Chronic complications of diabetes. (Featured CME Topic: Diabetes Mellitus).

Diabetes complications can be avoided, and if they occur can be treated to prevent their progress and ameliorate any disability caused by these complications; however, to be treated, the complication must be diagnosed. The appropriate approach to diabetes complications, therefore, is to first use therapies that can avoid complications and also to detect complications at the earliest possible time so that treatment of these complications can be initiated.

THERAPIES TO PREVENT CHRONIC DIABETIC COMPLICATIONS

Glycemic Control

It has never been clearer that hyperglycemia, as assessed by the hemoglobin [A.sub.lc] ([HbA.sub.lc]) measurement, is the prime cause of diabetic microvascular complications (retinopathy, nephropathy, and neuropathy) and plays a role in the premature and accelerated development of diabetic macrovascular complications (coronary artery disease, cerebrovascular disease, and peripheral vascular disease). The Diabetes Control and Complications Trial (DCCT) showed that with a 2% difference (9% vs 7%) in the [HbA.sub.lc] level there was a 63% decrease in development of retinopathy, a 54% decrease in the development of nephropathy, a 60% decrease in the development of neuropathy, and a 41% decrease in the development of macrovascular disease in type 1 diabetic patients (1); furthermore, the incidence of these complications was low if the [HbA.sub.lc] level was maintained at 7%. Since below 7% the incidence of severe hypoglycemia increases dramatically, the recommendation from the American Diabetes Association (ADA) w as that the goal of diabetic therapy should be an [HbA.sub.lc] level of 7%. In addition, the DCCT showed that if the [HbA.sub.lc] level was above 8%, the rate of development of microvascular complications accelerated dramatically; as a result, the ADA recommended that intensification of therapy was required if the [HbA.sub.lc] level was above 8%.

Two prospective studies have shown an association between glycemic control and chronic diabetic complications in type 2 diabetes. The Kumamoto study (2) used thin, insulin-requiring, Japanese type 2 patients and used a protocol similar to that used by the DCCT. As expected, the outcomes were similar, with a 2.0% difference in [HbA.sub.lc] level being associated with a 69% decrease in retinopathy and a 70% decrease in nephropathy. The United Kingdom Prospective Diabetes Study (UKPDS) showed that with a 0.8% difference in [HbA.sub.lc] level (7.1% vs 7.9%), there was a 17% to 21% decrease in retinopathy, a 24% to 33% decrease in nephropathy, and a 16% decrease in macrovascular disease. (3) A later analysis of the UKPDS showed that the lower the [HbA.sub.lc] level was, the lower was the incidence of retinopathy, nephropathy, neuropathy, amputations, cataracts, congestive heart failure, myocardial infarctions, and stroke. Of special importance was the finding that there was no threshold below which a further reduc tion in the incidence of diabetic complications did not occur. (4) This is particularly important since a recent population study showed that even within the normal, nondiabetic [HbA.sub.lc] range the lower the [HbA.sub.lc] level attained, the lower was the incidence of cardiac events (5); therefore, the lower the [HbA.sub.lc] level in the type 2 patient, the better is the outcome. Fortunately, lower [HbA.sub.lc] levels are easier to achieve in the type 2 patient than in the type 1 patient because severe hypoglycemia is less common, and severe hypoglycemia is rare in patients taking metformin and/or a thiazolidinedione (TZD).

Hypertension Control

Controlling hypertension in both the type 1 patient and type 2 patient is as important as controlling hyperglycemia with regard to avoiding both microvascular and macrovascular complications. The UKPDS showed that, above a baseline systolic pressure of 110 mm Hg, the higher the blood pressure was, the greater was the risk of both microvascular and macrovascular diabetic complications. (6) The Hypertension Optimal Therapy (HOT) Study compared the outcomes of maintaining diastolic blood pressure to goals 80, 85, or 90 mm Hg in a large number of subjects. In the nondiabetic group, there was almost a 10% difference in cardiac events when diastolic blood pressures of 90 mm Hg were compared with diastolic blood pressures of 80 mm Hg, whereas in the diabetic group there was almost a 50% difference. (7) Because of these and other studies, the current recommendations are that hypertension should be treated to a blood pressure level of 130/80 mm Hg or below in the diabetic patient, and if albuminuria is present (>20 mg /min, 30 mg/day, or 30 mg/g of creatinine) to a level of 120/75 mm Hg or below. (8)

