Content on this page requires a newer version of Adobe Flash Player.

Get Adobe Flash player

Complications of Diabetes

VI. PREVENTION AND MANAGEMENT OF DIABETES COMPLICATIONS

Section Overview

This section covers a wide variety of topics, and for the average person suffering with diabetes, will be where they will find suggestions to deal with some of the most common problems once you have been diagnosed or diabetes has started to cause complications in performing your daily activities. This section details the screening and treatment for: cardiovascular disease, which causes hypertension and high blood pressure; Dyslipidemia, which is lipid management and cholesterol goals; Antiplatelet agents to deal with clotting, or lack thereof; Smoking cessation; CHD; Nephropathy, or kidney disease; Retinopathy, retina damage or retinopathy is an ocular manifestation of systemic disease; Neuropathy, referring to disorders of the nerves of the peripheral nervous system; foot and leg care. Use the menu to the left to navigate this section.

A. Cardiovascular Disease CVD

CVD is the major cause of morbidity and mortality for individuals with diabetes and the largest contributor to the direct and indirect costs of diabetes. The common conditions coexisting with Type 2 diabetes (e.g., hypertension and dyslipidemia) are clear risk factors for CVD, and diabetes itself confers independent risk. Numerous studies have shown the efficacy of controlling individual cardiovascular risk factors in preventing or slowing CVD in people with diabetes. Large benefits are seen when multiple risk factors are addressed globally. Evidence is summarized in the following sections and reviewed in detail in the ADA technical reviews on hypertension, dyslipidemia, aspirin therapy, and smoking cessation and in the American Heart Association (AHA)/ADA scientific statement on prevention of CVD in people with diabetes.

back to top

1. Hypertension/blood pressure control

Recommendations

Screening and diagnosis

  • Blood pressure should be measured at every routine diabetes visit. Patients found to have a systolic blood pressure of ≥130 mmHg or a diastolic blood pressure of ≥80 mmHg should have blood pressure confirmed on a separate day. Repeat systolic blood pressure of ≥130 mmHg or diastolic blood pressure of ≥80 mmHg confirms a diagnosis of hypertension.

Goals

  • Patients with diabetes should be treated to a systolic blood pressure <130 mmHg.
  • Patients with diabetes should be treated to a diastolic blood pressure <80 mmHg.

Treatment

  • Patients with a systolic blood pressure of 130–139 mmHg or a diastolic blood pressure of 80–89 mmHg may be given lifestyle therapy alone for a maximum of 3 months and then, if targets are not achieved, be treated with the addition of pharmacological agents.
  • Patients with more severe hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg) at diagnosis or follow-up should receive pharmacologic therapy in addition to lifestyle therapy. 
  • Pharmacologic therapy for patients with diabetes and hypertension should be with a regimen that includes either an ACE inhibitor or an angiotensin receptor blocker (ARB). If one class is not tolerated, the other should be substituted. If needed to achieve blood pressure targets, a thiazide diuretic should be added to those with an estimated GFR (see below) ≥30 ml/min per 1.73 m2 and a loop diuretic for those with an estimated GFR <30 ml/min per 1.73 m2.
  • Multiple drug therapy (two or more agents at maximal doses) is generally required to achieve blood pressure targets.
  • If ACE inhibitors, ARBs, or diuretics are used, kidney function and serum potassium levels should be closely monitored.
  • In pregnant patients with diabetes and chronic hypertension, blood pressure target goals of 110–129/65–79 mmHg are suggested in the interest of long-term maternal health and minimizing impaired fetal growth. ACE inhibitors and ARBs are contraindicated during pregnancy.

Hypertension is a common comorbidity of diabetes, affecting the majority of patients, with prevalence depending on type of diabetes, age, obesity, and ethnicity. Hypertension is a major risk factor for both CVD and microvascular complications. In Type 1 diabetes, hypertension is often the result of underlying nephropathy, while in Type 2 it usually coexists with other cardiometabolic risk factors.

Screening and diagnosis

Measurement of blood pressure in the office should be done by a trained individual and follow the guidelines established for nondiabetic individuals: measurement in the seated position, with feet on the floor and arm supported at heart level, after 5 min of rest. Cuff size should be appropriate for the upper arm circumference. Elevated values should be confirmed on a separate day. Because of the clear synergistic risks of hypertension and diabetes, the diagnostic cutoff for a diagnosis of hypertension is lower in people with diabetes (blood pressure ≥130/80) than in those without diabetes (blood pressure ≥140/90 mmHg).

Home blood pressure self-monitoring and 24-h ambulatory blood pressure monitoring may provide additional evidence of “white coat” and masked hypertension and other discrepancies between office and “true” blood pressure, and studies in nondiabetic populations show that home measurements may better correlate with CVD risk than office measurements. However, the preponderance of the clear evidence of benefits of treatment of hypertension in people with diabetes is based on office measurements.

