Diabetes mellitus (DM) is a chronic disorder. caused by partial or complete insulin defi therefore, the American Diabetes. Association (ADA) recommends that …
Diabetes Mellitus:
Complications
A SERIES OF 3 ARTICLES ON DIABETES MELLITUS FROM PHARMERICA
Diabetes mellitus DM is a chronic disorder caused by partial or complete insulin deficiency, which produces inadequate blood glucose control and leads to acute and chronic complications[1] Acute complications include diabetic ketoacidosis and hyperosmolar nonketotic coma[2] Chronic complications can involve the kidneys, eyes, nervous system, and cardiovascular system and can be classified as either macrovascular or microvascular[1]
elevated low-density lipoproteins, and elevated triglycerides may be responsible for macrovascular complications in patients with DM[2] Hyperglycemia and hyperinsulinemia also have been implicated as contributors to macrovascular complications, although it is difficult to determine the extent of their contribution[2,5] Reduction of the degree and duration of hyperglycemic episodes through aggressive control of blood glucose can lower the risk of macrovascular Trials focusing on the outcomes of patients complications, although this has not been with types 1 and 2 DM have been relatively confirmed[3,5] The second endpoint of the short-term More recently, the
utility of pre- DCCT evaluated the rates of macrovascular venting diabetic complications was evaluat- events in patients with type 1 DM treated ed in two large, multicenter, prospective, with intensive therapy compared with those treated with conventional randomized trials The therapy[3] The investigators Diabetes Control and noted a nonsignificant trend Complications Trial DCCT Treatment toward reduced risk for for patients with type 1 DM has a greater macrovascular disease despite and the United Kingdom a relatively young patient effect if Prospective Diabetes Study population, making detection UKPDS of patients with instituted in of these complications less type 2 DM provided definithe early stages likely[3] Similarly, macrotive evidence that tight convascular complications did trol of blood glucose can preof diabetic not differ between intensive vent or delay the onset of cernephropathy[12] and conventional treatment tain diabetic complicagroups in the UKPDS after 10 tions[3,4] years of follow-up[4] Macrovascular Complications Prevention of macrovascular complications Macrovascular complications include corofocuses on eliminating all preventable risk nary artery disease,
peripheral vascular disfactors eg, obesity, hypertension for these ease, and cerebrovascular disease[1,2] disease states[2,5] Macrovascular disease occurs at a younger age[1] and with increased frequency in Microvascular Complications patients with DM compared with the gener- Microvascular complications, which include al population[1,2,5] In particular, elderly nephropathy, retinopathy, and neuropapatients with DM are at an increased risk for thy,[6] are specific to patients with DM, these sequelae[6] The diagnosis of type 2 occurring infrequently in the general popuDM often is made 4 to 7 years after the dis- lation[5] Unlike macrovascular complicaease process has begun, when most patients tions, a definite association exists between already have an increased risk of macrovas- the severity and duration of hyperglycemia cular processes[7] Despite this, 20 to 25 and microvascular complications[3,4] of patients with DM do not develop Patients whose hemoglobin A1c levels exceed 8 are at an increased risk of these macrovascular complications[1] complications[7] Additionally, the aging An increased prevalence of hypertension and process contributes to the occurrence of concurrent lipid
abnormalities ie, abnormicrovascular complications[6] When type mally decreased high-density lipoprotein,
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2 DM is diagnosed, 20 of patients present with retinopathy; 8, nephropathy; and 9, neuropathy[7] Diabetic Nephropathy Renal complications associated with DM are described using the general term diabetic nephropathy Diabetic nephropathy can refer to diffuse or nodular glomerulosclerosis, arterionephrosclerosis, chronic interstitial nephritis, papillary necrosis, and various tubular lesions[8] The number of patients with type 1 DM who develop clinical nephropathy is estimated to be 30 to 45,[9-11] while fewer than 20 of patients with type 2 DM progress to clinical disease[10,11] However, of the long-term complications associated with DM, diabetic nephropathy is associated with the highest mortality[10] Diabetic nephropathy occurs when proteins deposit in the glomerulus[11] Thickening of the glomerular capillary basement membrane narrows the lumen of the capillaries, impeding blood flow and subsequently reducing the filtering surface of the glomerulus[1] The principal manifestation of diabetic nephropathy is proteinuria Other associated conditions
include hypertension, nephrotic syndrome, and progressive renal failure[8] Treatment has a greater effect if instituted in the early stages of diabetic nephropathy [12]; therefore, the American Diabetes Association ADA recommends that patients receive annual screenings for microalbuminuria For those patients with type 1 DM, screening should begin at puberty or 5 years after diagnosis, whichever occurs first Because many patients have type 2 DM for some time before their diagnosis, annual screens should begin as soon as the diagnosis is made[12] The specific treatment approach varies depending on the type of DM present and concomitant disease states; however, in general, treatment focuses on tight control of blood glucose levels,[12] management of
