8Macro-vascular Complications Ischemic heart diseaseCerebrovascular diseasePeripheral vascular diseaseDiabetic patients have a 2 to 6 times higher risk fordevelopment of these complications than thegeneral population
9Macro-vascular Complications The major cardiovascular risk factors in the non-diabetic population (smoking, hypertension and hyperlipidemia) also operate in diabetes, but the risks are enhanced in the presence of diabetes.Overall life expectancy in diabetic patients is 7 to 10 years shorter than non-diabetic people.
10Macro-vascular Disease Once clinical macro-vascular disease develops in diabetic patients they have a poorer prognosis for survival than normoglycemic patients with macrovascular diseaseThe protective effect females have for the development of vascular disease are lost in diabetic females
11CAD Morbidity and Mortality in Type 2 DM Framingham Data: 20 year follow-up:Age 45-74:2-3 fold increase in clinically evident atherosclerotic disease in diabeticswomen diabetics=male diabetics in terms of CAD mortalityMultiple Risk Factor Intervention Trial (MRFIT)5000 men with type 2 DMFollowed for 12 yearsMen with type 2 DM had absolute risk of CAD-related death 3 times higher than non-diabetic cohortTo further focus on the epidemiology of coronary disease in type 2 diabetes, it is important to understand that diabetics have a significantly increased risk when compared to their non-diabetic cohorts. Framingham data with 20 year follow-up on patients aged 45 to 74 revealed that diabetics had a 2-3 fold increase in clinically evident atherosclerotic disease. Furthermore, women diabetics were equal to male diabetics in terms of CAD mortality. There was a loss of the normal female cardiovascular protective benefit seen in non-diabetics when controlling for age and other CV risk factors. Similarly in the Multiple Risk Factor Intervention Trial which followed 5000 men with type 2 DM for 12 years, it was noted that men with type 2 DM had an absolute risk of CAD-related death which was 3 times higher than their non-diabetic cohort.
12Risk Factor Clustering in Diabetes Type 2 Diabetes at Diagnosis:50% have hypertension30% have dyslipidemiaUKPDS:Prospective studyNewly detected type 2 DM:335 with CAD, 8 year follow-upAssociated with elevated LDL-C, low levels of HDL-C, systolic hypertensionThis slide illustrates the phenomenon of risk factor clustering in diabetic patients. In terms of patients with type 2 diabetes at diagnosis, 50% have hypertension and 30% have dyslipidemia in addition to their diabetes. In the United Kingdom prospective diabetes study (UKPDS), a prospective study looking at newly detected diabetic patients. Of the patients with newly detected diabetes 335 developed CAD over an 8 year follow-up. Of those patients 30% had high LDL-C, low HDL-c while 50% had systolic hypertension.
13Cardiovascular Death Rates: MRFIT data This slide shows that the age-adjusted CVD mortality rates per 10,000 person years increases steeply with increasing number of risk factors in patients with type 2 diabetes at baseline when compared to their non-diabetic cohorts. Note that at every level of risk factor, diabetics have a higher age-adjusted mortality rate. Also, there is a synergistic effect of diabetes and other risk factors such that the steep of the increase in risk is much greater in the diabetic population.Stamler J., et al Diabetes Care: 16:
14Risk of MI in Diabetes Haffner, SM et al NEJM: 339: 229-234 This data here shows the marked increase in the risk of myocardial infarction in type 2 diabetes. This data is from a Finnish study which compared the incidence of first MI in Non-diabetics to those with type 2 diabetes. Important points from this data include the fact that in diabetics with no history of MI have a similar incidence of MI when compared to patients who are non-diabetic and have had an MI. Note also that diabetics who have had an MI, have more than a 2 fold increase in risk of another MI compared to non-diabetics with a history of MI over 7 years of follow-up. Also, diabetics with MI have an approximately 9 fold increase in risk than patients without diabetes and have not had an MI.This data supports current recommendations to treat diabetic patients as though they have established CAD when considering risk factor reduction.Haffner, SM et al NEJM: 339:
15Plasma Glucose as Independent Risk Factor This study, published in diabetes care in 1995, revealed that when blood glucose is stratified by quintiles, fasting blood glucose is independently related to all cause, cardiovascular, and ischemic heart disease mortality. There was no clear threshold for this outcome-the lower the glucose, the better the outcome.Andersson, DK et al. Diabetes Care 18:
16Glycemic Control to Reduce CAD DCCT trial:1441 patients, type 1 diabetesRandomized to intensive glycemic control vs. conventional therapyMonitored prospectively for 6.5 yearsResults:Less retinopathy by 50%Macrovascular complications: 41% reduction (not statistically significant)-small number of events in young patient cohortUKPDS:3867 patients with newly diagnosed type 2 DMIntensive vs. Conventional therapy10 year follow-upMicrovascular endpoints improvedTrend only towards reduced incidence of MI ( p=0.052)Intensive Glycemic control has been shown to be beneficial in terms of microvascular complications of diabetes such as retinopathy. There is much less convincing data regarding macrovascular complications. For example, in the Diabetes Control and Complications trial, 1441 patients with a mean age of 27 years and no significant retinopathy at baseline were randomized to intensive glycemic control: using insulin pump or 3 or more daily insulin injections targetting a glucose between 4 and 7. Patients were monitored for 6.5 years. Results showed a 50% reduction in retinopathy in the group with tight glycemic control. Macrovascular complications(cardiovascular and peripheral vascular) were reduced by 41% but this was not statistically significant. There were only a small number of events in a young patient cohort.In the UKPDS, which randomized 3867 patients with newly diagnosed type 2 DM to intensive vs. conventional therapy. Over 10 years of follow-up, there was a trend only towards reduced incidence of MI which did not reach statistical significance.