Treatment goals

Randomized clinical trials have demonstrated the benefit (reduction of CHD events, stroke, and nephropathy) of lowering blood pressure to <140 mmHg systolic and <80 mmHg diastolic in individuals with diabetes. Epidemiologic analyses show that blood pressure >115/75 mmHg is associated with increased cardiovascular event rates and mortality in individuals with diabetes. Therefore, a target blood pressure goal of <130/80 mmHg is reasonable if it can be safely achieved. The ongoing ACCORD trial is designed to determine whether blood pressure lowering to systolic blood pressure <120 mmHg provides greater cardiovascular protection than a systolic blood pressure level of <140 mmHg in patients with Type 2 diabetes (www.accord.org).

Treatment strategies

Although there are no well-controlled studies of diet and exercise in the treatment of hypertension in individuals with diabetes, studies in nondiabetic individuals have shown anti-hypertensive effects similar to pharmacologic monotherapy of reducing sodium intake and excess body weight; increasing consumption of fruits, vegetables, and low-fat dairy products; avoiding excessive alcohol consumption; and increasing activity levels. These nonpharmacological strategies may also positively affect glycemia and lipid control. Their effects on cardiovascular events have not been established. An initial trial of nonpharmacologic therapy may be reasonable in diabetic individuals with mild hypertension (systolic blood pressure 130–139 mmHg or diastolic blood pressure 80–89 mmHg). If the blood pressure is ≥140 mmHg systolic and/or ≥90 mmHg diastolic at the time of diagnosis, pharmacologic therapy should be initiated along with nonpharmacologic therapy.

Lowering of blood pressure with regimens based on a variety of antihypertensive drugs, including ACE inhibitors, ARBs, β-blockers, diuretics, and calcium channel blockers, has been shown to be effective in reducing cardiovascular events. Several studies have suggested that ACE inhibitors may be superior to dihydropyridine calcium channel blockers in reducing cardiovascular events. However, a variety of other studies have shown no specific advantage to ACE inhibitors as initial treatment of hypertension in the general hypertensive population, but rather an advantage on cardiovascular outcomes of initial therapy with low-dose thiazide diuretics.

In people with diabetes, inhibitors of the renin-angiotensin system (RAS) may have unique advantages for initial or early therapy of hypertension. In a nonhypertension trial of high-risk individuals, including a large subset with diabetes, an ACE inhibitor reduced CVD outcomes. In patients with congestive heart failure (CHF), including diabetic subgroups, ARBs have been shown to reduce major CVD outcomes, and in Type 2 patients with significant nephropathy, ARBs were superior to calcium channel blockers for reducing heart failure. Though evidence for distinct advantages of RAS inhibitors on CVD outcomes in diabetes remains conflicting, the high CVD risks associated with diabetes, and the high prevalence of undiagnosed CVD, may still favor recommendations for their use as first-line hypertension therapy in people with diabetes. Recently, the blood pressure arm of the ADVANCE trial demonstrated that routine administration of a fixed combination of the ACE inhibitor perindopril and the diuretic indapamide significantly reduced combined microvascular and macrovascular outcomes, as well as CVD and total mortality. The improved outcomes could also have been due to lower achieved blood pressure in the perindopril-indapamide arm. The compelling benefits of RAS inhibitors in diabetic patients with albuminuria or renal insufficiency provide additional rationale for use of these agents (see section VI.B below).

An important caveat is that most patients with hypertension require multi-drug therapy to reach treatment goals, especially diabetic patients whose targets are lower. Many patients will require three or more drugs to reach target goals. If blood pressure is refractory to multiple agents, clinicians should consider an evaluation for secondary forms of hypertension.

During pregnancy in diabetic women with chronic hypertension, target blood pressure goals of systolic blood pressure 110–129 mmHg and diastolic blood pressure 65–79 mmHg are reasonable, as they contribute to long-term maternal health. Lower blood pressure levels may be associated with impaired fetal growth. During pregnancy, treatment with ACE inhibitors and ARBs is contraindicated, since they are likely to cause fetal damage. Antihypertensive drugs known to be effective and safe in pregnancy include methyldopa, labetalol, diltiazem, clonidine, and prazosin. Chronic diuretic use during pregnancy has been associated with restricted maternal plasma volume, which might reduce uteroplacental perfusion.

back to top

2. Dyslipidemia/lipid management

Recommendations

Screening

In most adult patients, measure fasting lipid profile at least annually. In adults with low-risk lipid values (LDL cholesterol <100 mg/dl, HDL cholesterol >50 mg/dl, and triglycerides <150 mg/dl), lipid assessments may be repeated every 2 years.