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Diabetes Complications
Continued
nancy[18] The ADA developed screening guidelines for diabetic retinopathy as part of their Clinical Practice Recommendations 1998 In patients age 10 to 29 years, a baseline eye exam should be done within three to five years of a DM diagnosis Screening for diabetic retinopathy should continue annually thereafter[18,19] Patients 30 years and older should have a baseline eye exam when
DM is diagnosed and annually thereafter[18,19] Because of the increased risk of progression of retinopathy during pregnancy, an eye exam is recommended before conception [19] and during the first trimester, with continued follow-up until delivery[18,19] Diabetic retinopathy can present as nonproliferative or proliferative disease, the latter having a poorer visual prognosis[1] Elimination of risk factors is an important aspect of diabetic retinopathy prevention and management[1] Treatment with laser photocoagulation can prevent vision loss in many patients[19] Studies demonstrated successful outcomes in patients with either form of diabetic retinopathy[1,18] In addition, DCCT demonstrated that intensive glucose control in patients with type 1 DM delays the onset and progression of diabetic retinopathy A total of 1,441 patients with type 1 DM were randomized to intensive or conventional therapy At randomization, 726 patients had no retinopathy primaryprevention cohort, while the remaining 715 patients had mild retinopathy secondaryintervention cohort[3] Intensive therapy produced a 63 risk reduction P 001 in sustained, clinically important retinopathy in the combined primary and
secondary intervention groups[3] Furthermore, the investigators found a 47 risk reduction P 005 for the development of severe nonproliferative or proliferative retinopathy[3] Similarly, the UKPDS demonstrated a significant decrease in the progression of retinopathy in those patients with type 2 DM who were treated with intensive therapy compared with conventional therapy after 6 years of follow-up[4] Diabetic Neuropathy Diabetic neuropathy is classified as either peripheral or autonomic Peripheral neuropathy is the most common manifestation of diabetic neuropathy,[2] with symptomatic disease occurring in approximately 25 of patients with DM[1] The clinical
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hypertension,[8,11,12] and, in some cases, dietary protein restriction[11,12] Both the DCCT and UKPDS demonstrated that strict control of blood glucose is useful in preventing and delaying the onset of diabetic nephropathy[3,4] Patients with type 1 DM in the DCCT had a significant risk reduction in albuminuria 54 and clinical neuropathy 60 at 5 years[3] Patients with type 2 DM in the UKPDS had an insignificant risk reduction in microalbuminuria and proteinuria over 15 years[4] While -blockers and diuretics
are useful for the treatment of hypertension in the general population, agents in these classes can adversely affect glycemic control and lipid profiles[1,11] Neither ACE inhibitors nor calcium channel blockers have negative effects on these parameters[13] Variability within the calcium channel blocker class was demonstrated[14] In contrast, the beneficial effects of ACE inhibitors appear to be a class action[15] In addition, it is believed that ACE inhibitors are beneficial in patients with diabetic nephropathy independent of their antihypertensive effect[2,15] Captopril is the only medication approved by the Food and Drug Administration for the treatment of diabetic nephropathy in type 1 DM[1,16] Treatment alternatives for selected patients whose diabetic nephropathy has progressed to end-stage renal disease include chronic dialysis and renal transplant[8,9] Diabetic Retinopathy Ocular complications of DM include cataracts,[2,17] macular degeneration,[2] glaucoma, and retinopathy[1,2] Diabetic retinopathy is the most common visual complication of the disease [1] and the leading cause of blindness in patients age 20 to 74 in the United States[2,18,19] Most patients with type 1 DM
and more than 60 of patients with type 2 DM will develop some degree of diabetic retinopathy after 20 years with DM[19] Diabetic retinopathy develops when new retinal blood vessels are formed because of initial ischemia within the retina These new vessels are structurally inferior and tend to bleed into the retina and vitreous, which causes transient abnormal vision Fibrous lesions, formed when the body resorbs the blood, cause blindness[20] Several risk factors for diabetic retinopathy are identified, including smoking,[1] hyperglycemia, hypertension,[1,18] nephropathy, and preg-
presentation of peripheral neuropathy can range from mild-to-severe pain to decreased sensation primarily in the lower extremities[1] Tingling and burning sensations are typical[2] Because of peripheral neuropathies, patients may be unable to perceive foot injuries,[1,2] which can become infected[2] Ultimately, diabetic foot ulcers can form These conditions, in addition to a decreased blood supply to the lower extremities, predispose patients with DM to amputation[20] Autonomic neuropathy can manifest as impotence, gastroparesis,[1,2] urinary retention, and diarrhea[1] Diabetic nephropathy results from
