Epidemiologia, diagnosi e terapia delle complicanze diabetiche croniche Pierluigi Melga U.O. Malattie del Metabolismo e Diabetologia DISEM – Università di Genova

Diabete Mellito: Prevalenza stimata in Italia OMS P. Melga -DiSEM - Univ. Genova

Diabete Mellito: Prevalenza stimata nel mondo* *x milione OMS P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Impatto della malattia diabetica - Nel 2025 il diabete interesserà 300 milioni di individui nel mondo intero, un incremento del 122% a partire dal 1990. - Il prolungamento della vita media del paziente diabetico porta alla comparsa nel tempo di un maggior numero di complicanze tardive che aumentano i costi della malattia e diminuiscono la qualità di vita del paziente 1King et al (1998); 2Murray et al (1996); 3IDF taskforce (1999); 4Hopkinson et al (1999) P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Diabete Mellito Complicanze croniche Microangiopatia Retinopatia Nefropatia Neuropatia Macroangiopatia Coronarica Cerebrale Periferica P. Melga -DiSEM - Univ. Genova

Le complicanze croniche del diabete Ictus Mortalità cardiovascolare e stroke sono da 2 a 4 volte più frequenti Malattia cardiovascolare Retinopatia diabetica La principale causa di cecità nella popolazione adulta La principale causa di amputazioni non traumatiche Neuropatia diabetica La principale causa di insufficienza renale terminale Nefropatia diabetica P. Melga -DiSEM - Univ. Genova

Complicanze croniche Storia naturale Iperglicemia Fase precoce Suscettibilità individuale fattori genetici, etnici Fase precoce reversibile alterazioni funzionali Fase tardiva irreversibile strutturali Fattori aggiuntivi fumo, ipertensione, iperlipidemia, obesità Iperglicemia P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Diabete Mellito: Meccanismi con cui l’ iperglicemia induce danno d’organo P. Melga -DiSEM - Univ. Genova

RIDUZIONE DEL RISCHIO* La lezione dello UKPDS: controllo migliore, meno complicanze RIDUZIONE DEL RISCHIO* OGNI 1% di riduzione dell’HbA1c -21% Morte per diabete -14% Attacchi cardiaci -37% Complicanze microvascolari -43% Malattia vascolare periferica 1% *p <0.0001 P. Melga -DiSEM - Univ. Genova UKPDS 35. BMJ 2000; 321: 405-412.

P. Melga -DiSEM - Univ. Genova Livelli di HbA1c e rischio realtivo di complicanze microvascolari: i risultati dello studio DCCT 20 retinopatia 15 nefropatia neuropatia 13 microalbuminuria 11 9 Rischio relativo 7 5 3 1 6 7 8 9 10 11 12 HbA1c (%) DCCT, Diabetes Control and Complications Trial. 1. Tratto e modificato da Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254. 2. DCCT. N Engl J Med. 1993;329:977-986. 3. DCCT. Diabetes. 1995;44:968-983. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova MICROANGIOPATIA P. Melga -DiSEM - Univ. Genova

Microangiopatia Tipo 1 Tipo 2 Retinopatia diabetica 46% 49% Neuropatia diabetica 28% 40% Nefropatia diabetica 30% 35% Mod. da Koivisto VA, et al. Diabetes Care 1996; 19: 689-697. Stephenson JM, et al. Diabetologia 1995; 38: 599-603. Sjolie AK, et al. Ophthalmology 1997 ; 104: 252-260. Tesfaye S, et al. Diabetologia 1996; 39: 1377-1384. Mod. da National Diabetes Information Clearinghouse. Diabetes Statistics–Complications of Diabetes. (website) http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm#comp. P. Melga -DiSEM - Univ. Genova

RETINOPATIA DIABETICA P. Melga -DiSEM - Univ. Genova

RETINOPATIA DIABETICA (RD) La cecità è una delle complicanze più gravi e frequenti del diabete . La RD è la causa più frequente di nuovi casi di cecità in Europa e nel Nord America nei pazienti di età compresa tra 30 e 70 anni Nei primi 20 anni di malattia quasi tutti i pazienti con diabete di tipo 1 e più del 60% dei tipi 2 hanno retinopatia Diabetic retinopathy develops, to some degree, in nearly all patients with diabetes, and is the most common cause of new cases of blindness among adults. The most predominant causes of vision loss are clinically significant macular edema (CSME) and proliferative diabetic retinopathy (PDR). Vision loss can be avoided or minimized with proper ophthalmic care and examination to identify retinopathy in its early stages. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Fattori di rischio - Durata della malattia (Il più forte predittore per lo sviluppo e la progressione della RD) DIABETE DI TIPO 1: rara nei primi 3-5 anni di malattia nelle successive 2 decadi l’ 80% sviluppano retinopatia DIABETE DI TIPO 2: Oltre il 20% dei soggetti presentano segni di retinopatia al momento della diagnosi di diabete P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Fattori di rischio - Scarso controllo glicemico DCCT: diabete di tipo1 La terapia intensiva riduceva il rischio di retinopatia del 76% in prevenzione primaria e del 54% in prevenzione secondaria. UKPDS: pazienti con diabete di tipo 2 Nel gruppo in terapia intensiva si otteneva una riduzione delle complicanze microvascolari del 25%. P. Melga -DiSEM - Univ. Genova

Peggioramento della retinopatia ed indici di controllo glicemico HbA1c (%) Glicemia basale (mg/dl) Glicemia post-prandiale 2° ora (mg/dl) 16 12 8 4 5 7 9 11 80 120 160 200 140 180 220 260 300 Velocità di peggioramento della retinopatia (per 100 pazienti-anno) P. Melga -DiSEM - Univ. Genova Shichiri M, et al. Diabetes Care 2000: 23, B21-9.

P. Melga -DiSEM - Univ. Genova Fattori di rischio - Ipertensione UKPDS: i pazienti ipertesi con DT2 con piu’ stretto, rispetto a quelli con meno stretto controllo pressorio mostravano riduzione nella progressione di RD e riduzione del rischio di perdita dell’ acuità visiva P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Fattori di rischio - Pubertà - Gravidanza - Mancanza di controlli oftalmoscopici periodici P. Melga -DiSEM - Univ. Genova

Screening della retinopatia (RD) DT1: entro 3-5aa dalla diagnosi DT2: alla diagnosi di diabete GRAVIDANZA: le donne con preesistente diabete dovrebbero essere controllate prima e durante il 1° trimestre Follow-up DT1 e DT2: una volta all’anno Retinopathy in Diabetes. ADA Position Statement. Diabetes Care (Suppl.1) 2004 P. Melga -DiSEM - Univ. Genova

TESTS di screening e di valutazione della Retinopatia Diabetica - Oftalmoscopia diretta e/o indiretta - Fotografia del fondo oculare - Fotografia digitale - Fluorangiografia retinica (non indicata per lo screening e la diagnosi di RD) P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Fondo oculare normale P. Melga -DiSEM - Univ. Genova

