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Diabetic Complications in Spain

Several studies have examined the prevalence and incidence of diabetes in the Spanish population. The prevalence of diabetes varies between age groups: 0.3% in the 1-15 year age group, 6.5% in the 30-65 year age group, and 10.3 % in the 30-89 year age group.[1] Overall prevalence among people older than age 20 has been estimated at 9.9%.[2] Studies examining Spanish populations have shown that the incidence of type 1 is 11-12 cases per 100,000 persons per year; type 2 is 8 cases per 1000 persons per year, with the incidence of type 2 increasing with age.[1] As the life expectancy of the Spanish population continues to increase, so does the incidence of type 2 diabetes, with a significant increase in age as a risk factor after age 60.[1] Because the ratio of known to unknown diabetes in the Spanish population is as high as 1-2:3, and because about half of those who are diagnosed with type 2 diabetes already have evidence of at least one complication, an increasing number of people in Spain are at risk, not only from the acute manifestations of diabetes such as hypoglycemia, diabetic ketoacidosis (DKA), and hyperosmotic nonketotic coma, but also from the unknown progression of the chronic complications of diabetes.[1],[2] In fact, one recent study showed that among European countries, the single factor having the greatest impact on costs of patients with diabetes was the presence of diabetes-related late complications.[3]

The targets of chronic pathological changes in the individual with diabetes include the arteries, small blood vessels, nerves, kidneys, eyes, and other organs. The adverse effects of these changes have made diabetes the third most common cause of death for women in Spain, (behind cardiovascular disease and ischemic heart disease) and the seventh most common cause of death in men.[1] However, these standings are likely to be underestimated due to the large number of undiagnosed cases of diabetes and the fact that diabetes is underreported as a cause of death, being superseded by associated complications that may have been associated with the disease.[1],[2],[4] In most developed nations, diabetes ranks as the fourth to the eighth most common cause of death; in European countries, mortality associated with diabetes varies from 8 to 33 per 100,000. In Spain in particular, the current mortality rate associated with diabetes is 23 per 100,000.[1] Chronic complications of diabetes are commonly categorized into macrovascular and microvascular types and are presented with their associated systems in Table 1.

Table 1. Major diabetic complications[4]

Target

Complication

Eyes

Retinopathy

Heart and coronary circulation

Coronary heart disease

Kidney

Nephropathy

Brain and cerebral circulation

Cerebrovascular disease

Lower limbs

Peripheral vascular disease

Diabetic foot (ulceration and amputation)

Peripheral nervous system

Neuropathy

Macrovascular complications

Diabetes is a major risk factor for cardiovascular disease (CVD), which is the most common cause of death in patients with either type 1 or type 2 diabetes.[5] Further, diabetes is the second most common etiological factor in atherosclerotic disease (following smoking); the progression of atherosclerosis can lead to myocardial infarction, stroke, and limb infection and amputation. People with diabetes are 2 to 4 times more likely to develop atherosclerosis than the general population.[5],[6] The risk of developing cardiovascular disease is significantly increased in the diabetic population, not only because diabetes is an independent risk factor, but also because other risk factors for CVD such as smoking, hypertension, and hypercholesterolemia are found more often in people with diabetes.[5] Patients with type 2 diabetes who have never had a myocardial infarction (MI) face the same risk of MI as patients without diabetes who have had a previous MI, and the risk of MI and sudden death in patients with diabetes is increased 2-fold compared with people who do not have diabetes.[5]

The pathological changes of diabetes also threaten the peripheral and cerebral vasculature. In fact, peripheral vascular disease and cerebrovascular disease are found 5 times as often in the diabetic population, and cerebrovascular disease is likely to be responsible for 15% of all deaths in these patients.[6] Peripheral vascular disease, along with microvascular neurological damage, contributes to the development of the commonly encountered diabetic foot ulceration and its accompanying infection, which can lead to amputation and life-threatening sepsis.[6] Compared with healthy individuals, patients with diabetes are 15 to 40 times more likely to require a lower-limb amputation, and diabetes is the leading cause of nontraumatic amputation.[5]

Control of cardiovascular risk factors may be considered to be just as important as the control of blood glucose in patients with diabetes, since cardiovascular disease is the most common complication of diabetes.[7] Each cardiovascular risk factor present in a diabetic patient represents about 3 times the risk of cardiovascular death when compared with healthy individuals.[7]

General recommendations from the Sociedad Española de Diabetes (SED) to decrease cardiovascular risk in patients with diabetesinclude:[8] a smoking cessation plan, aggressive lowering of blood pressure through lifestyle management and pharmacotherapy, diligent monitoring and treatment of glycemia, and lifestyle management and pharmacological intervention for dyslipidemia. Further, the following specific treatment criteria are advocated in adult patients with type 2 diabetes. Goal values are listed, as well as values that require intensification of interventions (Table 2).[8]