17Effect of Hypertension The combination of hypertension and diabetes is a serious situation, posing increased predisposition to cardiovascular morbidity and mortality.There is no doubt that hypertension occurs more commonly in diabetic patients, and confer a greater prospect of development of complications, it should therefore be taken as seriously as glycemic control when planning treatment strategies
18Why worry about Hypertension in Diabetic patients Treating hypertension can reduce the risk of:Death 32%Microvascular disease 37%Stroke 44%Heart failure 56%UKPDS BMJ 1998;317:
19Hypertension in Type 1 and 2 Diabetes Develop after several years of DMUltimately affects ~30% of patientsType 2Mostly present at diagnosisAffects at least 60% of patients
20Pathophysiology of hypertension Type 1 DMSecondary tonephropathyActivation of theRAASType 2 DMHyperinsulinemiaSecondary to insulin resistanceActivation of the sympathetic nervous system
21Goals of Treatment of Hypertension Lower target for diabetic patients than non-diabetic patients:130/85 vs. 140/90UKPDS 38. BMJ 1998;317:HOT. Lancet 1998;351:
22Effect of CholesterolHyperlipidemia can occur as result of poorly controlled diabetes, or may occur as a independent risk factor for macrovascular disease. About 25% of patients attending a diabetes clinic will have elevated lipid levels
23Dyslipidaemia in DMMost common abnormality is s HDL and s TriglyseridesA low HDL is the most constant predictor of CV disease in DMTarget lipid values: LDL <2.6 mmol/l, HDL >1.15 mmol/l, TG < 2.5 mmol/l
25Eye Complications Cataracts Non enzymatic glycation of lens protein and subsequent cross linkingSorbitol accumulation could also lead to osmotic swelling of the lens but evidence of involvement in cataract formation is less strong
27Diabetic Retinopathy (DR) DR is the leading cause of blindness in the working population of the Western worldThe prevalence increase with the duration of the disease (few within 5 years, 80 – 100% will have some form of DR after 20 years)Maculopathy is most common in type 2 patients and can cause severe visual loss
35Advanced Diabetic Eye Disease Retinal detachment with or without retinal tearsRubeosis iridisNeovascular glaucoma
36Maculopathy Macular edema (focal or diffuse) Ischaemic maculopathy Focal and diffuse maculopathy are caused y microvascular leakage, leading to fluid and hard exudates in the area of the macula.Ischaemic maculopathy is associated with areas of capillary non-perfusion and is difficult to detect. Hard exudates often occur in rings (circinate exudates) around the leaking area.