Classificazione e storia naturale della retinopatia diabetica RD non proliferativa o background retinopathy Lieve Moderata Severa RD proliferativa Malattia oculare avanzata There are several stages of retinopathy. The earliest clinical stage of diabetic retinopathy is identified as mild nonproliferative diabetic retinopathy (NPDR). Progression of disease from NPDR to proliferative diabetic retinopathy (PDR) is related to the level or severity of NPDR, and therefore the severity of NPDR should determine follow-up and management of diabetic retinopathy. The next four slides will review the clinical findings and management of each stage of retinopathy. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Mild NPDR Clinical Findings Increased vascular permeability Microaneurysms Intraretinal hemorrhages Clinically Significant Macular Edema (CSME) possible Management/Treatment Annual follow-up If CSME present: color fundus photography, fluorescein angiography, and photocoagulation Mild NPDR is characterized by increased vascular permeability, microaneurysms, and intraretinal hemorrhages. Macular edema can be present at this stage and is defined as retinal thickening within 3,000 m of the fovea (center of vision). Clinically significant macular edema (CSME) occurs when edema threatens the center of vision or is within 500 m of the fovea. If CSME is present, color fundus photography can be used to determine the extent of macular edema. Fluorescein angiography can be used to identify lesions, and focal photocoagulation used to reduce the risk of vision loss. Decision to treat CSME in patients with mild NPDR should be discussed between the patient and physician. If photocoagulation is not performed the patient should be carefully monitored and examined approximately every three months for progression. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Moderate NPDR Clinical Findings Venous caliber changes Intraretinal Microvascular Abnormalities (IRMAs) Clinically Significant Macular Edema (CSME) possible Management/Treatment 6-12 month follow-up without CSME Color fundus photography CSME present: color fundus photography, fluorescein angiography, focal photocoagulation, 3-4 month follow-up Patients with moderate NPDR experience gradual retinal ischemia, venous caliber abnormalities, intraretinal microvascular abnormalities (IRMAs), and, possibly, CSME. Patients at this stage of retinopathy without CSME should have ophthalmic exams every six to twelve months to monitor disease progression. Color fundus photography can be helpful in documenting the extent of retinopathy and in comparing changes in disease progression between follow-up visits. If macular edema is present, once again color fundus photography is used to document the extent of edema, fluorescein angiography is used to locate leaking blood vessels and photocoagulation to seal the vessels. Follow-up is required after three to four months to determine the effectiveness of the treatment. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Retinopatia diabetica semplice: fluorangiografia. Microaneurismi sparsi ed emorragie puntiformi P. Melga -DiSEM - Univ. Genova

Severe/Very Severe NPDR Clinical Findings Retinal ischemia IRMAs Extensive hemorrhage and microaneurysms CSME possible Management/Treatment 3-4 month follow-up Color fundus photography Possible panretinal photocoagulation CSME present: color fundus photography, fluorescein angiography, focal photocoagulation, 3-4 month follow-up Severe to very severe NPDR is characterized by even more extensive hemorrhage and microaneurysms. The microvasculature of the retina begins to deteriorate resulting in retinal ischemia. Patients at this stage of retinopathy should be evaluated every three to four months for progression to proliferative diabetic retinopathy (PDR). Color fundus photography should be used to document disease progression. Panretinal or “scatter” laser photocoagulation can be considered to shrink abnormal blood vessels. If CSME is present, the same methods of treatment can be used as for moderate NPDR. CSME should be treated prior to performing scatter photocoagulation. Patients should continue to be evaluated at three to four months after laser treatment to determine the effectiveness of the surgery. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Retinopatia diabetica preproliferativa: fluorangiografia. Presenza di alterazioni venose,emorragie a grappolo,anormalità microvascolari intraretiniche, iniziali aree ischemiche P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova PDR Clinical Findings Ischemia induced neovascularization at the optic disk (NVD) elsewhere in the retina (NVE) Vitreous hemorrhage Retinal traction, tears, and detachment CSME possible When proliferation of new blood vessels occurs, the patient is diagnosed as having PDR. New blood vessel formation is caused by retinal ischemia. Neovascularization can occur at the optic disk (NVD) or elsewhere in the retina (NVE). These new vessels are weak and, when they break, can cause vitreous hemorrhage. They can also cause retinal traction, retinal tears, and retinal detachment over time. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Retinopatia proliferante: fluorangiografia e fotogafia del fondo dell’occhio. Neovasi in corrispondenza del disco ottico P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova PDR, cont. Management/Treatment 2-4 month follow-up Color fundus photography Panretinal photocoagulation (3-4 month follow-up) Vitrectomy CSME present: focal photocoagulation, fluorescein angiography PDR should be managed with panretinal laser photocoagulation, color fundus photography, and follow-up every 3-4 months to monitor treatment success. If panretinal photocoagulation is not performed, patients should be evaluated every two to three months because of the high risk of developing CSME, retinal detachment, or vitreous hemorrhage that can lead to vision loss. Vitrectomy should be considered when there is substantial amount of hemorrhaging in the vitreous fluid, and when neovascularization causes retinal traction or retinal detachment. CSME is treated in the same manner as described for severe NPDR. P. Melga -DiSEM - Univ. Genova

Prevention of Diabetic Retinopathy Intensive glycemic control Tight blood pressure control (<130/80 mmHg) Comprehensive eye examinations The first step toward preventing or delaying the onset of diabetic retinopathy is maintaining tight blood pressure and blood sugar control. The protective effect of glycemic control on microvascular complications has been confirmed for patients with type 1 and type 2 diabetes. The UKPDS has shown that maintaining blood pressure at <150/85 mmHg reduces the rate of progression of retinopathy. However, because patients at risk for retinopathy are also at risk for nephropathy, maintaining a blood pressure of <130/80 mmHg is advised. Finally, comprehensive eye exams on a yearly basis will help the physician and patient identify any clinical signs of retinopathy prior to the patient developing symptoms. Monitoring the eye can give the patient the best opportunity for preventive care and may allow them to prevent or delay vision loss associated with diabetic retinopathy. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova NEFROPATIA DIABETICA P. Melga -DiSEM - Univ. Genova

Cause principali di nuovi casi di ESRD negli USA (1997) NEFROPATIA DIABETICA (prevalenza) - 20-30% dei DIABETICI di TIPO 1 e 2 Recenti dati suggeriscono che il rischio di nefropatia è equivalente nei due tipi di diabete Oltre il 40% dei nuovi casi di Insufficienza renale cronica (ESRD) sono dovuti al diabete Cause principali di nuovi casi di ESRD negli USA (1997) P. Melga -DiSEM - Univ. Genova USRDS 1999 Renal Data Report

Five Stages of Kidney Disease Stage 1: Hyperfiltration, or an increase in glomerular filtration rate (GFR) occurs. Kidneys increase in size. Stage 2: Glomeruli begin to show damage and microalbuminurea occurs. Stage 3: Albumin excretion rate (AER) exceeds 200 micrograms/minute(300mg/die), and blood levels of creatinine and urea-nitrogen rise. Blood pressure may rise during this stage. We can describe 5 stages or phases of diabetic nephropathy. In the first phase, the kidney is enlarged and GFR is elevated. It is not until the second stage of kidney disease development that clinical evidence of disease begins to show in the form of microalbuminurea when loss of albumin exceeds 30mg/day or 20 micrograms/min. Blood pressure usually begins to rise about the same time that microalbuminurea occurs. Individuals with type 1 and type 2 diabetes may remain at stage two for many years with good control of blood glucose and blood pressure. During stage three, loss of albumin and other proteins exceeds 300 mg/day or 200 micrograms/minute. When this occurs, the patient is diagnosed as having clinical albuminuria. During this stage the kidneys also demonstrate an inability to adequately filter wastes from the blood, and creatinine and urea-nitrogen blood levels begin to rise. P. Melga -DiSEM - Univ. Genova