Angiotensin-Converting Enzyme Inhibitors 

Prevention of almost all diabetic complications can be helped by using an ACE inhibitor. (9) This is particularly true for microvascular complications, but the Heart Outcomes Prevention Evaluation (HOPE) study, where type 2 diabetic patients without known ischemic heart disease but with at least one other cardiac risk factor were included, showed significant decreases in the incidence of myocardial infarction, stroke, and congestive heart failure with only a 4 mm Hg drop in blood pressure in those patients taking the ACE inhibitor ramipril when compared with those taking placebo. (10) This suggests that ACE inhibitors have an effect in lowering cardiac events in addition to lowering blood pressure. In my opinion, use of an ACE inhibitor is mandatory in the type 2 diabetic patient, since ACE inhibitors also significantly lower insulin resistance.

Lipid Control

As shown in the Scandinavian Simvastatin Survival Study (4S) and Cholesterol and Recurrent Events (CARE) study, which used simvastatin and pravastatin, respectively, lowering of low-density lipoprotein (LDL) cholesterol in the diabetic is at least as effective as lowering LDL cholesterol in the nondiabetic subject in avoiding cardiac events. (11,12.), furthermore, statins have been shown to decrease the progression of diabetic nephropathy and may help in its prevention. In addition to an elevated LDL, the insulin-resistant type 2 diabetic patient has a low total high-density lipoprotein (HDL). Small elevations of the HDL have been shown to decrease cardiac events significantly in diabetic patients. In the Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial (VAHIT), the fibrate gemfibrozil raised the HDL by 6%, which had the effect of reducing cardiac events by 22%. In the subgroup of insulin-resistant and diabetic patients who comprised 47% of the participants in this study, however, ther e was a 32% decrease in cardiac events, whereas the non-diabetic, non-insulin-resistant patients showed only a 6% reduction. (13) While lowering of triglycerides has never been shown to independently reduce cardiac events, it should increase the size of the LDL particle, thus making the LDL particle less atherogenic. We have recently shown that with rosiglitazone (but not with its predecessor, troglitazone) the LDL particle size increased from a small, dense, more atherogenic LDL particle to the larger, less atherogenic LDL particle in a significant percentage of diabetic patients. We also showed that concentration of the small, noncardioprotective HDL3 particle increased with both TZDs, but only with rosiglitazone did the larger, cardioprotective HDL2 particle concentration increase significantly; this increase was almost to the target level of 8 mg/dL. (14) Thus, at least with rosiglitazone and perhaps other TZDs, the beneficial effects of statins and/or fibrates in lowering cardiac events should be synergi stically magnified.

DETECTION OF DIABETIC COMPLICATIONS

Retinopathy

The current ADA recommendations of an annual eye examination through a dilated pupil in everyone with diabetes over age 21 years or who has had diabetes for more than five years is sufficient to detect diabetic retinopathy at a stage before which treatment is indicated.

Neuropathy

At least annual clinical examination of the feet in a diabetic patient will detect neuropathy before it has had time to cause complications such as foot ulcers. Usually a decrease in vibration sense is the first clinical sign of neuropathy; this is usually followed by loss of the ankle jerks and later by the loss of pinprick sensation in a stocking distribution. (15)

Nephropathy

Annual screening of the urine for the presence of excess albumin is currently recommended. The most convenient way to measure this is with a urinary albumin-to-creatinine ratio, preferably obtained from a morning first-void specimen. Normally, albumin is <30 mg/g of creatinine. Albumin levels between 30 and 300 mg/g of creatinine are diagnostic of microalbuminuria, and levels more than 300 mg/g of creatinine are diagnostic of macroalbuminuria and diabetic nephropathy. (16) Eighty percent of type 1 diabetic patients and 20% of type 2 diabetic patients with microalbuminuria will progress to diabetic nephropathy unless treatment to slow its advancement is utilized. Microalbuminuria in the type 2 patient may be caused by the endothelial dysfunction associated with insulin resistance rather than diabetic glomerulopathy, which would explain the lower rate of progression to diabetic nephropathy in the type 2 patient. (17)