Table 2. Treatment goals in adult patients with type 2 diabetes[8]

Indicator

Goal

Intensify Intervention

 

 

 

Lipids

Total Cholesterol

<185 mg/dL

>230 mg/dL

LDL

<100 mg/dL

>130 mg/dL

HDL

>40 mg/dL

<35 mg/dL

Fasting triglyceride

<150 mg/dL

>200 mg/dL

 

A1C

<7

>8

Blood pressure (BP)

≤130/80

>140/90

Microvascular complications

The most commonly encountered microvascular complications of diabetes are diabetic retinopathy, nephropathy, and neuropathy. The retinal, renal, and peripheral nervous system endothelia allow glucose entry without insulin, making these tissues particularly susceptible to damage from hyperglycemia. Suggested mechanisms linking hyperglycemia to the development of microvascular damage include increased activity of the polyol pathway, activation of protein kinase C, and non-enzymatic glycation of proteins, all of which result in deleterious effects, including the reduction in the bioavailability of nitric oxide, increasing oxidative stress.[6]

Diabetic retinopathy

Patients with diabetes face a relative risk of vision loss 20 times greater than people without the disease, and 20-30% of blindness in Spain is attributable to diabetic retinopathy (DR), which affects up to 50% of patients with diabetes.[1],[4] Among the affiliates of the Spanish National Organization of Blind People (SNOBP), diabetes is the third leading pathological cause of visual deficiency.[1] Twenty years after diagnosis, nearly all individuals with type 1 diabetes and 60% of people with type 2 diabetes will have developed some degree of diabetic retinopathy.[1] Up to 39% of patients have retinopathy at diagnosis, though they are most commonly asymptomatic and unaware of their condition.[6] Because of the long asymptomatic period experienced by most patients, early identification and treatment of diabetic retinopathy is important. Further, though it is evident that factors other than hyperglycemia play a part in the development of retinopathy (eg, hypertension, duration of diabetes, coexisting diabetic nephropathy, hypertriglyceridemia, pregnancy, smoking), the efficacy of modifying most of these factors has yet to be shown. However, control of hypertension has been shown to significantly reduce the risk of eye disease.[6]

Treatment options for diabetic retinopathy include peripheral retinal ablation, laser photocoagulation, and vitrectomy. Intravitreal injections and implants may target the inflammatory processes of DR with corticosteroids. The processes of neovascularization may be interrupted by blocking the activity of vascular endothelial growth factor (VEGF) with agents such as pegaptanib. The development of abnormal connective tissue may be blocked by dissolving proteoglycans with agents such as hyaluronidase.[9],[10],[11] Systemic agents such as statins, antihypertensives, COX-2 inhibitors, and agents targeting the somatostatin (SS) receptor have also shown promise.[12],[13] One recent study at the Instituto de Salud Carlos III in Barcelona, Spain, identified the SS-28 isoform of somatostatin as the predominant molecular variant in the vitreous fluid of patients with PDR, suggesting a rationale for the use of SS analogs in the treatment of PDR, findings that may contribute to the development of new strategies for the treatment of PDR, particularly for patients who are resistant to laser photocoagulation.[14],[15] Other treatments target various metabolic pathways such as the aldose reductase and protein kinase C (PKC) pathways with agents such as epalrestat, zenarestat (aldose reductase inhibitors), and ruboxistaurin (a PKC β inhibitor).[16],[17],[18]

One 2002 study examined the retinopathy screening program for diabetic patients in a rural area of the province of Valladolid, Spain, and found that 73% of participants had not received ophthalmologic care the preceding year, and 63.6% had not received a dilated eye examination either.[19] Efforts are currently underway to improve the effectiveness and the scope of retinopathy screening in Spain.[20] Current guidelines for diabetic retinopathy screening are available from the International Diabetes Federation (IDF) at http://www.idf.org/webdata/docs/ IDF%20GGT2D.pdf. Also useful are the European Working Party for Screening for Diabetic Retinopathy guidelines for referral to an ophthalmologist, which are available at http://www.academy.org.uk/lectures/ barnard16. htm#_Toc535510085.