Five Stages of Kidney Disease (con’t.) Stage 4: GFR decreases to less than 75 ml/min, large amounts of protein pass into the urine, and high blood pressure almost always occurs. Levels of creatinine and urea-nitrogen in the blood rise further. Stage 5: Kidney failure, or end stage renal disease (ESRD). GFR is less than 10 ml/min. The average length of time to progress from Stage 1 to Stage 4 kidney disease is 17 years for a person with type 1 diabetes. The average length of time to progress to Stage 5, kidney failure, is 23 years. Stage four nephropathy is also known as "advanced clinical nephropathy". A decrease in GFR signals that the patient is progressing to kidney failure. If an increase in blood pressure was not evident in prior stages, it is usually evident at this time. The final phase is stage five kidney disease, also known as kidney failure or end-stage renal disease. The glomeruli function at low levels and patients in this phase require dialysis or transplantation to survive. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Storia naturale della nefropatia nel diabete tipo 1 durata del diabete tipo I, anni modificata, da Mogensen et al, 1983 P. Melga -DiSEM - Univ. Genova

SCREENING DELLA MICROALBUMINURIA - Raccolte temporizzate Notturna : 20-200 microg/min Raccolta 24 ore: 30-300 mg/24 ore - A/C rapporto albuminuria/creatininuria su campioni delle urine raccolte al risveglio mattutino: 2,5-25 mmol/l - Alla diagnosi nei diabetici di tipo 2 - Dopo 5 anni dalla diagnosi nel diabete di tipo 1 - Dopo lo screening iniziale dovrebbe essere ripetuta una volta all’anno P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova MAJOR RISK FACTORS FOR THE DEVELOPMENT AND PROGRESSION OF RENAL DAMAGE IN DIABETES poor glycemic control systemic hypertension microalbuminuria or proteinuria early hyperfiltration and hypertrophy (?) high duration of diabetes genetic factors - male sex - family predisposition to hypertension, nephropathies and CV disease - ethnic predisposition - mutations in specific candidates genes lipid abnormalities smoking high intake of protein (?) abnormalities in hemostatic parameters (?) oligonephropathy(?) P. Melga -DiSEM - Univ. Genova

Peggioramento della nefropatia ed indici di controllo glicemico HbA1c (%) Glicemia basale (mg/dl) Glicemia post-prandiale 2° ora (mg/dl) 16 12 8 4 5 7 9 11 80 120 160 200 140 180 220 260 300 Velocità di peggioramento della nefropatia (per 100 pazienti-anno) Shichiri M, et al. Diabetes Care 2000: 23, B21-9. P. Melga -DiSEM - Univ. Genova

How Can You Prevent Diabetic Kidney Disease? Maintain blood pressure <130/80 mm/Hg Maintain preprandial plasma glucose 90-130 mg/dl Maintain postprandial plasma glucose <180 mg/dl Maintain A1C <7.0% Diabetic nephropaty. ADA Position Statement DIABETES CARE, 27 (Suppl. 1),2004 The steps that can be taken to prevent diabetic kidney disease are similar to the ones that are used to treat patients once they are diagnosed with microalbuminuria: maintain blood pressure below 130/80 mmHg and maintain glycemic control according to ADA guidelines. Helping patients to achieve good control of blood pressure and blood glucose levels will help significantly in delaying progression to diabetic kidney disease. P. Melga -DiSEM - Univ. Genova

Treatment of Diabetic Nephropathy Hypertension Control - Goal: lower blood pressure to <130/80 mmHg Antihypertensive agents Angiotensin-converting enzyme (ACE) inhibitors captopril, enalapril, lisinopril, benazepril, fosinopril, ramipril, quinapril, perindopril, trandolapril, moexipril Angiotensin receptor blocker (ARB) therapy candesartan cilexetil, irbesartan, losartan potassium, telmisartan, valsartan, esprosartan Beta-blockers Nephropathy can be successfully treated during its early stages by lowering blood pressure and making lifestyle and dietary changes. Hypertension control is key in preventing the progression of diabetic nephropathy, and the goal for all patients with diabetes is to maintain a blood pressure of <130/80 mmHg. ACE inhibitors have been shown to not only reduce blood pressure but also reduce microalbuminuria. Therefore, ACE inhibitors can be used in normotensive type 1 patients who present with microalbuminuria. In type 2 patients with hypertension and microalbuminuria (Stage 2 kidney disease), ACE inhibitors and ARBs have been shown to delay the progression to macroalbuminuria (Stage 3 kidney disease). Finally, in type 2 patients with macroalbuminuria, hypertension, and renal insufficiency (serum creatinine >1.5mg/dL), ARBs are known to delay the progression to end stage renal disease. Beta-blockers are another treatment option and, although the UKPDS did not show a difference in effectiveness between beta-blockers and ACE inhibitors in lowering blood pressure or microalbuminuria, ACE inhibitors continue to be the drug of choice because some studies have shown that they can slow the rate of progression of nephropathy more than other antihypertensive agents. Beta-blockers or non-DCCBs should be considered when patients cannot tolerate ACE inhibitors or ARBs. Many patients need two or more agents to adequately control blood pressure. ACE inhibitors are contraindicated during pregnancy, and patients taking ACE inhibitors or ARBs should be monitored for hyperkalemia. Because microalbuminuria is a marker of increased cardiovascular disease risk, lifestyle modifications including weight loss, exercise, and reduction of dietary salt and alcohol are recommended to reduce the chances of a CVD event. P. Melga -DiSEM - Univ. Genova

Treatment of Diabetic Nephropathy (cont.) Glycemic Control Preprandial plasma glucose 90-130 mg/dl A1C <7.0% Peak postprandial plasma glucose <180 mg/dl Self-monitoring of blood glucose (SMBG) Medical Nutrition Therapy Restrict dietary protein to RDA of 0.8 g/kg body weight per day Glycemic control has been shown to delay the progression of diabetic nephropathy. ADA recommendations state that adults with diabetes should strive to maintain an A1C of <7.0%, preprandial plasma glucose of 90-130 mg/dl (5.0-7.2 mmol/L), and peak postprandial plasma glucose of <180 mg/dl (<10.0 mmol/L). Components of a successful glycemic control plan include: self-monitoring of blood glucose (SMBG), performing an A1C test at least two times each year for patients who meet treatment goals and quarterly in patients who do not, and individualized medical nutrition therapy (MNT). The UKPDS, DCCT, and Minnesota Medical school Trial have shown that intensive management of blood glucose can be helpful to patients in preventing the progression to kidney disease. Protein restriction has been shown to prevent the decline in GFR in some patients. Current ADA guidelines recommend that patients with nephropathy restrict their dietary protein intake to the adult Recommended Daily Allowance (RDA) which equals ~10% of daily calories. Further restriction to 0.6g/kg body weight per day may be useful, however patients should follow a low-protein diet developed by a registered dietition to prevent nutrition deficiency. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Raccomandazioni dell’A.D.A. per il trattamento della Nefropatia Diabetica - Nei pazienti con diabete di tipo 1, con micro o con macro albuminuria, gli ACE inibitori hanno dimostrato di rallentare la progressione della nefropatia. - Nei pazienti ipertesi con diabete di tipo 2 e microalbuminuria, sia gli ACE inibitori che gli ARB hanno rallentato la progressione a macroalbuminuria - Nei pazienti ipertesi con diabete di tipo 2 con macroalbuminuria gli ARB hanno dimostrato di rallentare la progressione della nefropatia P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova - Per ridurre ulteriormente la pressione in pazienti già trattati con ACE inibitori o con ARBs o in pazienti che non tollerano gli ACE inibitori e/o gli ARBs si possono utilizzare i Ca-antagonisti non diidropiridinici (non-DCCBs, nifedipina), i beta bloccanti, i diuretici. - In presenza di nefropatia conclamata avviare restrizione proteica di circa 0,8g/kg/day. - In corso di trattamento con ACE inibitori o ARBs monitorare i livelli di K serico (iperpotassiemia). Target controllo pressorio: P.A. ottimale: < 130/80 mmHg P.A. ottimale nei pz. micro- e macroalb.: < 125/75 mmHg Diabetic nephropaty. ADA Position Statement DIABETES CARE, 27 (Suppl. 1),2004 P. Melga -DiSEM - Univ. Genova

