CHRONIC DIABETIC COMPLICATIONS MACROVASCULAR DISEASE Coronary heart disease Cerebrovascular disease Peripheral vascular disease Coronary heart

art disease in diabetes It is more common and occurs earlier than in people without diabetes. Women lose gender protection. Myocardial infarction is often painless (silent). Two- to three-fold higher risk of heart failure. Diabetic patients with myocardial infarction have poor prognosis even after adjustments of infarct size and risk factors. Albuminuria increases risk of vascular event. Cerebrovascular disease in diabetes Strokes occur twice as often in diabetes and hypertension than those with hypertension alone Transient Ischaemic Attacks (TIAs) occur two to six times more often Prevention & Management of Macrovascular Complications Intensive treatment of modifiable risk factors; increase physical activity. improve diet: reduce total and saturated fat, increase monounsaturated fat. Aggressive treatment of dyslipidaemia. Aggressive treatment of hypertension. Smoking cessation. Coronary heart disease Antiplatelet therapy. Known risk factors Age Dyslipidaemia Gender Typical pattern of dyslipidemia in type 2 diabetes; Family history 1) raised triglycerides Lipid abnormalities 2) low HDL Hypertension 3) raised small dense LDL particles Smoking Diabetes Targets of therapy Atherogenic diet 1) LDL-C < 100 mg/dl (optional <70mg/dl) Physical inactivity 2) TG < 150 mg/dl 3) HDL-C > 40 mg/dl (men), >50 mg/dl (women) Lipid Lowering Drug Therapy For LDL lowering, HMG-CoA Reductase Inhibitors (statins) are 1st line therapy. Cholesterol absorption inhibitors may provide additional LDL lowering in combination with a statin. Bile acid sequestrants may increase TG. Niacin is the best drug for increasing HDL, but may affecct glucose homeostasis( increase insulin resistace). Glycemic control may significantly reduce triglycerides

Hypertension and Diabetes Hypertension may be linked to development and progression of nephropathy, retinopathy, and atherosclerosis In patients with Type 1 diabetes, persistent hypertension is often a manifestation of diabetic nephropathy (concomitant elevated levels of urinary albumin and, in later stages, by a decrease in the glomerular filtration rate) In patients with Type 2 diabetes, hypertension is often part of a syndrome that includes glucose intolerance, insulin resistance, obesity, dyslipidemia, and coronary artery disease Initial Treatment and Goals for Adult Hypertensive Diabetic Patients Systolic <130 130-139 140 Diastolic <80 80-89 90

Goal (mmHg) Lifestyle/Behavioral therapy alone (max 3 month) then add pharmacologic therapy Lifestyle / pharmacologic therapy

Hypertension and Diabetes-Treatment options ACE Inhibitors Angiotensin receptor blockers (ARB) Calcium channel blockers -blockers Thiazide diuretics (low dose) -blockers Many people require three or more drugs to achieve the recommended target Antiplatelet Therapy Recommendations in Patients with Diabetes Use aspirin therapy 75-162 mg/dl as a primary prevention in diabetic patients (type 1&2) at increased cardiovascular risk. This includes; men >50 or women > 60 years of age who have at least one additional CV risk factor(family history of CVD , hypertension, dyslipidemia , or albuminuria). (C) Use aspirin therapy 75-162 mg/dl as a secondary prevention in diabetic patients (type 1&2) with cardiovascular disease. (A) Aspirin allergy, bleeding tendency, anticoagulant therapy, recent GI bleeding, under the age of 30 and clinically active hepatic disease are contraindications for aspirin therapy. Clopidogrel (75mg/day) should be used. Role of tight glycemic control in CVD outcomes Trials of intensive (tight) versus standard glycemic control have not shown a significant reduction in CVD outcomes . (B) However,long-term follow-up suggests that A1c targets below or around 7% in diabetic patients (type 1&2) is associated with long term reduction in the risk of macrovascular disease. So, the general goal of A1c < 7% is resonable for macrovascular risk reduction. (B)

MICROVASCULAR DISEASE DIABETIC RETINOPATHY It is the most frequent late complication of type 1 diabetes. Diabetes is the leading cause of blinding in persons aged 20 to 74 years in the United States. The incidence of retinopathy, it's progression and development of proliferative retinopathy were highest in patients with type 1, intermediate in insulin-treated patients with type 2 diabetes, and lowest in patients with type 2 diabetes treated with oral agents or diet. Stages of diabetic retinopathy
1. Mild non proliferative diabetic retinopathy (Mild NPDR) These changes begin 3 to 5 years after diagnosis in type 1 diabetics. First signs are microaneurysms with subsequent retinal haemorrhages and hard exudates. Infarctions of nerve fiber layer, known as soft exudates. Visual acuity is generally unaffected. Characterized by microvascular abnormalities such as: o Venous beading, venous caliber changes. o Increased capillary dilatation and permeability. Manifested by: o Progressive retinal ischemia. o Extensive hemorrhages, exudates and microaneurysms. At 5 years; mild, moderate and severe NPDR are associated with 15%, 30% and 60% risk of progression to PDR Involves: o Neovascularization in the retina "early PDR" o Neovascularization in the vitreous body "High risk PDR" Retinal detachment. Retinal hemorrhages. Blindness. Occasionally, new vessels can invade the iris and the anterior chamber, leading to sight threatening closed-angle glaucoma.