Macrovascular Disease

Detecting cerebrovascular disease depends upon taking a careful history for transient ischemic attacks or other cerebral symptoms and carefully examining the carotid arteries for decreased pulsation and bruits. Peripheral vascular disease in the diabetic patient is less likely to be associated with intermittent claudication, since the most common area for arterial narrowing or obstruction is below the popliteal artery at the trifurcation of the tibialartery, so peripheral vascular disease can be present even in the presence of palpable pulses. More subtle signs of peripheral vascular disease, therefore, such as a decrease in hair growth on the feet and legs, rubor, coldness of the feet, and poor capillary return after blanching the skin, need to be sought at least annually on a comprehensive foot examination. (18)

Detection of ischemic heart disease is more controversial. There is thought to be a higher prevalence of silent myocardial ischemia in the diabetic patient than in the nondiabetic patient due to the presence of diabetic neuropathy and that this justifies periodic stress testing. Silent ischemia is only more common in the diabetic patient because ischemic heart disease is more common, however, and the proportion of diabetic patients with ischemic heart disease who have silent ischemia is no different than in the nondiabetic patient with ischemic heart disease. Screening with ultrafast computed tomography or nuclear scintigraphy scans that detect coronary artery calcification is inappropriate, since arterial calcification is common in diabetic patients and the appropriate test should screen for myocardial ischemia rather than coronary artery calcification. The key to screening for myocardial ischemia in the diabetic patient, therefore, is based upon clinical suspicion. Obviously, a person with good exercise tol erance and no chest pains should not be investigated; however, findings such as chest pain, decreased or decreasing exercise tolerance, or subtle signs of congestive heart failure (eg, ankle swelling, increased jugular venous pressure, extra heart sounds, or EGG changes) should precipitate an investigation for myocardial ischemia. In addition, screening is appropriate in those diabetic patients with peripheral vascular disease or cerebrovascular disease and can be justified in those with other risk factors such as dyslipidemia or hypertension. Supplementation of the standard stress test with radionucleotide scanning or echocardiography will add increased sensitivity to the detection of myocardial ischemia, particularly in women. (19)

TREATMENT OF DIABETIC COMPLICATIONS

On detection of more than background diabetic retinopathy, flourescein angiography can document the severity of the retinopathy by showing areas of retinal ischemia, proliferation of new blood vessels, and especially permeability of the retinal vessels. Documentation of advanced retinopathy leads to panretinal photocoagulation (laser therapy), which destroys retinal tissue outside the macula and optic nerve so that the remaining retina is not ischemic and will therefore not produce the growth factors that result in proliferative diabetic retinopathy. Panretinal photocoagulation achieves this goal at the cost of night vision, visual fields, and color discrimination. Vitrectomy can be used not only to remove blood from the vitreous, but also to reattach a retina that is either buckling or detaching because of vitreous bands (scar tissue) accompanying the new blood vessel growth that is characteristic of diabetic proliferative retinopathy. (20) The use of ACE inhibitors has been shown to prevent progression of d iabetic retinopathy; they should be used in all diabetic patients with retinopathy. (21)

On detecting albuminuria, the blood pressure must be lowered to 120/70 mm Hg or below and an ACE inhibitor and/or an angiotensin II type 2 (AT2) blocker must be included in this therapy. These two drugs and thiazide diuretics lower or correct urine albumin levels by decreasing intraglomerular pressure, (9,22,23) and lowering the albuminuria will result in a deceleration of the decline in renal function. A low-protein diet (0.8 g/kg of body weight) may also be helpful in lowering albuminuria and slowing the decline in renal function. (24) Use of radiocontrast materials has the potential to acutely worsen renal function in the patient with diabetic nephropathy, with the greatest risk being when patients with the worst renal function are exposed to high volumes of radiocontrast material (such as with angiography). When angiography has to be done, therefore, the patient should be well hydrated and the lowest possible dose of radiocontrast materials should be used. Previously, it was believed that intravenous mann itol would be renoprotective in this situation, but this has been shown not to be true. High-volume intravenous fluids before, during, and after radiocontrast material use is the only proven renoprotective therapy. (25)