Treatment of End-Stage Renal Disease (ESRD) There are three primary treatment options for individuals who experience ESRD: 1. Hemodialysis 2. Peritoneal Dialysis 3. Kidney Transplantation There are currently three treatment options available to patients who experience kidney failure: Hemodialysis, peritoneal dialysis, and kidney transplantation. Although kidney transplantation is a serious operation, it offers patients with kidney failure their best opportunity for survival. For patients who choose dialysis, approximately one third are still alive after five years of treatment vs. a possible 90% survival rate for individuals who receive a kidney from a living relative. The next part of this presentation will review the procedures, risks and complications associated with each of these options. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova NEUROPATIA DIABETICA P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Diabetic Neuropathy About 60-70% of people with diabetes have mild to severe forms of nervous system damage, including: Impaired sensation or pain in the feet or hands Slowed digestion of food in the stomach Carpal tunnel syndrome Other nerve problems More than 60% of nontraumatic lower-limb amputations occur among people with diabetes. Up to 70% of people with diabetes will experience nervous system damage in their lifetime. The pain and discomfort caused by diabetic neuropathy, at a minimum, contributes to a diminished quality of life. At it’s worst, diabetic neuropathy is a major contributing cause of lower-limb amputation. The next three slides will review the risk factors, pathogenesis, and diagnosis of diabetic neuropathy. P. Melga -DiSEM - Univ. Genova

Pathogenesis of Diabetic Neuropathy Metabolic factors High blood glucose Advanced glycation end products Sorbitol Abnormal blood fat levels Ischemia Nerve fiber repair mechanisms The mechanisms by which diabetic neuropathy develops are still being researched. It is thought that neuropathy can be caused or aggravated by metabolic factors, ischemia, or impaired nerve fiber repair mechanisms. High blood glucose levels have been correlated to increase risk of diabetic neuropathy, and there are several theories as to why this occurs. Patients with diabetes have increased levels of serum advanced glycation end products (AGEs). AGEs form when excess blood glucose combines with amino acids to form, initially, early reversible glycation products. Later, irreversible advanced glycation end products are formed. AGEs are thought to contribute to blood vessel injury due to their effects on increasing vascular permeability, blood coagulation, and their effects on collagen. Glucose entering the cells is partially metabolized into sorbitol -this occurs even more so with hyperglycemia. Excess sorbitol leads to problems with cell metabolism, and could contribute to nerve damage in this way. Nerve ischemia, or reduced nerve blood flow, is involved in the pathogenesis of diabetic neuropathy. Evidence of vascular occlusions and thickened endoneural blood vessel walls have been found in patients with diabetic neuropathy. Finally, the nerve fiber repair mechanisms present in persons without diabetes are impaired in those with diabetes. Nerve growth factor and other neurotrophic factors are decreased in diabetes, which leads to a decreased ability to repair damaged nerves. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Risk Factors Glucose control Duration of diabetes Damage to blood vessels Mechanical injury to nerves Autoimmune factors Genetic susceptibility Lifestyle factors Smoking Diet There are several risk factors for developing diabetic neuropathy. Two of the main contributing factors are glucose control and duration of diabetes. Those who have had diabetes for at least 25 years and/or those who have had poor glucose control are at greatest risk of developing symptoms. Mechanical injury can lead to compression of the nerves and cause disorders such as carpal tunnel syndrome and other compression neuropathies. Autoimmune dysfunction can cause inflammation of the nerves which can aggravate neuropathy. Inherited traits can increase susceptibility to nerve disease. Finally, lifestyle factors such as smoking and alcohol abise can cause blood vessel damage leading to nerve damage. P. Melga -DiSEM - Univ. Genova

Classification of Diabetic Neuropathy Symmetric polyneuropathy Autonomic neuropathy Mononeuropathy Polyradiculopathy Most forms of diabetic neuropathy fall into one of four categories: symmetric polyneuropathy, autonomic neuropathy, polyradiculopathy, and mononeuropathy. As their names imply, neuropathy can affect the sympathetic or autonomic nervous system, can affect one or more nerves, and can affect one or more sides of the body at one time. P. Melga -DiSEM - Univ. Genova

Screening neuropatia diabetica (Linee guida A.D.A.) - Polineuropatia diabetica: alla diagnosi nel diabete di tipo 2 e dopo 5 anni dalla diagnosi nel tipo 1. - Neuropatia autonomica: alla diagnosi nel diabete tipo 2 e dopo 5 anni dalla diagnosi; esecuzione dei test di funzione cardiovascolare. Se lo screening é negativo ripeterlo annualmente. P. Melga -DiSEM - Univ. Genova

Symmetric Polyneuropathy Affects distal lower extremities and hands (“stocking-glove” sensory loss) Most common form of diabetic neuropathy Symptoms/Signs Pain Paresthesia/dysesthesia Loss of vibratory sensation Symmetric polyneuropathy is the most common form of neuropathy seen in diabetic patients. Symptoms generally begin distally in the toes and feet and move upward toward the calf. It is not uncommon for symptoms to also begin to appear in the hands, and the patient develops what is known as “stocking-glove” sensory loss. Symptoms include pain, abnormal sensation in the affected areas, and loss of vibratory sensation. Thermal sensation is also affected. P. Melga -DiSEM - Univ. Genova

Complications of Polyneuropathy Ulcers Charcot arthropathy Dislocation and stress fractures Amputation - Risk factors include: Peripheral neuropathy with loss of protective sensation Altered biomechanics (with neuropathy) Evidence of increased pressure (callus) Peripheral vascular disease History of ulcers or amputation Severe nail pathology Diminished sensation in the foot can prevent the patient from recognizing painful stimuli resulting from ill-fitting shoes, poor foot hygiene or minor trauma to the foot. Left unnoticed and untreated, these can lead to foot ulcers. Loss of nerve axons in the foot can also lead to muscle atrophy which can, in turn, lead to imbalance and weight shifting that can cause dislocation, stress fractures, and even lead to joint deterioration (Charcot arthropathy). The combination of poor blood flow to the extremities and loss of sensation in the foot due to nerve damage contribute to the development of ulcers and infections that can lead to amputation. In 2000-2001, about 82,000 nontraumatic lower-limb amputations were performed annually among people with diabetes. P. Melga -DiSEM - Univ. Genova

SCREENING della POLINEUROPATIA DISTALE SIMMETRICA Esame clinico del piede Riflessi achillei Sensibilità vibratoria Esame radiografico Studi di conduzione nervosa Elettromiografia P. Melga -DiSEM - Univ. Genova