Treatment recommendations and goals

  • Lifestyle modification focusing on the reduction of saturated fat, trans fat, and cholesterol intake; weight loss (if indicated); and increased physical activity should be recommended to improve the lipid profile in patients with diabetes.
  • Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients:
  • with overt CVD
  • without CVD who are over the age of 40 and have one or more other CVD risk factors.
  • For lower-risk patients than the above (e.g., without overt CVD and under the age of 40), statin therapy should be considered in addition to lifestyle therapy if LDL cholesterol remains above 100 mg/dl or in those with multiple CVD risk factors.
  • In individuals without overt CVD, the primary goal is an LDL cholesterol <100 mg/dl (2.6 mmol/l).
  • In individuals with overt CVD, a lower LDL cholesterol goal of <70 mg/dl (1.8 mmol/l), using a high dose of a statin, is an option.
  • If drug-treated patients do not reach the above targets on maximal tolerated statin therapy, a reduction in LDL cholesterol of ∼30–40% from baseline is an alternative therapeutic goal.
  • Triglycerides levels <150 mg/dl (1.7 mmol/l) and HDL cholesterol >40 mg/dl (1.0 mmol/l) in men and >50 mg/dl (1.3 mmol/l) in women are desirable. However, LDL cholesterol–targeted statin therapy remains the preferred strategy.
  • If targets are not reached on maximally tolerated doses of statins, combination therapy using statins and other lipid-lowering agents may be considered to achieve lipid targets but has not been evaluated in outcome studies for either CVD outcomes or safety.
  • Statin therapy is contraindicated in pregnancy.

Evidence for benefits of lipid-lowering therapy

Patients with Type 2 diabetes have an increased prevalence of lipid abnormalities, contributing to their high risk of CVD. For the past decade or more, multiple clinical trials demonstrated significant effects of pharmacologic (primarily statin) therapy on CVD outcomes in subjects with CHD and for primary CVD prevention. Subanalyses of diabetic subgroups of larger trials and trials specifically in subjects with diabetes showed significant primary and secondary prevention of CVD events ± CHD deaths in diabetic populations. As shown in Table 10, and similar to findings in nondiabetic subjects, reduction in “hard” CVD outcomes (CHD death and nonfatal MI) can be more clearly seen in diabetic subjects with high baseline CVD risk (known CVD and/or very high LDL cholesterol levels), but overall the benefits of statin therapy in people with diabetes at moderate or high risk for CVD are convincing.

Low levels of HDL cholesterol, often associated with elevated triglyceride levels, are the most prevalent pattern of dyslipidemia in persons with Type 2 diabetes. However, the evidence base for drugs that target these lipid fractions is significantly less robust than that for statin therapy. Nicotinic acid has been shown to reduce CVD outcomes, although the study was done in a nondiabetic cohort. Gemfibrozil has been shown to decrease rates of CVD events in subjects without diabetes and in the diabetic subgroup in one of the larger trials. However, in a large trial specific to diabetic patients, fenofibrate failed to reduce overall cardiovascular outcomes.

Dyslipidemia treatment and target lipid levels

For most patients with diabetes, the first priority of dyslipidemia therapy (unless severe hypertriglyceridemia is the immediate issue) is to lower LDL cholesterol to a target goal of <100 mg/dl (2.60 mmol/l). Lifestyle intervention, including MNT, increased physical activity, weight loss, and smoking cessation, may allow some patients to reach lipid goals. Nutrition intervention should be tailored according to each patient's age, type of diabetes, pharmacological treatment, lipid levels, and other medical conditions and should focus on the reduction of saturated fat, cholesterol, and trans unsaturated fat intake. Glycemic control can also beneficially modify plasma lipid levels, particularly in patients with very high triglycerides and poor glycemic control.

In those with clinical CVD or over age 40 with other CVD risk factors, pharmacological treatment should be added to lifestyle therapy regardless of baseline lipid levels. Statins are the drugs of choice for LDL cholesterol lowering.

In patients other than those described above, statin treatment should be considered if there is an inadequate LDL cholesterol response to lifestyle modifications and improved glucose control, or if the patient has increased cardiovascular risk (e.g., multiple cardiovascular risk factors or long duration of diabetes). Very little clinical trial evidence exists for Type 2 patients under the age of 40, or for Type 1 patients of any age. In the Heart Protection Study, the subgroup of 600 patients with Type 1 diabetes (lower age limit 40 years) had a proportionately similar reduction in risk as patients with Type 2 diabetes, although not statistically significant. Although the data are not definitive, consideration should be given to similar lipid-lowering goals in Type 1 diabetic patients as those in Type 2 diabetic patients, particularly if they have other cardiovascular risk factors.