2.

Moderate NPDR

3.

Severe or very severe NPDR

4.

Proliferative diabetic retinopathy (PDR)

Management of Diabetic Retinopathy

I.General Recommendations To reduce the risk or slow progression of retinopathy; * optimize glycemic control(A): 1) A1C should be lowered to below or around 7% 2) FPG(preprandial) should be lowered to (70-130 mg/dl) 3) 2h-PPG(peak postprandial) should be lowered to below or around 180 mg/dl To reduce the risk or slow progression of retinopathy; * optimize blood pressure control(A): Diabetic patient (without renal affection) should be treated; 1) to a systolic BP <130 mmHg and 2) to a diastolic BP <80 mmHg.

Improved and tight glycemic control as well as BP control can significantly delay the development of non proliferative retinopathy and postpone its progression to proliferative retinopathy.

II.Screening

Initial fundus examination is recommended within 3 to 5 years of diagnosis of type 1 diabetes, and at the time of diagnosis in type 2 patients. Subsequent examinations for both type 1 and type 2 diadetes should be repeated annually. In diabetes with pregnancy,fundus examination should occur in the first trimester with close follow-up throughout pregnancy and for 1 year postpartum. Other targets for medical management, all associated with accelerated retinal damage, include; 1. Treatment of hypertension and hyperlipidemia. 2. Treatment of nephropathy. 3. Careful follow-up during pregnancy "retinal pathology shows rapid progression". 4. Surgical management including; i. Vitrectomy. ii. Laser photocoagulation. The presence of retinopathy is not a contraindication to aspirin therapy for cardioprotection, as this therapy does not increase the risk of retinal hemorrhage.

III.Treatment

DIABETIC NEPHROPATHY Diabetes is the leading cause of ESRD in U.S., accounting for more than one third of the cases. The risk of diabetic nephropathy in type 2 diabetes seems to be similar to that in type 1 diabetes. Risk factors for diabetic nephropathy 1. The level of glycemia and glycosylated hemoglobin seems to be the strongest factor influencing the onset of microalbuminuria. 2. Several factors besides hyperglycemia influence the development of several stages of diabetic nephropathy including: i. Hypertension. ii. Cigarette smoking. iii. Hyperlipidemia. iv. Genetic susceptibility. Stages of diabetic nephropathy
Stage I: Glomerular hyperfiltration Starts immediately in the period following diagnosis. Characterized by increase glomerular filtration rate (GFR). These changes depend on hyperglycemia as they diminished by intensive therapy. Stars 3 to 5 years after diagnosis characterized by: Thickening of glomerular basement membrane. Mesangial matrix expansion. Arteriolosclerosis.

Stage II: Early glomerular lesions

 Stage III: Diffuse glomerulosclerosis Stage IV: End stage renal disease (CRF)

At this stage although renal function tests are normal "creatinine and urine analysisMicroalbuminuria appears (30 300 mg/24h urine). Systemic hypertension is present in 50% of cases. Most of cases exhibit this lesion several years after. Minority of cases have pathogenic Kimmelsteil-Wilson nodular lesions. Overt albuminuria (>300mg/24h urine) begins in this stage causing nephrotic syndrome. Progressive decline of GFR. Increase in serum creatinine. Characterized by marked reduction of GFR.

Management of Diabetic Nephropathy

I.General Recommendations To reduce the risk or slow progression of nephropathy; * optimize glycemic control(A): 1) A1C should be lowered to below or around 7% 2) FPG(preprandial) should be lowered to (70-130 mg/dl) 3) 2h-PPG(peak postprandial) should be lowered to below or around 180 mg/dl To reduce the risk or slow progression of nephropathy; * optimize blood pressure control(A): Diabetic patient (with renal affection) should be treated; 1) to a systolic BP <125 mmHg and 2) to a diastolic BP <75mmHg. Patients with type 1 diabetes should be screened for microalbuminuria yearly 3-5 years after diagnosis. Patients with type 2 diabetes should be screened yearly but early, starting at the time of diagnosis.. Microalbuminuria is diagnosed when the urinary albumin excretion rate(UAE) is: * 30 -300 mg/24 hour urine or * 30 -300 g/mg creatinine(spot collection) Measure serum creatinine annually in all adults with diabetes regardless of the degree of UAE. For patients with established microalbuminuria or proteinuria : 1Tight control of the blood glucose 2Tight control of the blood pressure (irrespective of agent used is beneficial in albuminuria) 3Use of ACE inhibitors or AR blockers(Dual Effect) in all patients including normotensives as reno-protection (Renoprotective drugs): They reduce microalbuminuria and slow progression of D.nephropathy independent of their antihypertensive effect Mechaism of action of Renoprotective drugs * Early stages of Diabetic nephropathy are characterized by increase in intracapillary pressure regardless of systemic arterial blood pressure.