Treatment of Symmetric Polyneuropathy Glucose control Pain control Topical creams Anticonvulsants Tricyclic antidepressants Foot care Symmetric polyneuropathy is treated with glycemic control, treatment of pain, and foot care. The DCCT and other studies provide evidence that intensive glucose control is effective in both preventing the development of neuropathy and, to a lesser degree, improving neuropathic symptoms. Pain can be treated with tricyclic antidepressants such as amitriptyline or desipramine. These drugs are contraindicated in patients with cardiac disease, and in these cases doxepin, trazodone, or paroxetine can be substituted. Nortriptyline can be substituted if cholinergic side effects are present. Topical pain relievers such as capsaicin cream can be added to the antidepressant regimen if pain persists. Anticonvulsants such as carbamazepine, gabapentin, and lamotrigine can be added to the pain relief regimen if the above remedies do not successfully alleviate pain. Foot care is not only important in the treatment of diabetic neuropathy, it is necessary to prevent amputation. The essentials of foot care are covered in the next slide. P. Melga -DiSEM - Univ. Genova

Essentials of Foot Care Examination Annually for all patients Patients with neuropathy - visual inspection of feet at every visit with a health care professional Advise patients to: Use lotion to prevent dryness and cracking File calluses with a pumice stone Cut toenails weekly or as needed Always wear socks and well-fitting shoes Notify their health care provider immediately if any foot problems occur Proper foot care consists of regular foot examinations by a physician to detect early neuropathy and treat existing lesions, as well as daily foot examinations by the patient. Patients should check for dry, cracking skin, calluses, and signs of infection between the toes and around the toenail. The American Diabetes Association Clinical Practice Guidelines recommend that all individuals with diabetes receive an annual foot exam to identify high-risk foot conditions. This exam should include assessment of sensation, foot structure, vascular status, and skin integrity. Patients with neuropathy should have a visual inspection of their feet at every health care visit. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Mononeuropathy Peripheral mononeuropathy Single nerve damage due to compression or ischemia Occurs in wrist (carpal tunnel syndrome), elbow, or foot (unilateral foot drop) Cranial mononeuropathy Affects the 12 pairs of nerves that are connected with the brain and control sight, eye movement, hearing, and taste Mononeuropathy multiplex The two main types of mononeuropathy caused by diabetes are peripheral mononeuropathy and cranial mononeuropathy. Mononeuropathies are caused by damage to a single nerve due to compression or vessel disease. Peripheral mononeuropathy occurs with damage to the peroneal nerve of the leg or damage to nerves affecting the wrist or elbow. Symptoms of both include numbness, swelling, pain and prickling sensations. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Mononeuropathy, cont. Treatment Foot care Glucose control Pain control Topical creams Anticonvulsants Tricyclic antidepressants Treatment for mononeuropathy includes the three main elements previously described: foot care in the case of peripheral mononeuropathy, intensive glucose control, and treatment for pain. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Polyradiculopathy Lumbar polyradiculopathy (diabetic amyotrophy) Thigh pain followed by muscle weakness and atrophy Thoracic polyradiculopathy Severe pain on one or both sides of the abdomen, possibly in a band-like pattern Diabetic neuropathic cachexia Polyradiculopathy + peripheral neuropathy Associated with weight loss and depression Polyradiculopathy is a term used to describe nerve damage to nerve roots, normally lumbar and thoracic. Lumbar polyradiculopathy is the most common type of polyradiculopathy. Damage to the L2, L3, and L4 nerve roots causes pain in the thigh followed by muscle weakness and wasting of the thigh muscle (hence this disorder is also called diabetic amyotrophy). The symptoms generally resolve themselves within six months to two years. Thoracic polyradiculopathy is caused by damage to the T4 through T12 nerve roots, and results in abdominal pain which can occur in a band-like pattern around the abdomen. Both lumbar and thoracid polyradiculopathies can occur at the same time. Diabetic neuropathic cachexia is a syndrome which results when polyradiculopathy and peripheral neuropathy occur simultaneously. Severe weight loss, wasting and muscle weakness result. P. Melga -DiSEM - Univ. Genova

Polyradiculopathy, cont. Polyradiculopathies are diagnosed by electromyographic (EMG) studies Treatment Foot care Glucose control Pain control Patients should be diagnosed based on history, clinical examination, and electromyographic (EMG) studies. Foot care, intensive glucose control, and treatment for pain are the three main elements of treatment for polyradiculopathy, similar to peripheral neuropathy. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Autonomic neuropathy Affects the autonomic nerves controlling internal organs Peripheral Genitourinary Gastrointestinal Cardiovascular Is classified as clinical or subclinical based on the presence or absence of symptoms Autonomic neuropathy can affect the limbs, the genitals and urinary tract, the gastrointestinal tract, or the heart. This form of neuropathy is classified as clinical or subclinical based on the presence or absence of symptoms. The next five slides will review the four main categories of neuropathy affecting the autonomic nervous system. P. Melga -DiSEM - Univ. Genova

NEUROPATIA AUTONOMICA (NA) Subdola, in quanto spesso asintomatica, la sua incidenza è molto variabile (dall’ 1,6% al 20% e oltre a seconda della popolazione esaminata e dei tests diagnostici utilizzati). Dal momento che la N.A. può interessare qualsiasi apparato (cardiovascolare, gastrointestinale, genitourinario, periferico), quando è presente la qualità della vita peggiora e la mortalità aumenta del 25-50% entro 5-10anni. P. Melga -DiSEM - Univ. Genova

NEUROPATIA AUTONOMICA CARDIOVASCOLARE La neuropatia autonomica cardiovascolare (CAN) è la forma più studiata, e associata ad aumento di rischio di ischemia miocardica silente e morte improvvisa. Test diagnostici non invasivi (HRV) : - Breath test - Lying to standing - Ipotensione posturale P. Melga -DiSEM - Univ. Genova

Cardiovascular Autonomic Neuropathy Symptoms/Signs Exercise intolerance Postural hypotension Treatment Discontinue aggravating drugs Change posture (make postural changes slowly, elevate bed) Increase plasma volume Subclinically, cardiovascular autonomic neuropathy is diagnosed by cardiovascular reflex testing. Clinically, the disorder manifests itself in the form of an inability to exercise and postural or orthostatic hypotension. Exercise intolerance can be caused by impaired modulation of the sympathetic nerves leading to irregular heartbeat. Denervation of the heart muscle can also occur in advanced cases and is characterized by a fixed heart rate of 80-90 beats per minute. In such cases, myocardial infarction can occur. Postural hypotension is defined as a fall in systolic blood pressure in excess of 20mmHg when in an upright position.This condition is caused by a combination of central and peripheral cardiovascular sympathetic denervation. Hypertension can also occur at night when the patient is supine. Postprandial hypotension is not uncommon, and could be caused by a pooling of bloodin the abdomen. Postural symptoms can be treated by discontinuing drugs which may aggravate the disorder, and by making slow rather than sudden changes in posture. Elevating the head of the bed at night can prevent hypertension. Another method of treatment is to cross the legs while standing, and “tense” the leg muscles to increase cardiac output. Increasing the plasma volume of the blood with mineralocorticoid fludrocortisone and a high salt diet can be helpful in severe cases. P. Melga -DiSEM - Univ. Genova