Alternative LDL cholesterol goals

Virtually all trials of statins and CVD outcomes have tested specific doses of statins against placebo, other doses of statin, or other statins, rather than aiming for specific LDL cholesterol goals. As can be seen in Table 10, placebo-controlled trials generally achieved LDL cholesterol reductions of 30–40% from baseline. Hence, LDL cholesterol lowering of this magnitude is an acceptable outcome for patients who cannot reach LDL cholesterol goals due to severe baseline elevations in LDL cholesterol and/or intolerance of maximal, or any, statin doses. Additionally, for those with baseline LDL cholesterol minimally above 100 mg/dl, prescribing statin therapy to lower LDL cholesterol about 30–40% from baseline is probably more effective than prescribing just enough to get LDL cholesterol slightly below 100 mg/dl.

Recent clinical trials in high-risk patients, such as those with acute coronary syndromes or previous cardiovascular events, have demonstrated that more aggressive therapy with high doses of statins to achieve an LDL cholesterol of <70 mg/dl led to a significant reduction in further events. Therefore, a reduction in LDL cholesterol to a goal of <70 mg/dl is an option in very-high-risk diabetic patients with overt CVD.

In individual patients, LDL cholesterol lowering with statins is highly variable, and this variable response is poorly understood. Reduction of CVD events with statins correlates very closely with LDL cholesterol lowering. When maximally tolerated doses of statins fail to significantly lower LDL cholesterol (<30% reduction from patients baseline), the primary aim of combination therapy should be to achieve additional LDL cholesterol lowering. Niacin, fenofibrate, ezetimibe, and bile acid sequestrants all offer additional LDL cholesterol lowering. The evidence that combination therapy provides a significant increment in CVD risk reduction over statin therapy alone is still elusive.

Treatment of other lipoprotein fractions or targets

Severe hypertriglyceridemia may warrant immediate therapy of this abnormality with lifestyle and usually pharmacologic therapy (fibric acid derivative or niacin) to reduce the risk of acute pancreatitis. In the absence of severe hypertriglyceridemia, therapy targeting HDL cholesterol or triglycerides has intuitive appeal but lacks the evidence base of statin therapy. If the HDL cholesterol is <40 mg/dl and the LDL cholesterol is between 100 and 129 mg/dl, gemfibrozil or niacin might be used, especially if a patient is intolerant to statins. Niacin is the most effective drug for raising HDL cholesterol. It can significantly increase blood glucose at high doses, but recent studies demonstrate that at modest doses (750–2,000 mg/day), significant improvements in LDL cholesterol, HDL cholesterol, and triglyceride levels are accompanied by only modest changes in glucose that are generally amenable to adjustment of diabetes therapy.

Combination therapy, with a statin and a fibrate or a statin and niacin, may be efficacious for treatment for all three lipid fractions, but this combination is associated with an increased risk for abnormal transaminase levels, myositis, or rhabdomyolysis. The risk of rhabdomyolysis is higher with higher doses of statins and with renal insufficiency and seems to be lower when statins are combined with fenofibrate than gemfibrozil. Several ongoing trials may provide much-needed evidence for the effects of combination therapy on cardiovascular outcomes.

In 2008, a consensus panel convened by ADA and the American College of Cardiology recommended a greater focus on non-HDL cholesterol and apolipoprotein B (apo B) in patients who are likely to have small LDL particles, such as people with diabetes. The consensus panel suggested that for statin-treated patients in whom the LDL cholesterol goal would be <70 mg/dl (non-HDL cholesterol <100 mg/dl), apo B should be measured and treated to <80 mg/dl.

For patients on statins with an LDL cholesterol goal of <100 mg/dl (non-HDL cholesterol <130 mg/dl), apo B should be measured and treated to below 90 mg/dl.

back to top

3. Antiplatelet agents

Recommendations

  • Use aspirin therapy (75–162 mg/day) as a primary prevention strategy in those with Type 1 or Type 2 diabetes at increased cardiovascular risk, including those who are >40 years of age or who have additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria).
  • Use aspirin therapy (75–162 mg/day) as a secondary prevention strategy in those with diabetes with a history of CVD.
  • For patients with CVD and documented aspirin allergy, clopidogrel (75 mg/day) should be used.
  • Combination therapy with ASA (75–162 mg/day) and clopidogrel (75 mg/day) is reasonable for up to a year after an acute coronary syndrome.
  • Aspirin therapy is not recommended in people under 30 years of age due to lack of evidence of benefit and is contraindicated in patients under the age of 21 years because of the associated risk of Reye's syndrome.