Measures to maintain integrity of the skin and avoid foot ulcers must be undertaken when distal symmetrical polyneuropathy is diagnosed, since neuropathy is the most common cause of amputation in the diabetic patient. (26) With neuropathy, anesthesia and deformity of the foot occurs so that, particularly over the head of the first metatarsal, an ulcer may develop. Infection in this ulcer, accompanied by compromised circulation, can result in gangrene and amputation. The most effective tool in preventing amputation is patient education (Table 1); by following the simple rules of foot care, a patient can avoid foot ulcers, infections, ischemia, and amputation. The burning and tingling of the feet due to diabetic neuropathy can be successfully treated with antiepileptic and tricyclic medications (Table 2). (27) Only in severe cases should analgesics be used, since neuropathic pain differs from somatic pain in that larger doses of narcotics need to be used for pain relief. Complete relief is not possible in most patients, and attempts to give enough medication to totally relieve symptoms will result in significant dose-related medication side effects. My rule of thumb is to provide enough medication to ensure adequate sleep, since the symptoms of neuropathy are invariably worse at night. Untreated, the patient will seek relief by getting out of bed and walking around, only to have the symptoms recur upon returning to bed. Often the patient will not be able to tolerate the bedclothes or nightclothes touching the skin of the feet and legs. With loss of sleep, depression and worsening of symptoms occur so that relief of nocturnal symptoms is the primary goal. Better glycemic control (which raises the threshold for any pain) and ACE inhibitor use (which improves the microcirculatory blood flow to the nerve) are also essential in the treatment of painful diabetic neuropathy. (28)

With peripheral vascular disease, the same preventative measures to avoid amputation as are undertaken with neuropathy should be used. In addition, medical therapy (antiplatelets and pentoxifylline) or revascularization should be considered. (18) With coronary artery disease and cerebrovascular disease, medical therapy with ACE inhibitors, AT2 blockers, statins, antiplatelet therapy, fibrates, folic acid, and particularly [beta]-blockers, with or without revascularization, are essential. [29,30]

CONCLUSION

The chronic complications of diabetes can be avoided by striving for normal levels of serum glucose, blood pressure, and lipids. They can be effectively treated, but only if they are detected; the earlier they are detected, then the greater the chance of successful treatment. Aggressive therapy can prevent or ameliorate the progression of diabetic complications and should be started at the time of diagnosis.

References:

(1.) Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and the progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977-978

(2.) Ohkubo Y, Kishikawa H, Araki E, et al: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin dependent diabetes mellitus: a randomized prospective 6 year study. Diabetes Res Clin Pract 1995; 28:103-117

(3.) UK Prospective Diabetes Study (UKPDS) Group: Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837-853

(4.) Stratton IM, Adler AI, Neil H, et al: Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321:405-412

(5.) Khaw K-T, Wareham N, Luber R, et al: Glycated hemoglobin, diabetes and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC Norfolk). BMJ 2001; 322:15-18

(6.) Adler AI, Stratton IM, Neil HA, et al: Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000; 321:394-395

(7.) Hansson L, Zanchotti A, Carruthers SG, et al, for the HOT Study Group: Effects of intensive blood pressure lowering and low dose aspirin in patients with hypertension: principle results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet 1998; 351:1755-1762

(8.) The sixth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1997; 157:2413-2446

(9.) Bell DSH: Should angiotensin-converting enzyme inhibitors be added to the water supply of patients with diabetes? Endocr Prac 2001; 7:59-63

(10.) Yusuf S, Sleight P, Pogue J: Effects of angiotensin-converting enzyme inhibitor, ramapril, on cardiovascular events in high-risk patients. Heart Outcomes Prevention Evaluation Study Investigators. [Published errata appear in New Engl J Med 2000 342:1376]. New Engl J Med 2000; 342:145-153