Genitourinary Autonomic Neuropathy Denervation of the genitourinary system can cause a number of symptoms, including bladder dysfunction, retrograde ejaculation, erectile dysfunction, and painful intercourse (dyspareunia) due to lack of vaginal lubrication. Bladder dysfunction should be diagnosed with a cystometrogram. The inability to sense a full bladder can lead to bladder infections and urinary incontinence which can be treated by having the patient participate in a strict voluntary urination schedule. Catheterization can be performed in advanced cases. Retrograde ejaculation is caused by a dysfunction in internal and external sphincter closure during ejaculation, and patients may present with cloudy urine postcoitally. This symptom can be successfully treated with antihistamines. Erectile dysfunction can be caused by a number of factors other than diabetic neuropathy, and an attempt to discover the cause of impotence must be made prior to treatment. Sildenafil has been used successfully in treating men with impotence due to neuropathy. Finally, painful intercourse, most common in diabetic women, is usually due to decreased libido, depression, and reduced vaginal lubrication. Treatment for sexual dysfunction in women includes use of vaginal lubricants and estrogen creams. P. Melga -DiSEM - Univ. Genova

Gastrointestinal Autonomic Neuropathy Symptoms/Signs Gastroparesis resulting in anorexia, nausea, vomiting, and early satiety Diabetic enteropathy resulting in diarrhea and constipation Treatment Other causes of gastroparesis or enteropathy should first be ruled out Gastroparesis - Small, frequent meals, metoclopramide, erythromycin Enteropathy - loperamide, antibiotics, stool softeners or dietary fiber Neuropathy of the gastrointestinal tract can affect the esophagus, stomach and intestines causing pain, nausea, vomiting, diarrhea and constipation. Symptoms vary depending on which area of the digestive tract is affected. Gastroparesis can cause anorexia, nausea, vomiting, early satiety, and postprandial fullness. Diagnosis can be confirmed by radiolabeled breath tests, radionuclide gastric emptying tests, ultrasonography or measurement of gastric impedence. Gastroparesis is treated by encouraging the patient to eat smaller, more frequent meals to prevent nausea. A dietitian should be consulted when designing a meal plan for someone with gastroparesis. Dompamine antagonists such as metoclopramide and domperidone can be used before meals to improve gastric emptying. Patients with gastroparesis and impaired absorption should be monitored for hypoglycemia. Widespread neuropathy of the intestines can cause enteropathy, which can lead to diarrhea, constipation, or incontinence. Diarrhea can be caused by a number of factors in patients with diabetes, including bacterial overgrowth, poor intestinal motility, celiac disease, and other disorders. The cause of the diarrhea should be determined before treatment is initiated. Loperamide may be administered to treat intestinal motility disorders. Antibiotics can be used for bacterial overgrowth. Stool softeners and increased dietary fiber can be used to treat constipation. P. Melga -DiSEM - Univ. Genova

Peripheral Autonomic Dysfunction Contributes to the following symptoms/signs: Neuropathic arthropathy (Charcot foot) Aching, pulsation, tightness, cramping, dry skin, pruritus, edema, sweating abnormalities Weakening of the bones in the foot leading to fractures Testing Direct microelectrode recording of postglanglionic C fibers Galvanic skin responses Measurement of vascular responses Peripheral autonomic denervation can contribute to many different symptoms including changes in the texture of the skin, itching, edema, and sweating abnormalities in the feet. Peripheral autonomic dysfunction can also contribute to neuropathic arthropathy and fractures. Patients who already suffer from symmetric polyneuropathy are at greater risk for Charcot arthropathy. Patients should be aware of symptoms such as swelling, redness, heat, strong pulse, and insensitivity of the foot. Peripheral autonomic dysfunction can be diagnosed using specialized techniques such as microelectrode recordings of postglanglionic C fibers. It can also be diagnosed using galvanic skin responses and quantitative sudomotor axon reflex testing (QSART) to measure the presence of sympathetic innervation in hands and feet Vascular responses can also be measured to determine peripheral sympathetic denervation. Constriction of the blood vessels in the presence of heat indicates vascular denervation P. Melga -DiSEM - Univ. Genova

Peripheral Autonomic Dysfunction, cont. Treatment Foot care/elevate feet when sitting Eliminate aggravating drugs Reduce edema midodrine diuretics Support stockings Screen for CVD Peripheral autonomic dysfunction therapy includes foot care, elimination of drugs that can aggravate symptoms (tranquilizers, antidepressants, diuretics), efforts to reduce swelling and promote blood flow. Patients with autonomic dysfunction in peripheral nerves should also be screened for cardiovascular dysfunction. Foot care includes physician exams and patient daily examination as described in the previous slide. Vascular denervation causes excess peripheral blood flow and edema. Diuretics, midrodrine, and ephedrine can be used to alleviate swelling, as can elevating the feet when sitting. Support stockings can promote blood flow as well. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova MACROANGIOPATIA P. Melga -DiSEM - Univ. Genova

Framingham Heart Study CVD Events in Diabetics Relative risk ratio Men Women * * * * * * * † * Framingham Heart Study CVD Events in Diabetics There was a strong association between diabetes and cardiovascular risk factors in the Framingham Heart Study. This figure depicts the age-adjusted annual relative risk of vascular disease endpoints over 30 years of follow-up in men and women 35 to 64 years old. Compared to the nondiabetics in the cohort, diabetic women and men had age-adjusted risks for cardiac failure, coronary heart disease (CHD), intermittent claudication and total CVD that were very significantly greater (P <0.01) whereas the relative risk for stroke was significant (P<0.05) only for diabetic women. Except for stroke risk, the relative risk of having any of the other CVD events was greater in diabetic women compared to nondiabetic women than in diabetic men compared to nondiabetic men. Reference: Wilson PWF, Kannel WB. Epidemiology of Hyperglycemia and Atherosclerosis. In: Ruderman N, Williamson J, Brownlee M, eds. Hyperglycemia, Diabetes, and Vascular Disease. New York: Oxford University Press; 1992:21-29. CHD Cardiac failure Intermittent claudication Total CVD Stroke CVD=cardiovascular disease CHD=coronary heart disease *P<0.01 †P<0.05 Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N, et al. eds. Oxford;1992. ©Copyright 1992, American Physiological Society. Used by permission of Oxford University Press, Inc. P. Melga -DiSEM - Univ. Genova

Increased CHF Prevalence in Diabetics CHF cases per 1,000 subjects 377 400 350 Diabetic subjects 300 300 241 224 250 250 200 135 Control subjects 150 105 68 100 44 33 Increased CHF Prevalence in Diabetics The purpose of this study was to estimate the prevalence and incidence of congestive heart failure (CHF) in patients with and without diabetes and to identify risk factors for diabetes-associated CHF. Subjects for this study included 9,591 individuals diagnosed with type 2 diabetes and an age- and sex-matched control group without diabetes. Patients were followed for 30 months. CHF was identified in 11.8% (n=1,131) of diabetic subjects at baseline compared with 4.5% (n=435) of control subjects. Of the 8,460 diabetic subjects who did not have CHF at baseline, 7.7% (n=650) developed CHF during follow-up. Of the 9,156 control subjects free of CHF at baseline, 3.4% developed CHF during follow-up. Reference: Nichols GA, Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors. Diabetes Care. 2001 Sep;24(9):1614-1619. 50 8 12 4 45-54 65-74 85-94 <45 55-64 75-84 95+ Age at baseline Nichols GA, et al. Diabetes Care. 2001:24;1614-1619. Copyright ©2002, American Diabetes Association. Reprinted with permission. P. Melga -DiSEM - Univ. Genova