The use of aspirin in diabetes is reviewed in detail in the ADA technical review and position statement on this topic. Aspirin has been recommended for primary and secondary prevention of cardiovascular events in high-risk diabetic and nondiabetic individuals. One large meta-analysis and several clinical trials demonstrate the efficacy of using aspirin as a preventive measure for cardiovascular events, including stroke and myocardial infarction. Many trials have shown an ∼30% decrease in myocardial infarction and a 20% decrease in stroke in a wide range of patients, including young and middle-aged patients, patients with and without a history of CVD, men and women, and patients with hypertension.

Dosages used in most clinical trials ranged from 75 to 325 mg/day. There is little evidence to support any specific dose, but using the lowest possible dosage may help reduce side effects. Conversely, a randomized trial of 100 mg of aspirin daily showed less of a primary prevention effect, without statistical significance, in the large diabetic subgroup in contrast to significant benefit in those without diabetes, raising the issue of aspirin resistance in those with diabetes.

The systematic review of evidence for the U.S. Preventive Services Task Force (USPSTF) estimated that aspirin reduced the risk for nonfatal and fatal MI (odds ratio 0.72 [95% CI 0.60–0.87]). The review acknowledged the low numbers of diabetic subjects in most trials but concluded that subset analyses and a single trial in diabetic patients suggested that the estimates extended to those with diabetes. The USPSTF stated that the risk-to-benefit ratio favors aspirin use when 5-year CHD risk equals or exceeds 3% and suggested aspirin therapy be considered for men >40 years of age, postmenopausal women, and younger persons with CHD risk factors (including diabetes).

There is no evidence for a specific age at which to start aspirin, but aspirin has not been studied at ages <30 years.

Clopidogrel has been demonstrated to reduce CVD events in diabetic individuals. Adjunctive therapy in the first year after acute coronary syndrome in very-high-risk patients, or as alternative therapy in aspirin-intolerant patients, should be considered.

back to top

4. Smoking cessation

Recommendations

  • Advise all patients not to smoke.
  • Include smoking cessation counseling and other forms of treatment as a routine component of diabetes care.

Issues of smoking in diabetes are reviewed in detail in the ADA technical review and position statement on this topic. A large body of evidence from epidemiological, case-control, and cohort studies provides convincing documentation of the causal link between cigarette smoking and health risks. Cigarette smoking contributes to one of every five deaths in the U.S. and is the most important modifiable cause of premature death. Much of the prior work documenting the impact of smoking on health did not separately discuss results on subsets of individuals with diabetes, suggesting that the identified risks are at least equivalent to those found in the general population. Other studies of individuals with diabetes consistently found a heightened risk of CVD and premature death among smokers. Smoking is also related to the premature development of microvascular complications of diabetes and may have a role in the development of

Type 2 diabetes.

A number of large randomized clinical trials have demonstrated the efficacy and cost-effectiveness of smoking cessation counseling in changing smoking behavior and reducing tobacco use. The routine and thorough assessment of tobacco use is important as a means of preventing smoking or encouraging cessation. Special considerations should include assessment of level of nicotine dependence, which is associated with difficulty in quitting and relapse. Free telephone quit lines are available in each state (see www.naquitline.org).

back to top

5. CHD screening and treatment

Recommendations

Screening

  • In asymptomatic patients, evaluate risk factors to stratify patients by 10-year risk, and treat risk factors accordingly.

Treatment

  • In patients with known CVD, ACE inhibitor, aspirin, and statin therapy (if not contraindicated) should be used to reduce the risk of cardiovascular events.
  • In patients with a prior myocardial infarction, add β-blockers (if not contraindicated) to reduce mortality.
  • In patients >40 years of age with another cardiovascular risk factor (hypertension, family history, dyslipidemia, microalbuminuria, cardiac autonomic neuropathy, or smoking), aspirin and statin therapy (if not contraindicated) should be used to reduce the risk of cardiovascular events.
  • In patients with CHF, TZD use is contraindicated.
  • Metformin may be used in patients with stable CHF if renal function is normal. It should be avoided in unstable or hospitalized patients with CHF.

Screening for CAD is reviewed in a recently updated consensus statement. To identify the presence of CAD in diabetic patients without clear or suggestive symptoms, a risk factor–based approach to the initial diagnostic evaluation and subsequent follow-up has intuitive appeal. However, recent studies concluded that using this approach fails to identify which patients will have silent ischemia on screening tests.

Candidates for cardiac testing include those with 1) typical or atypical cardiac symptoms and 2) an abnormal resting electrocardiogram (ECG). The screening of asymptomatic patients remains controversial, especially as intensive medical therapy indicated in diabetic patients at high risk for CVD has an increasing evidence base for providing equal outcomes to invasive revascularization, including in diabetic patients. There is also recent preliminary evidence that silent myocardial ischemia may reverse over time, adding to the controversy concerning aggressive screening strategies. Finally, a recent randomized observational trial presented at the ADA's Scientific Sessions in June 2008 demonstrated no clinical benefit to routine screening of asymptomatic patients with Type 2 diabetes and normal ECGs. Despite abnormal myocardial perfusion imaging in more than one in five patients, cardiac outcomes were essentially equal (and very low) in screened versus unscreened patients.