Diabetic nephropathy

Diabetic nephropathy is the leading cause of patient inclusion in dialysis regimens in Spain and is present in as many as 35% of patients with type 2 diabetes.[1] The relative risk of renal insufficiency for people with diabetes is 25 times greater than for people without the disease.[1] Further, within the first 2 decades after diagnosis, up to 50% of patients with diabetes have developed some degree of renal involvement.[1] Various studies have shown the prevalence rate for the general stages of renal disease throughout several regions of Spain, finding the prevalence of microalbuminuria to be 13% for patients with type 1 and 23% for those with type 2, the prevalence of macroproteinuria to be around 5% for both types, and the prevalence of renal insufficiency to be between 5% and 8.5% for both types.[1],[21],[22],[23]

Detection and surveillance of diabetic kidney disease is best achieved by monitoring albumin excretion rate and serum creatinine; IDF guidelines are listed in Table 3.[24]

Table 3. IDF Guidelines for the Detection and Surveillance of Diabetic Nephropathy[24]

General Guidelines

Check for proteinuria yearly using reagent strips

Measure urinary albumin excretion yearly (if not proteinuric) using pre-breakfast albumin:creatinine ratio OR pre-breakfast urinary albumin concentration

If ratio >2.5 mg/mmol ( >30 mg/g ) in men or >3.5 mg/mmol ( >40 mg/g ) in women or concentration >20 mg/L, repeat to confirm

Monitor any progression of kidney damage by more frequent measurement

Check for infection and consider other renal disease if proteinuria positive

Exclude infection with leukocyte/nitrate strips and microscopy; culture if positive

Measure serum creatinine yearly (more often if abnormal, or if rising and metformin-treated )

Measure blood pressure yearly for surveillance purposes

For patients with an increased albumin excretion rate:

With normal serum creatinine:

  • Monitor albumin excretion rate yearly to detect progression suggestive of specific diabetic kidney damage

  • Intensify management of modifiable arterial risk factors (glucose, lipids, blood pressure)

With abnormal serum creatinine:

  • Review other possible causes of renal impairment (recurrent infection, renal arterial/hypertensive damage, loop diuretic therapy/cardiac failure, glomerulonephritis)
  • Monitor albumin excretion and serum creatinine more frequently to detect progression of renal damage

If diabetic nephropathy is suspected:

  • Treat blood pressure aggressively with a target of <130/80 mm Hg
  • Reduce salt intake
  • Use ACE-inhibitors as first-line drug therapy
  • Add loop diuretics, other agents if necessary
  • Reduce protein intake with target of <0.8 g/kg
  • Maintain optimal glycemic control and tight arterial risk factor control
  • Treat urinary infections aggressively; consider papillary necrosis if recurrent
  • Arrange evaluation by a nephrologist before creatinine rises to 250 µmol/L (3.0 mg/dL)

Diabetic neuropathy

Diabetic neuropathy is present in approximately 40% of patients at the time of diagnosis, and prevalence rates increase with age and time since diagnosis.[1] The relative risk of neuropathy faced by people with diabetes is 7 times that of the general population, and diabetic polyneuropathy affects more than 40% of patients who have had diabetes for more than 10 years. 1One Spanish study of 1430 diabetic patients from a limited clinical population (no family practice or internal medicine practices), found a prevalence of diabetic neuropathy of 14%, while others have found prevalence rates in other geographical regions varying from 14-63%.[1],[25],[26]

Diabetic neuropathy presents as several clinical syndromes, including:

  • Symmetrical distal polyneuropathy, which may be asymptomatic or associated with pain, paresthesia, numbness, allodynia, or gait impairment[6]
  • Focal neuropathy, particularly of cranial nerves[6]
  • Motor neuropathy, including diabetic amyotrophy[6]
  • Autonomic neuropathy resulting in erectile dysfunction in men, orthostatic hypotension, gastroparesis, diabetic diarrhea, and cardiovascular autonomic neuropathy[6]

Annual screening for neuropathy should be provided to all patients and should include sensation testing and reported neuropathic changes, inquiry into history of sensory neuropathic symptoms, erectile dysfunction in men, or evidence of autonomic neuropathies such as gastroparesis, poor blood pressure control, or gustatory sweating.[24] Agents such as basic analgesics, tricyclic antidepressants, and anticonvulsants (eg, gabapentin, pregabalin, and carbamazepine, as tolerated) may be used for symptomatic control, but prevention and therapy of diabetic neuropathy currently centers around the optimization of glycemic control and blood pressure normalization.[24]