Causes of Death in People With Diabetes Percent of deaths Causes of Death in People With Diabetes Based on data collected from 4 cohort studies in the US conducted between 1965 and 1988, it was determined that the leading causes of death listed on the death certificates of persons with diabetes were diseases of the heart (55%), diabetes (13%), malignant neoplasms (13%), and cerebrovascular disease (10%). Despite variation in the way underlying cause of death was classified, the proportion of persons dying from these causes was similar across the 4 studies. Geiss et al also found that the risk of heart disease mortality and ischemic heart disease mortality was 2 to 4 times higher in persons with diabetes than in persons without diabetes. For persons with diabetes, the excess risk of dying from heart disease and ischemic heart disease was higher than the excess risk of mortality for all other causes combined. While the studies may not have distinguished between insulin-dependent diabetes and non-insulin-dependent diabetes (NIDDM), it was assumed that the diabetes deaths were NIDDM deaths because of the older age of the populations and the increased prevalence of NIDDM in older age groups. Reference: Geiss LS, Herman WH, Smith PJ. Mortality in Non-Insulin-Dependent Diabetes. In: National Diabetes Data Group, eds. Diabetes in America. 2nd ed. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995. Diabete Malignant neoplasms All other Other heart disease Pneumonia/ influenza Ischemic heart disease Cerebrovascular disease Geiss LS, et al. In: Diabetes in America. National Institutes of Health;1995. P. Melga -DiSEM - Univ. Genova

Coronary Heart Disease Risk Markersin Diabetes Modifiable Not modifiable Elevated LDL-C Low HDL-C Elevated blood pressure Elevated triglycerides Thrombogenic factors PAI-1 Fibrinogen C-reactive protein Diet Tobacco smoking Excess alcohol consumption Physical inactivity Obesity Age Male gender Family history of CHD Personal history of CHD Coronary Heart Disease Risk Markers in Diabetes Reference: Pyorala K, De Backer G, Graham I, Poole-Wilson P, Wood D. Prevention of coronary heart disease in clinical practice. Recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. Eur Heart J. 1994;15:1300-1331. Pyorala K, et al. Eur Heart J. 1994;15:1300-1331. P. Melga -DiSEM - Univ. Genova

Systolic BP and CV Death in MRFIT Nondiabetic (n=342,815) CV mortality rate per 10,000 person-years Diabetic (n=5,163) Systolic BP and CV Death in MRFIT A total of 347,978 men screened for the Multiple Risk Factor Intervention Trial (MRFIT) were studied to assess predictors of cardiovascular disease (CVD) mortality among men with and without diabetes and to assess the effect of diabetes on CVD death. Participants were 35 to 57 years old. The outcome measure was CVD mortality. To evaluate the effects of 3 CV risk factors, serum cholesterol, systolic blood pressure, and reported number of cigarettes smoked per day, participants were grouped into 8 strata for comparison: level of serum cholesterol <200 or 200 mg/dL; SBP <120 or 120 mmHg, and also <140 and 140 mmHg; and cigarette use or no cigarette use. CVD death rates for those with and without diabetes were compared according to the presence of 1, 2, or 3 of these risk factors. The relative risk for CVD death in participants with none of the risk factors was 5.10 for diabetics compared to nondiabetics. With all 3 risk factors, the relative risk for CVD death was 2.64 for diabetics compared to nondiabetics. Systolic blood pressure was positively related to CVD death risk with a significant trend in both diabetics and nondiabetics (P<0.001). For men with diabetes, CVD death rates increased from 53.6 to 242.6 deaths per 10,000 person years, and from 12.2 to 128.7 in those without diabetes. As with serum cholesterol and cigarette smoking, at every level of SBP the CVD death rate was greater for diabetic compared to nondiabetic men. Reference: Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16(2):434-444. <120 120-139 140-159 160-179 180-199 200 Systolic BP (mmHg) MRFIT=Multiple Risk Factor Intervention Trial Stamler J, et al. Diabetes Care. 1993;16:434-444. P. Melga -DiSEM - Univ. Genova

Incidence of MI and Microvascular Endpoints by Mean SBP and HbA1c in UKPDS Myocardial infarction Myocardial infarction Adjusted incidence per 1000 person-years (%) Adjusted incidence per 1000 person-years (%) Incidence of MI and Microvascular Endpoints by Mean SBP and HbA1c in UKPDS In the UK Prospective Diabetes Study (UKPDS) reported by Adler et al, the relation between systolic blood pressure over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes was considered. Rates for both myocardial infarction and microvascular endpoints were strongly associated, to a similar degree, with increasing systolic blood pressure. Each 10 mmHg decrease in updated mean systolic blood pressure was associated with reductions of risk of 11% for myocardial infarction (14% to 7%, P<0.0001), and 13% for microvascular complications (16% to 10%, P<0.0001). In the UKPDS study reported by Stratton et al, the relation between exposure to glycemia over time and the risk of microvascular or macrovascular complications in patients with type 2 diabetes was considered. The incidence of clinical complications was associated significantly with glycemia. Each 1% reduction in updated mean HbA1c was associated with reductions in risk of 14% for myocardial infarction (21% to 8%, P<0.0001), and 37% for microvascular complications (41% to 33%, P<0.0001). References: Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321(7258):412-419. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405-412. Microvascular endpoints Microvascular endpoints 110 120 130 140 150 160 170 5 6 7 8 9 10 11 Mean SBP (mmHg) Updated mean HbA1c concentration (%) Adler AI, et al. BMJ. 2000;321:412-419.Stratton IM, et al. BMJ. 2000;321:405-412. P. Melga -DiSEM - Univ. Genova

CVD mortality/ 1,000 person years Age-Adjusted CVD Mortality by Quintile* of Fasting Serum Triglyceride (mmol/l) Men Women * * CVD mortality/ 1,000 person years Age-Adjusted CVD Mortality by Quintile of Fasting Serum Triglyceride In this study of 4,743 participants in the World Health Organization Multi-National Study of Vascular Disease in Diabetes (WHO MSVDD), the association between classic cardiovascular risk factors and diabetes-specific risk factors and the incidence of fatal and non-fatal cardiovascular disease outcomes was determined. The relation between CVD mortality and quintiles of fasting serum triglyceride was positive for both type 2 diabetic men (P=0.001 for trend) and women (P=0.0007 for trend). Reference: Fuller JH, Stevens LK, Wang SL. Risk factors for cardiovascular mortality and morbidity: the WHO Mutinational Study of Vascular Disease in Diabetes. Diabetologia. 2001;44[Suppl 2]:S54-64. Q1 Q2 Q3 Q4 Q5 Q1 Q2 Q3 Q4 Q5 CVD=cardiovascular disease *P<0.01 compared to Q1 Q1<1.10; Q2=1.11-1.50; Q3=1.51-2.02; Q4=2.03-2.93; Q5>2.94. Fuller JH, et al. Diabetologia. 2001;44[suppl2]:S54-S64.Copyright ©2001, Springer-Verlag.. P. Melga -DiSEM - Univ. Genova