In all patients with diabetes, cardiovascular risk factors should be assessed at least annually. These risk factors include dyslipidemia, hypertension, smoking, a positive family history of premature coronary disease, and the presence of micro- or macroalbuminuria. Abnormal risk factors should be treated as described elsewhere in these guidelines. Patients at increased CHD risk should receive aspirin and a statin and ACE inhibitor or ARB therapy if hypertensive, unless there are contraindications to a particular drug class. While clear benefit exists for ACE inhibitor and ARB therapy in patients with nephropathy or hypertension, the benefits in patients with CVD in the absence of these conditions is less clear, especially when LDL cholesterol is concomitantly controlled.

B. Nephropathy screening and treatment

Recommendations

  • To reduce the risk or slow the progression of nephropathy, optimize glucose control.
  • To reduce the risk or slow the progression of nephropathy, optimize blood pressure control.

Screening

  • Perform an annual test to assess urine albumin excretion in Type 1 diabetic patients with diabetes duration of ≥5 years and in all Type 2 diabetic patients, starting at diagnosis.
  • Measure serum creatinine at least annually in all adults with diabetes regardless of the degree of urine albumin excretion. The serum creatinine should be used to estimate GFR and stage the level of chronic kidney disease (CKD), if present.

Treatment

  • In the treatment of the nonpregnant patient with micro- or macroalbuminuria, either ACE inhibitors or ARBs should be used.
  • While there are no adequate head-to-head comparisons of ACE inhibitors and ARBs, there is clinical trial support for each of the following statements:
  • In patients with Type 1 diabetes, hypertension, and any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy.
  • In patients with Type 2 diabetes, hypertension, and microalbuminuria, both ACE inhibitors and ARBs have been shown to delay the progression to macroalbuminuria.
  • In patients with Type 2 diabetes, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine >1.5 mg/dl), ARBs have been shown to delay the progression of nephropathy.
  • If one class is not tolerated, the other should be substituted.
  • Reduction of protein intake to 0.8–1.0 g • kg body wt−1 • day−1 in individuals with diabetes and the earlier stages of CKD and to 0.8 g • kg body wt−1 • day−1 in the later stages of CKD may improve measures of renal function (urine albumin excretion rate, GFR) and is recommended.
  • When ACE inhibitors, ARBs, or diuretics are used, monitor serum creatinine and potassium levels for the development of acute kidney disease and hyperkalemia.
  • Continued monitoring of urine albumin excretion to assess both response to therapy and progression of disease is recommended.
  • Consider referral to a physician experienced in the care of kidney disease when there is uncertainty about the etiology of kidney disease (active urine sediment, absence of retinopathy, rapid decline in GFR), difficult management issues, or advanced kidney disease.


Diabetic nephropathy occurs in 20–40% of patients with diabetes and is the single leading cause of end-stage renal disease (ESRD). Persistent albuminuria in the range of 30–299 mg/24 h (microalbuminuria) has been shown to be the earliest stage of diabetic nephropathy in Type 1 diabetes and a marker for development of nephropathy in Type 2 diabetes. Microalbuminuria is also a well-established marker of increased CVD risk. Patients with microalbuminuria who progress to macroalbuminuria (300 mg/24 h) are likely to progress to ESRD. However, a number of interventions have been demonstrated to reduce the risk and slow the progression of renal disease.


Intensive diabetes management with the goal of achieving near normoglycemia has been shown in large prospective randomized studies to delay the onset of microalbuminuria and the progression of micro- to macroalbuminuria in patients with Type 1 and Type 2 diabetes. The UKPDS provided strong evidence that control of blood pressure can reduce the development of nephropathy. In addition, large prospective randomized studies in patients with Type 1 diabetes have demonstrated that achievement of lower levels of systolic blood pressure (<140 mmHg) resulting from treatment using ACE inhibitors provides a selective benefit over other antihypertensive drug classes in delaying the progression from micro- to macroalbuminuria and can slow the decline in GFR in patients with macroalbuminuria. In Type 2 diabetes with hypertension and normoalbuminuria, ACE inhibition has been demonstrated to delay progression to microalbuminuria.


In addition, ACE inhibitors have been shown to reduce major CVD outcomes (i.e., myocardial infarction, stroke, death) in patients with diabetes, thus further supporting the use of these agents in patients with microalbuminuria, a CVD risk factor. ARBs have also been shown to reduce the rate of progression from micro- to macroalbuminuria as well as ESRD in patients with Type 2 diabetes. Some evidence suggests that ARBs have a smaller magnitude of rise in potassium compared with ACE inhibitors in people with nephropathy. It is important to note that the benefits of both ACE inhibitors and ARBs in those with diabetic nephropathy are strongly associated with the reduction in albuminuria. Combinations of drugs that block the rennin-angiotensin-aldosterone system (e.g., an ACE inhibitor plus an ARB, a mineralocorticoid antagonist, or a direct renin inhibitor) have been shown to provide additional lowering of albuminuria.

