paramount in the treatment of diabetes. Many clinical trials have showcased the importance of glycemic control by demonstrating conclusively that normalization, or near-normalization, of blood glucose substantially delays, or in certain cases prevents, the vascular complications associated with diabetes.4,5 The Diabetes Control and Complications Trial (DCCT) showed that intensively lowering the hemoglobin A1C (A1C) significantly reduced the incidence and rate of progression of common diabetic complications such as retinopathy, clinical neuropathy, and albuminuria in patients with type 1 diabetes. In this study, the strict glycemic control group had a mean A1C of ~7%.4

The idea that strict glycemic control is essential to reducing diabetic complications was further emphasized by the UK Prospective Diabetes Study (UKPDS). This study demonstrated that treatment regimens that reduced the A1C to ~7% reduced long-term microvascular complications in patients with type 2 diabetes.5 The DCCT and the UKPDS also demonstrated that intensive glycemic control greatly reduced the risk and progression of retinopathy. These benefits come with some disadvantages, however, such as weight gain and hypoglycemia from increased insulin availability.

The starting point for glycemic control is the maintenance of preprandial glucose levels of between 80 and 120 mg/dL and the reduction of the A1C to <7%.6 A patient-kept record of blood glucose measurements is helpful in diagnosing diabetes and in identifying when the patient is most in need of tighter blood glucose control.

Therapy for strict glycemic control should be individualized. Before medication is initiated, lifestyle modification—including medical nutrition therapy (MNT) and increased physical activity—should be considered as a way to manage blood glucose.

The medication starting point for patients with type 2 diabetes is the secretagogues—mainly the sulfoylureas—with the stepwise addition of a biguanide and/or a thiazolidinedione as indicated. In general, insulin is the last addition, when other therapies have failed to help the type 2 patient obtain the blood glucose control needed or when it is known that the other therapies will not yield the reduction necessary. Therapy should be initiated with insulin in patients with type 1 diabetes. Intensive blood glucose control is crucial to the successful reduction of all of the complications associated with diabetes.

Hypertension

Although intensive glycemic control is the initial leg in the triad, further prevention of both microvascular and macrovascular complications may be achieved through adequate blood pressure control. Several studies have demonstrated that a reduction in blood pressure to <130/80 mm Hg results in a decreased risk for stroke, myocardial infarction, kidney disease, and retinopathy.7

Patients should be treated for hypertension if their blood pressure is >130/80 mm Hg in 2 separate measurements about 1 month apart. Also, a patient-kept record of daily blood pressures is helpful when attempting to diagnose high blood pressure.

The DASH [Dietary Approaches to Stop Hypertension] diet showed that, in nondiabetic individuals, blood pressure can be reduced by diet modification (increasing fresh fruits and vegetables, decreasing salt, and choosing low-fat dairy products); by increasing activity levels; and by smoking cessation. This approach can be applied to most individuals and is a good starting point for blood pressure reduction in diabetic patients.8 It is unlikely, though, that a reduction of blood pressure to <130/80 mm Hg will be obtained by lifestyle modification alone, and, in most cases, medication therapy will need to be initiated.

The blood pressure-lowering effects of an angiotensin-converting enzyme (ACE) inhibitor have been shown to improve cardiovascular (CV) outcomes in high-CV-risk patients with or without previous CV events, hypertension, or microalbuminuria, and regardless of type of diabetes.9 Nephropathy is most strongly associated with elevated blood pressure. Therefore, the reduction of blood pressure to <130/80 mm Hg is optimal for slowing its progression. ACE inhibitors or angiotensin II receptor blockers are considered first-line agents for the treatment of hypertension in diabetic patients and have been shown to slow the progression of nephropathy.10,11 The UKPDS also demonstrated that a 10/5-mm Hg reduction in blood pressure reduced the risk of deterioration in visual acuity by 3 lines on an eye chart.12 Therefore, intensive glycemic control and blood pressure reduction are important in reducing the progression of retinopathy and the possible complication of blindness.

An ACE inhibitor should be initiated in patients with diabetes, unless otherwise contraindicated. The "start-low-go-slow" approach should be used when initiating any medication, especially antihypertensives, to avoid adverse drug reactions and to obtain the lowest therapeutic dose. Patients will need frequent monitoring until the lowest therapeutic dose is achieved. If the patient cannot obtain good blood pressure control with one medication, another medication from a different class can be added, such as a diuretic. These medications should be added in a stepwise fashion and titrated to a maximum therapeutic dose or until the blood pressure goal of <130/80 mm Hg is obtained.

Lipids

Type 2 diabetes is associated with a 2-to 4-fold excess risk of coronary heart disease (CHD). Therefore, treatment of lipid disorders is imperative.13 Elevated lipids, including low-density lipoprotein (LDL) and triglycerides, are responsible for the macrovascular complications associated with diabetes, such as heart attack and stroke. As evidenced by the growing obesity epidemic, macrovascular complications in patients often are present long before diabetes is diagnosed.

Experts disagree about which component of the cholesterol panel to target in order to reduce CV events. A few clinical trials have attempted to clarify this issue, but all have resulted in slightly different conclusions. It appears from observational studies that high-density lipoprotein (HDL) may be the most consistent predictor of CHD in type 2 diabetic subjects, followed by triglycerides and total cholesterol. 13 Strict glycemic control may contribute to a reduction in triglyceride levels but will not completely eliminate the excess risk of CHD in type 2 diabetic patients.

The current guidelines indicate that the following goals are optimal for a reduction in CV end points in diabetic patients without previous CHD: LDL <100 mg/dL; HDL: for men, >40 mg/dL, for women, >50 mg/dL; and triglycerides <150 mg/dL. These guidelines have been set forth in the National Cholesterol Education Program.14 These goals may be reached in mildly elevated patients (LDL >140 mg/dL) through lifestyle modification, including MNT and increased physical activity. If the patient has a high risk for CHD or an LDL level >25 mg/dL above the goal (ie, LDL >125 mg/dL), a provider may decide to initiate medication therapy along with lifestyle modification. Providers ought to start medication in patients with LDL >160 mg/dL.

Statins, also known as 5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are the initial medications of choice, unless otherwise contraindicated. This class of medication provides a reduction in total cholesterol, LDL, and triglycerides, as well as an increase in HDL. If patients cannot reach individual lipid panel goals, other classes of medications can be added, such as the fibrates, for targeting hypertriglyceridemia; or a selective cholesterol absorption inhibitor, which blocks intestinal absorption of dietary and biliary cholesterol. Reduction of LDL cholesterol remains the initial target for dyslipidemia management.

The clinical triad of improvement in glycemic control, reduction of blood pressure, and improvement in the lipid panel is essential for the reduction of all complications associated with diabetes. Controlling these factors will not only reduce the morbidity and mortality associated with diabetes, but also will provide a better quality of life for diabetic patients. A little preventive medicine will go a long way in reducing future health care dollars for the treatment of diabetic complications.

Dr. Muzyk is a clinical pharmacy specialist at the Portland VA Medical Center in Portland, Ore.

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