II. Screening

III.Treatment

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* They cause efferent arteriolar vasodilatation with resulting reduction of the high intraglomerular pressure and gradual decrease of glomerular membrane permeability to protein. * The intraglomerular pressure is the main factor in preserving renal function Adverse effects of ACEIs/ARBs and Contrindications Cough : 0-39%, F>M, class effect Angioedema: 0.1-0.2 %: 1hr to <1 wk Metallic taste: captopril Hyperkalemia; they should be discontiued if potassium is more than 5.5 meq/L Worsening renal function; they should be discontiued if serum creatinine is more than 2.5mg/dl Pegnancy&Lactation Evaluate diet and reduce protein intake (0.6 0.8g/kg/day),salt and fluid restriction. Evaluate lipid profile aim for control as near as possible to healthy ranges. Encourage patient to stop smoking.

~~So the prevention of increases in proteinuria is the main goal.

Diabetic neuropathy The prevalence of symmetric neuropathy is similar in type 1 and type 2 diabetes, whereas focal syndromes are more common in older, type 2 patients. Diabetes is the most common cause of neuropathy in developed nations and is the leading cause of nonhealing skin ulcers and limb amputations.
Diabetic neuropathy

Symmetric neuropathy

Focal and multifocal neuropathy:

Distal symmetric sensorimotor polyneuropathy.

Proximal symmetric lower extremity neuropathy.

Autonomic neuropathy.

Others:

Cranial neuropathy.

a) Hyperglycemic neuropathy.

Diabetic amyotrophy.

b) Acute peripheral neuropathy.

Entrapment neuropathy.

c) Treatment induced neuropathy.

Thoracoabdominal neuropathy (radiculopathy).

Symmetric neuropathy 1) Distal symmetric sensorimotor polyneuropathy It is the most common neurologic syndrome seen in diabetes with strong predilection for distal sensorimotor nerves of the feet and hands. *Diagnostic clinical criteria: 1. Stocking-glove paresthesia of distal extremities. 2. Loss of deep sensations: Joint sense. Vibration sense. 3. Loss of deep tendon reflexes in upper & lower limbs. 4. Distal muscle wasting. 5. Loss of coordination (sensory ataxia). *Complications: 1. Charcot joint (neuropathic arthropathy): It occurs in the late stages of sever sensory loss. It's common in knee and ankle joints. Characterized by painless swelling of the joint with abnormal degree of mobility. 2. Foot ulcers: It can occur at any stage but is more common in advanced stages of anesthesia. It appears at pressure sites; under heel and under head of first ,last metatarsal. It is completely painless and very difficult to heal. 3. Repeated minor injuries A) Cardiovascular system: 1. Postural hypotension; defined as: Drop of systolic BP > 20 mmHg in response to standing(2-3 min). Manifested clinically by dizziness in response to standing. 2. Resting tachycardia > 90 beats/minute. 3. Silent myocardial ischemia. 4. ECG changes. B) Gastrointestinal system: 1. Constipation is the most common clinical syndrome. 2. Diarrhea is frequent complaint: profuse, watery, typically nocturnal, lasts few hours or days and alternates with constipation. 3. Gastroparesis manifested by bloating, early satiety, nausea and vomiting. 4. Fecal incontinence which is often exacerbated by diarrhea. C) Genitourinary system: 1. Urinary incontinence "overflow incontinence". 2. Bladder hypotonia, incomplete bladder emptying, dribbling. 3. Urinary tract infections. 4. Erectile dysfunction in male diabetics. D) Sudomotor system: Anhidrosis "lack of sweating" of the extremities, which may

2) Autonomic neuropathy

be associated with hyperhidrosis of the trunk. Gustatory sweating "abnormal appearance of sweat over face, head, neck, shoulders and chest after eating. E) Hypoglycemic unawareness: Failure to perceive the early warning adrenergic signs (anxiety, palpitations, hunger, tremors, excess sweating) and the patient goes to the neuro glycopenic symptoms (headache, blurred vision, confusion, seizures, coma). It is due to attenuated sympathoadrenal response.

Cranial neuropathy Cranial neuropathies belong to the category of focal neuropathies whereas one cranial nerve (mononeuropathy) or more than one cranial nerve (mononeuropathy multiplex) are affected on one side. 1) The most common cranial nerves affected are the occulomotor group (III, IV, VI) leading to: i. Weakness involves all extraocular muscles. ii. Diplopia. iii. Ophthalmoplegia. 2) 2) Bell's palsy due to VII nerve paralysis may occur with increased frequency in diabetics and prognosis of recovery may be worse than in patients without diabetes. 3) 3) Trigeminal neuralgia due to involvement of the first and second divisions of V nerve causing pain which is characteristically in the frontal and periorbital region.