Proteinuria as a Risk Factor for Mortality in Type 2 Diabetes 1.0 Normoalbuminuria (n=191) 0.9 Microalbuminuria (n=86) 0.8 Survival (all-cause mortality) 0.7 Macroalbuminuria (n=51) 0.6 Proteinuria as a Risk Factor for Mortality in Type 2 Diabetes In this study, the impact of microalbuminuria and macroalbuminuria on mortality was evaluated prospectively in 328 non-insulin-dependent diabetic patients followed for 5 years. During follow-up, 51 patients died (16%). A total of 18 out of 51 patients with macroalbuminuria died (35%) compared to 17 out of 86 with microalbuminuria (20%), and 16 out of 191 with normoalbuminuria (8%). Reference: Gall MA, Borch-Johnsen K, Hougaard P, Nielsen FS, Parving HH. Albuminuria and poor glycemic control predict mortality in NIDDM. Diabetes. 1995;44(11):1303-1309. 0.5 1 2 3 4 5 6 P<0.01 normoalbuminuria vs microalbuminuria P<0.001 normoalbuminuria vs macroalbuminuria P<0.05 microalbuminuria vs macroalbuminuria Years Gall MA, et al. Diabetes. 1995;44:1303-1309.Copyright ©1995, American Diabetes Association. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Summary of Key Points The protection afforded nondiabetic women is lost in diabetic women Diabetics are at increased risk for all types of fatal and non-fatal cardiovascular (CV) events There is an increasingly negative impact on CV morbidity and mortality as the number of risk factors increases. The risk of myocardial infarction (MI) in a diabetic without prior MI is as great as the risk of MI in a nondiabetic with a previous MI Proteinuria is a potent predictor of cardiovascular risk in diabetics, even more than in nondiabetics Summary of Key Points Diabetics are at increased risk for all types of fatal and no-fatal cardiovascular (CV) events. The protection afforded nondiabetic women is lost in diabetic women. There is an increasingly negative impact on CV morbidity and mortality as the number of risk factors increases. The risk of myocardial infarction (MI) in a diabetic without prior MI is as great as the risk of MI in a non-diabetic with a previous MI. Proteinuria is a potent predictor of cardiovascular risk in diabetics, even more than in non-diabetics. P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova

Popolazioni dell’Europa e Nord America Diabete Tipo 2 Diabete Tipo 1 10-15 volte più frequente P. Melga -DiSEM - Univ. Genova Mod. da Vora JP, Bailliere’s Clinical Endocrinology and Metabolism, 13: 239-264, 1999

Patogenesi delle complicanze del diabete FASE POST-PRANDIALE Iperglicemia Spike (Variabilità) Esposizione “continua” Lipidi, acidi grassi liberi, etc. Tossicità “acuta” Tossicità “cronica” Lesione tissutale Complicanze del diabete Altri fattori di rischio associati P. Melga -DiSEM - Univ. Genova

complicanze microvascolari Retinopatia diabetica Neuropatia diabetica Nefropatia diabetica P. Melga -DiSEM - Univ. Genova

Peggioramento della retinopatia, nefropatia ed indici di controllo glicemico HbA1c (%) Glicemia basale (mg/dl) Glicemia post-prandiale 2° ora (mg/dl) 16 12 8 4 5 7 9 11 80 120 160 200 140 180 220 260 300 Velocità di peggioramento della retinopatia 16 12 8 4 5 7 9 11 80 120 160 200 140 180 220 260 300 Velocità di peggioramento della nefropatia (per 100 pazienti-anno) P. Melga -DiSEM - Univ. Genova Shichiri M, et al. Diabetes Care 2000: 23, B21-9.

IPERTENSIONE ARTERIOSA P. Melga -DiSEM - Univ. Genova

Prevenzione nefropatia Target controllo glicemico - HbA1c < 7.0% (v.n. 4-6%) - Glicemia a digiuno o preprandiale 90-130 mg/dl - Glicemia postprandiale < 180 mg/dl Diabetic nephropaty. ADA Position Statement. DIABETES CARE, 27 (Suppl. 1) 2004 P. Melga -DiSEM - Univ. Genova

P. Melga -DiSEM - Univ. Genova Diagnostic Tests Assess symptoms - muscle weakness, muscle cramps, prickling, numbness or pain, vomiting, diarrhea, poor bladder control and sexual dysfunction Comprehensive foot exam Skin sensation and skin integrity Quantitative Sensory Testing (QST) X-ray Nerve conduction studies Electromyographic examination (EMG) Ultrasound There are several diagnostic tests that can be used to determine the presence and type of diabetic neuropathy. Reviewing the patients’ symptoms can help determine if neuropathy is present and to what extent. It is important to remember that all other potential causes of, for example, muscle weakness and numbness, be ruled out before making a diagnosis of diabetic neuropathy. All patients with diabetes should receive an annual foot exam in which the foot is assessed for skin sensation using a monofilament (Semmes-Weinstein 5.07 (10-g)), skin integrity (calluses and sores, especially between toes), bone deformities or deformities in the foot’s structure or biomechanics, and vibration perception. Ankle reflexes should also be tested. Quantitative sensory testing (QST) (responses to pressure, vibration, and temperature) should be used to determine loss of sensation or sensitivity of nerves. X-ray can be used to verify bone deformities. Nerve conduction studies can detect possible nerve damage by assessing the transmission of nerve impulses. Impulses that are slower or weaker than normal may indicate damaged nerves. EMG, in conjunction with nerve conduction studies, can help determine if there is damage to muscle or nerve by assessing how well muscles respond to nerve impulses. When autonomic neuropathy is suspected, ultrasound of internal organs such as the bladder can assist in determining if there is any abnormal function or structure to the organ. For example, does the bladder empty completely after urination? P. Melga -DiSEM - Univ. Genova

Classification and Natural History of Diabetic Retinopathy Mild nonproliferative diabetic retinopathy (NPDR) Moderate NPDR Severe NPDR Very Severe NPDR Proliferative diabetic retinopathy (PDR) There are several stages of retinopathy. The earliest clinical stage of diabetic retinopathy is identified as mild nonproliferative diabetic retinopathy (NPDR). Progression of disease from NPDR to proliferative diabetic retinopathy (PDR) is related to the level or severity of NPDR, and therefore the severity of NPDR should determine follow-up and management of diabetic retinopathy. The next four slides will review the clinical findings and management of each stage of retinopathy. P. Melga -DiSEM - Univ. Genova

Increased Risk of CV Events Over 7 years in Type 2 Diabetics Myocardial Infarction Stroke CV Death Incidence rate (%) Nondiabetic –MI (n=1,304) Diabetic –MI (n=890) Nondiabetic +MI (n=69) P<0.001* Diabetic +MI (169) P<0.001* P<0.001* Increased Risk of CV Events Over 7 Years in Type 2 Diabetics In this study of 1,373 nondiabetic and 1,059 diabetic subjects, the 7-year incidence of fatal and nonfatal myocardial infarction (MI) was examined to determine whether patients with diabetes who have not had MIs should be treated as aggressively for cardiovascular (CV) risk factors as patients who have had MIs. In both diabetic and non-diabetic subjects, a history of MI at baseline was significantly associated with an increased incidence of MI during 7 years of follow-up. Further, a history of MI at baseline was also associated with an increased incidence of stroke and death from CV causes. Reference: Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4):229-234. -MI=no prior myocardial infarction/+MI=prior myocardial infarction CV=cardiovascular *For diabetes vs. no diabetes and prior MI vs. no prior MI Haffner SM, et al. N Engl J Med. 1998;339:229234. P. Melga -DiSEM - Univ. Genova