However, the long-term effects of such combinations on renal or cardiovascular outcomes have not yet been evaluated in clinical trials.


Other drugs, such as diuretics, calcium channel blockers, and β-blockers, should be used as additional therapy to further lower blood pressure in patients already treated with ACE inhibitors or ARBs or as alternate therapy in the rare individual unable to tolerate ACE inhibitors or ARBs.


Studies in patients with varying stages of nephropathy have shown that protein restriction helps slow the progression of albuminuria, GFR decline, and occurrence of ESRD. Protein restriction should be considered particularly in patients whose nephropathy seems to be progressing despite optimal glucose and blood pressure control and use of ACE inhibitor and/or ARBs.


Assessment of albuminuria status and renal function


Screening for microalbuminuria can be performed by measurement of the albumin-to-creatinine ratio in a random spot collection (preferred method); 24-h or timed collections are more burdensome and add little to prediction or accuracy. Measurement of a spot urine for albumin only, whether by immunoassay or by using a dipstick test specific for microalbumin, without simultaneously measuring urine creatinine, is somewhat less expensive but susceptible to false-negative and -positive determinations as a result of variation in urine concentration due to hydration and other factors.


Abnormalities of albumin excretion are defined in Table 12. Because of variability in urinary albumin excretion, two of three specimens collected within a 3- to 6-month period should be abnormal before considering a patient to have crossed one of these diagnostic thresholds. Exercise within 24 h, infection, fever, CHF, marked hyperglycemia, and marked hypertension may elevate urinary albumin excretion over baseline values.


Information on presence of abnormal urine albumin excretion in addition to level of GFR may be used to stage CKD. The National Kidney Foundation classification is primarily based on GFR levels and therefore differs from other systems, in which staging is based primarily on urinary albumin excretion. Studies have found decreased GFR in the absence of increased urine albumin excretion in a substantial percentage of adults with diabetes. Epidemiologic evidence suggests that a substantial fraction of those with CKD in the setting of diabetes have little or no detectable albuminuria. Serum creatinine should therefore be measured at least annually in all adults with diabetes, regardless of the degree of urine albumin excretion.


Serum creatinine should be used to estimate GFR and to stage the level of CKD, if present. GFR can be estimated using formulae such as the Cockroft-Gault equation or a prediction formula using data from the Modification of Diet and Renal Disease study. GFR calculators are available at http://www.nkdep.nih.gov. Many clinical laboratories now report estimated GFR in addition to serum creatinine.


The role of continued annual quantitative assessment of albumin excretion after diagnosis of microalbuminuria and institution of ACE inhibitor or ARB therapy and blood pressure control is unclear. Continued surveillance can assess both response to therapy and progression of disease. Some suggest that reducing abnormal albuminuria (>30 mg/g) to the normal or near-normal range may improve renal and cardiovascular prognosis, but this approach has not been formally evaluated in prospective trials.


Complications of kidney disease correlate with level of kidney function. When the estimated GFR is <60 ml/min per 1.73 m2, screening for anemia, malnutrition, and metabolic bone disease is indicated. Early vaccination against hepatitis B is indicated in patients likely to progress to end-stage kidney disease.


Consider referral to a physician experienced in the care of kidney disease when there is uncertainty about the etiology of kidney disease (active urine sediment, absence of retinopathy, rapid decline in GFR), difficult management issues, or advanced kidney disease. The threshold for referral may vary depending on the frequency with which a provider encounters diabetic patients with significant kidney disease. Consultation with a nephrologist when stage 4 CKD develops has been found to reduce cost, improve quality of care, and keep people off dialysis longer. However, nonrenal specialists should not delay educating their patients about the progressive nature of diabetic kidney disease, the renal preservation benefits of aggressive treatment of blood pressure, blood glucose, and hyperlipidemia, and the potential need for renal replacement therapy.


C. Retinopathy screening and treatment

Recommendations

  • To reduce the risk or slow the progression of retinopathy, optimize glycemic control.
  • To reduce the risk or slow the progression of retinopathy, optimize blood pressure control.