(11.) Pyorala K, Pedersen TR, Kjekshus J, et al: Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary artery disease. Diabetes Care 1997; 20:614-620

(12.) Goldberg RB, Mellies MJ, Sacks FM, et al: Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Circulation 1998; 98:2513-2519

(13.) Rubins HB, Robins SJ, Collin D, et al, for the Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial Study Group: Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999; 34:410-418

(14.) Ovalle F, Bell DSH: Differing effects of thiazolidinediones on HDL subfractions, LDL subfractions, and Lp(a). Diabetes 2001; 5O(suppl 2):A453-A461

(15.) Bell DSH, Ward J: Peripheral and cranial neuropathies in diabetes. Clinical Diabetes Mellitus. Davidson JK (ed). New York, Thieme, 3rd Ed, 2000, pp 621-635

(16.) Bell DSH, Alele J: Dealing with diabetic nephropathy. Postgrad Med 1999; 105:83-94

(17.) Weston WM, Heise MA, Porter CE, et al: Rosiglitazone-mediated reductions in urinary albumin excretion are associated with changes in ambulatory blood pressure in type 2 diabetes patients. Diabetes 2001; 50(suppl 2):A134

(18.) Bell DSH: Lower limb problems in diabetic patients. what are the causes? what are the remedies? Postgrad Med 1991; 89:237-244

(19.) American Diabetes Association: Clinical practice recommendations 2001. Diabetes Care 2001; 24(suppl 1):S1-S133

(20.) Neely KA, Quillen DA, Schachat AP, et al: Diabetic retinoathy. Med Clin North Am 1998; 82:847-876

(21.) Chaturvedi N, Sjolie AK, Stephenson JM: Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group EURO DIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 1998; 351:28-31

(22.) UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317:703-713

(23.) Lewis EJ, Hunsicker LG, Bain RR, et al, for the Collaborative Study Group: The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329:1456-1462

(24.) Morgensen CE: The kidney in diabetes: how to control renal and related cardiovascular complications. Am J Kidney Dis 2001; 37(suppl 2):S2-S6

(25.) Solomon R, Werner C, Mann D, et al: Effects of saline, mannitol, and furosemide on acute decreases in renal function induced by radiocontrast agents. N Engl J Med 1994; 331:1416-1420

(26.) Jude EB, Boulton AJM: End-stage complications of diabetic neuropathy. Diabetes Rev 1999; 7:395-410

(27.) Woolf CT, Mannion RJ: Neuropathic pain: etiology, symptoms, mechanisms and management. Lancet 1999; 353:1959-1966

(28.) Boulton AJM: Current and emerging treatments for the diabetic neuropathies. Diabetes Rev 1999; 7:379-386

(29.) Bell DSH: Diabetes mellitus and coronary artery disease. J Cardiovasc Risk 1997; 4:83-90

(30.) Bell DSH: Stroke in the diabetic patient. Diabetes Care 1994; 17:217-219

TABLE 1.

Prophylactic Diabetic Foot Care

  Always wear shoes.

  When purchasing new shoes, buy leather shoes with adequate
width and break them in slowly (starting with 4 hours per day).

  Inspect feet morning and evening, and if skin breakdown occurs
get off feet and inform physician.

Get regular foot care with a health care provider.

Avoid hot water and hot surfaces (sand or tarmac during summer).

  Extra-depth shoes with molded insoles and rocker-bottom soles
may be needed.
TABLE 2.

Treatments That. May Help Symptoms of Diabetic Neuropathy

Antiepileptics
  Clonazepam (0.5-1.0 mg hs)
  Gabapentin (900-3600 mg qd)
  Carbamazepine (100-600 mg qd)
  Topiramate (25-100 mg qd)

Tricyclics
  Amitriptyline HCl (10-30 mg hs)
  Imipramine (25-100 mg hs)

Others
  Prolixin (1 mg tid)
  Opioids
  Pentoxifylline (400 mg tid)
  Capsaicin (0.75% cream)
  Mexiletene HCl (50-450 mg qd)
  Transcutaneous electrical nerve stimulation (TENS)
  Acupuncture