References

  1. Goday A. Epidemiology of diabetes and its non-coronary complications. Rev Esp Cardiol. 2002;55:657-670. Available at: www.revespcardiol.org.
  2. International Diabetes Federation. Diabetes: the policy puzzle: towards benchmarking in the EU 25. Available at: http://www.idf.org/webdata/docs/idf-europe/DiabetesReport2005.pdf. Accessed March 2006.
  3. Jönsson B. Revealing the cost of Type II diabetes in Europe. Diabetologia. 2002;45:S5–S12.
  4. International Diabetes Federation (IDF) Diabetes Atlas Executive Summary. Available at: http://www.eatlas.idf.org/Diabetes_Atlas___Executive_Summary_download/. Accessed March 2006.
  5. IDF fact sheet: diabetes and cardiovascular disease. Available at: http://www.idf.org/home/index.cfm?node=1158. Accessed March 2006.
  6. British Medical Association. Diabetes mellitus: an update for professionals. Available at: http://www.bma.org.uk/ap.nsf/Content/Diabetes/$file/diabetes.pdf. Accessed March 2006.
  7. IDF fact file. Available at: http://www.cvd.idf.org/Fact_File/. Accessed March 2006.
  8. www.sediabetes.org/grupos_trabajo/doc_diabetes_tipo2_1.pdf. Accessed March 2006.
  9. Aiello LP, Cahill MT, Cavallerano JD. Growth factors and protein kinase C inhibitors as novel therapies for the medical management [of] diabetic retinopathy. Eye. 2004;18:117-125.
  10. Hyaluronidase (Vitrase)—ISTA: hyaluronidase—ISTA Pharmaceuticals. Drugs R D. 2003;4:194-197.
  11. FDA approves Vitrase (hyaluronidase for injection). FDA Talk Paper. T04-12. May 6, 2004. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01287.html. Accessed November 9, 2004
  12. Ayalasomayajula SP, Amrite AC, Kompella UB. Inhibition of cyclooxygenase-2, but not cyclooxygenase-1, reduces prostaglandin E2 secretion from diabetic rat retinas. Eur J Pharmacol. 2004;498:275-278.
  13. Frank RN. Diabetic retinopathy. N Engl J Med. 2004;350:48-58.
  14. Hammes, H. Focus on Diabetic Retinopathy. Available at : http://www.medscape.com/viewarticle/508217.
  15. Hernandez C, et al. Somatostatin molecular variants in the vitreous fluid: a comparative study between diabetic patients with proliferative diabetic retinopathy and non-diabetic control subjects. Program and abstracts of the 65th Scientific Sessions of the American Diabetes Association; June 10-14, 2005; San Diego, California. Abstract 29-OR.
  16. Sheetz MJ, King GL. Molecular understanding of hyperglycemia’s adverse effects for diabetic complications. JAMA. 2002;288:2579-2588.
  17. Aiello LP, et al. Initial results of the protein kinase C β inhibitor Diabetic Macular Edema Study (PKC-DMES). Diabetologia. 2003;46,suppl 2:A42.
  18. Milton RC, et al. Initial results of the protein kinase C β inhibitor Diabetic Retinopathy Study (PKC-DRS). Diabetologia. 2003;46,suppl 2:A42.
  19. Lopez I. Prevalence of diabetic retinopathy and eye care in a rural area of Spain. Ophthalmic Epidemiol . 2002;3:205-14.
  20. Screening for Diabetic Retinopathy in Europe 15 years after the St. Vincent Declaration: The Liverpool Declaration 2005, Report of Conference. Available at: http://reseau-ophdiat.aphp.fr/Document/Doc/confliverpool.pdf. Accessed May 2006.
  21. Esmatjes E, et al. Prevalencia de nefropatía diabética en la diabetes tipo 1. Med Clin (Barc). 1998;10:6-10.
  22. Esmatjes E, et al. (The Catalan Nephropathy Study Group). Epidemiology of renal involvement in type II diabetics (NIDDM) in Catalonia. Diabetes Res Clin Pract. 1996;32:157-163.
  23. De Pablos P, et al. Prevalence of nephropathy in a canarian population of non insulin-dependent diabetics. Relationship with obesity, blood pressure, lipid profile and metabolic control. Diabetes et Metabolism. 1998;24:337-343.
  24. International Diabetes Federation, European Region. A Desktop Guide to Type 2 Diabetes Mellitus. Diabetic Medicine. 1999;16. Available at: http://www.staff.ncl.ac.uk/philip.home/t2dgw97r.doc . Accessed April 2006.
  25. iguerola D, et al, Grupo Catalán de Estudio de la Diabetes (GCED). La asistencia al diabético en Cataluña. Estudio en una mu estra de población. Med Clin (Barc). 1992;99:90-95.
  26. Rajbhandari S, Piya M. A brief review on the pathogenesis of human diabetic neuropathy: Observations and Postulations. Int J Diabetes & Metabolism. 2005;13:135-140. Available at: http://ijod.uaeu.ac.ae/iss_1303/b.pdf.
 



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