both chronic and acute elevations in blood glucose Nerve function decreases with acute hyperglycemia, while chronic hyperglycemia reduces nerve fibers and nerve-fiber reproduction Although not completely understood, these changes are believed to occur because of the formation of sorbitol and advanced glycosylation end products [11] or microangiopathy, causing altered neuronal capillary flow[1] Neuropathies can develop anytime during the progression of DM;[20] therefore, no specific screening recommendations exist Several pharmacologic modalities have been used to treat peripheral neuropathies, including mexilitine,[2] anticonvulsants,[20] tricyclic antidepressants, and topical capsaicin [2,20]; however, none of these therapies is universally effective Tight control of blood glucose is the most important aspect of therapy[2] Intensive therapy in the DCCT trial produced a 57 risk reduction in clinical neuropathy at 5 years P 001[3] In addition to tight glucose control, patients should be instructed on the importance of proper foot care[20] Treatment of the manifestations of autonomic neuropathies is the same in patients with DM and the general population Several treatments for
erectile dysfunction exist, and the option chosen must reflect patient acceptance Gastroparesis can be effectively treated with metoclopramide or cisapride[2] Erythromycin represents another treatment alternative for patients with diabetic gastroparesis[20] More specific information can be obtained from treatment guidelines for these disorders in the general population Conclusion DM, a primary cause of both myocardial infarction and amputation, is associated
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PHARMERICA
Diabetes Complications Continued with significant morbidity and mortality[21] Because both microvascular and macrovascular complications are chronic in nature, the elderly population is at particular risk for developing them[6] As efforts to reduce the impact of microvascular complications become more successful, the number of patients with macrovascular complications will likely increase[5] Screening for diabetic complications should take place regularly, so treatment can begin as necessary Methods of reducing the impact of diabetic complications involve tight control of blood glucose and the reduction of other important risk factors, such as hypertension
2001 PHARMERICA
References
1
Koda-Kimble MA, Carlisle BA Diabetes mellitus In: Young LY, Koda-Kimble MA, Kradjan WA, Guglielmo BJ, editors Applied therapeutics: the clinical use of drugs 6th ed Vancouver WA: Applied Therapeutics; 1995; 48 p 48-1-48-58 2 Singh I, Marshall MC Diabetes mellitus in the elderly Endocrinol Metab Clin North Am 1995; 24:255-72 3 The Diabetes Control and Complications Trial Research Group The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus N Engl J Med 1993;329:977-86 4 UK Prospective Diabetes Study UKPDS Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes UKPDS 33 Lancet 1998;352:837-53 5 Savage PJ Cardiovascular complications of diabetes mellitus: what we know and what we need to know about their prevention Ann Intern Med 1996;124:123-6 6 Greene DA Acute and chronic complications of diabetes mellitus in older patients Am J Med 1986;80 Suppl 5A:39-53 7 Peters AL, Schriger DL The new diagnostic criteria for diabetes: the impact on management of diabetes and macrovascular risk
factors Am J Med 1998;105:15S-19 8 Glassock RJ, Brenner BM Glomer-ulopathies associated with multisystem diseases In: Isselbacher KJ, Braunwald AB, Wilson JD, Martin JB, Fauci AS, Kasper DL, editors Harrison s principles of internal medicine 13th ed New York: McGraw-Hill, Inc; 1994; 241 p 1306-14 9 Foster DW Diabetes mellitus In: Isselbacher KJ, Braunwald AB, Wilson JD, Martin JB, Fauci AS, Kasper DL, editors Harrison s principles of internal medicine 13th ed New York: McGraw-Hill, Inc; 1994; 337 p 1979-2000 10 Nathan DM Medical progress: long-term complications of diabetes mellitus N Engl J Med 1993;328:1676-85 11 Clark CM, Lee DA Drug therapy: prevention and treatment of the complications of diabetes mellitus review article N Engl J Med 1995;332:1210-7 12 Molitch ME Management of early diabetic nephropathy the science of medical care Am J Med 1997;102:392-8 13 Jungmann E Chemoprophylaxis of diabetic nephropathy in the elderly Drugs Aging 1996; 9:449-57 14 Demarie BK, Bakris GL Effects of different calcium antagonists on proteinuria associated with diabetes mellitus Ann Intern Med 1990;113:987-8 15 Kasiske BL, Kalil RSN, Ma JZ, Liao M, Keane WF Effect of antihypertensive therapy
on the kidney in patients with diabetes: a meta-regression analysis Ann Intern Med 1993;118:129-38 16 Kastrup EK, Cada DJ, Hussar DA, Olin BR, Brantley AJ, Golshar VE, editors Facts and comparisons St Louis MO: Facts and Comparisons; 1998 17 Bron AJ, Brown NAP, Harding JJ, Ganea E The lens and cataract in diabetes Int Ophthalmol Clin 1998;38:37-67 18 Cooney MJ, Schachat AP Screening for diabetic retinopathy Int Ophthalmol Clin 1998;38:111-22 19 American Diabetes Association Diabetic retinopathy: strategies for managing retinopathy, nephropathy, and neuropathy Diabetes Care 1998;21 Suppl 1:143-56 20 Seaquist ER Microvascular complications of diabetes Postgrad Med 1998;103:61-8 21 Pulido JS, Patz A Diabetes 2000 Int Ophthalmol Clin 1998; 38:227-35
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