Screening

  • Adults and children aged 10 years or older with Type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years after the onset of diabetes.
  • Patients with Type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist shortly after the diagnosis of diabetes.
  • Subsequent examinations for Type 1 and Type 2 diabetic patients should be repeated annually by an ophthalmologist or optometrist. Less frequent exams (every 2–3 years) may be considered following one or more normal eye exams. Examinations will be required more frequently if retinopathy is progressing.
  • Women with preexisting diabetes who are planning pregnancy or who have become pregnant should have a comprehensive eye examination and be counseled on the risk of development and/or progression of diabetic retinopathy. Eye examination should occur in the first trimester with close follow-up throughout pregnancy and 1 year postpartum.

Treatment

  • Promptly refer patients with any level of macular edema, severe NPDR, or any PDR to an ophthalmologist who is knowledgeable and experienced in the management and treatment of diabetic retinopathy.
  • Laser photocoagulation therapy is indicated to reduce the risk of vision loss in patients with high-risk PDR and clinically significant macular edema and in some cases of severe NPDR.
  • The presence of retinopathy is not a contraindication to aspirin therapy for cardioprotection, as this therapy does not increase the risk of retinal hemorrhage.

Diabetic retinopathy is a highly specific vascular complication of both Type 1 and Type 2 diabetes, with prevalence strongly related to the duration of diabetes. Diabetic retinopathy is the most frequent cause of new cases of blindness among adults aged 20–74 years. Glaucoma, cataracts, and other disorders of the eye occur earlier and more frequently in people with diabetes.

In addition to duration of diabetes, other factors that increase the risk of, or are associated with, retinopathy include chronic hyperglycemia, the presence of nephropathy, and hypertension. Intensive diabetes management with the goal of achieving near normoglycemia has been shown in large prospective randomized studies to prevent and/or delay the onset and progression of diabetic retinopathy. Lowering blood pressure has been shown to decrease the progression of retinopathy. Several case series and a controlled prospective study suggest that pregnancy in Type 1 diabetic patients may aggravate retinopathy; laser photocoagulation surgery can minimize this risk.

One of the main motivations for screening for diabetic retinopathy is the established efficacy of laser photocoagulation surgery in preventing vision loss. Two large trials, the Diabetic Retinopathy Study (DRS) and the Early Treatment Diabetic Retinopathy Study (ETDRS), provide the strongest support for the therapeutic benefits of photocoagulation surgery.

The DRS showed that panretinal photocoagulation surgery reduced the risk of severe vision loss from PDR from 15.9% in untreated eyes to 6.4% in treated eyes. The benefit was greatest among patients whose baseline evaluation revealed high-risk characteristics (chiefly disc neovascularization or vitreous hemorrhage). Given the risks of modest loss of visual acuity and contraction of the visual field from panretinal laser surgery, such therapy is primarily recommended for eyes with PDR approaching or having high-risk characteristics.

The ETDRS established the benefit of focal laser photocoagulation surgery in eyes with macular edema, particularly those with clinically significant macular edema, with reduction of doubling of the visual angle (e.g., 20/50 to 20/100) from 20% in untreated eyes to 8% in treated eyes. The ETDRS also verified the benefits of panretinal photocoagulation for high-risk PDR, but not for mild or moderate NPDR. In older-onset patients with severe NPDR or less-than-high-risk PDR, the risk of severe vision loss or vitrectomy was reduced ∼50% by early laser photocoagulation surgery at these stages.

Laser photocoagulation surgery in both trials was beneficial in reducing the risk of further vision loss, but generally not beneficial in reversing already diminished acuity. This preventive effect and the fact that patients with PDR or macular edema may be asymptomatic provide strong support for a screening program to detect diabetic retinopathy.

As retinopathy is estimated to take at least 5 years to develop after the onset of hyperglycemia, patients with Type 1 diabetes should have an initial dilated and comprehensive eye examination within 5 years after the onset of diabetes. Patients with Type 2 diabetes, who generally have had years of undiagnosed diabetes and who have a significant risk of prevalent diabetic retinopathy at time of diabetes diagnosis, should have an initial dilated and comprehensive eye examination soon after diagnosis. Examinations should be performed by an ophthalmologist or optometrist who is knowledgeable and experienced in diagnosing the presence of diabetic retinopathy and is aware of its management. Subsequent examinations for Type 1 and Type 2 diabetic patients are generally repeated annually. Less frequent exams (every 2–3 years) may be cost effective after one or more normal eye exams, while examinations will be required more frequently if retinopathy is progressing.

Examinations can also be done with retinal photographs (with or without dilation of the pupil) read by experienced experts. In-person exams are still necessary when the photos are unacceptable and for follow-up of abnormalities detected. This technology has great potential in areas where qualified eye care professionals are not available and may enhance efficiency and reduce costs when the expertise of ophthalmologists can be utilized for more complex examinations and for therapy.

Results of eye examinations should be documented and transmitted to the referring health care professional. For a detailed review of the evidence and further discussion of diabetic retinopathy, see the ADA's technical review and position statement on this subject.