38Diabetic Nephropathy (DN) Diabetes has become the most common cause of end stage renal failure in the US and EuropeAbout 20 – 30% of patients with diabetes develop evidence of nephropathyThe prevalence of DN is higher in Black Americans than in Whites (Figures for South Africa is not available)
39Stages of Diabetic Nephropathy Stage 3: Overt diabetic nephropathyAfter 15 – 25 years in 35% of diabetic patientsPronounced abnormalities of the glomeruliGFR decline by 10 ml/min/yearProgressive clinical proteinuriaBP increase by 5 mmHg per yearNor reversible but progression can be slowed by good glucose control and use of ACE inhibitorStage 4: ESRDFinal outcome after yearsGlomerular closureGFR < 10 ml/minInvariably hypertensiveIrreversible
40Stages of DN Stage I glomerular filtration and kidney hypertrophy Stage IIu-albumin excretion < 30mg/24hStage IIIMicroalbuminuria (30 – 300 mg/24h)Stage I: This stage is usually not clinically evidentStage II: Renal lesions are found on biopsyStage III: Without intervention the average increase in albuminuria in patients with type 1 DM is 20% per year. Blood pressure usually starts to increase once fixed albuminuria existStages I – III are reversible
41Stages of DN (cont) Stage IV Overt nephropathy (> 300mg/24h, positive u dipstick)Stage VESRD characterized by blood urea and creatinine levels, hyperkalaemia and fluid overloadStage IV: Kidney damage is considered to be irreversible at this stage and renal function deteriorates on average at a rate of 1mL per month. Without treatment uremia and death occur in 7 – 10 years. Because of late diagnosis of type 2 DM up to 15% of newly diagnosed diabetic patients are already in this stage.
43Sensorimotor Neuropathy Patients may be asymptomatic / complain of numbness, paresthesias, allodynia or painFeet are mostly affected, hands are seldom affectedIn Diabetic patients sensory neuropathy usually predominates
44Complications of Sensorimotor neuropathy Ulceration (painless)Neuropathic edemaCharcot arthropathyCallosities
46Mononeuropathies Cranial nerve palsies (most common are n. IV,VI,VII) Truncal neuropathy (rare)
47Entrapment Neuropathies Carpal tunnel syndrome (median nerve)Ulnar compression syndromeMeralgia paresthetica (lat cut nerve to the thigh)Lat Popliteal nerve compression (drop foot)All the above are more common in diabetic patients
48Proximal Motor Neuropathy Amyotrophy – most common proximal neuropathy, affects the Quadriceps muscles with weakness and atrophy(synonym: Diabetic Femoral radiculo-neuropathy)
49Diabetic AmyotrophyDiabetic amyotrophy. This syndrome is known by several names, including diabetic proximal motor neuropathy and diabetic polyradiculoneuropathy. Patients typically present with pain and weakness in the proximal large muscles of the legs and pelvic area. Muscle wasting may be unilateral or bilateral, but is usually asymmetric with bilateral involvement.4 Patients complain of severe pain in the lumbar and sacral regions. Many patients report a loss of appetite and depression as well. Improvement may take from 6 months to 2 years. Immunotherapy may be beneficial and accelerate recovery.11
50Thoracoabdominal Radiculopathy Thoracoabdominal radiculopathy. Truncal radiculopathies are rare but can present at the initial diagnosis of diabetes.2 Nerve roots T8 through T12 are commonly affected. Patients complain of a tight bandlike or constricting pain in the chest or abdomen. The chest or abdominal wall skin becomes sensitive to the touch.2 Motor involvement may lead to abdominal muscle weakness, which may lead to herniation and an asymmetric bulge in the abdominal wall.3 Examination of spinal fluid may show an increase of protein.4 Prognosis is generally good; most patients recover within several months.
51Sudomotor Dysautonomia Patients often complain of hyperhidrosis or anhidrosis of the extremities, venous congestion, pain and redness of the feet, and gustatory sweating.5 Gustatory sweating is common in patients with cervical sympathetic denervation, demonstrated by profuse sweating of the face, neck, and upper trunk while eating.12
52SummaryDiabetic neuropathy is a common complication, and result in significant morbidityDiabetic neuropathy present in numerous waysHyperglycemia is the cause of diabetic neuropathy
53Summary (cont) Diabetic neuropathy have bad consequences Diabetic neuropathy can be prevented in only one wayOnce diabetic neuropathy is present it can only be managed symptomaticallyEarly diagnosis and aggressive management can prevent progression
54InfectionsThe association between diabetes and increased susceptibility to infection in general is not supported by strong evidenceHowever, many specific infections are more common in diabetic patients and some occur almost exclusively in themOther infections occur with increased severity and are associated with an increased risk of complications
55Infections (cont)Several aspects of immunity are altered in patients with diabetesThere is evidence that improving glycemic control patients improves immune functionPMN leukocyte function is depressed, particularly when acidosis is also present. Leukocyte adherence, chemotaxis, and phagocytosis may be affected. Antioxidant systems involved in bactericidal activity may also be impaired.
56Specific Infections Community acquired pneumonia Acute bacterial cystitisAcute pyelonephritisEmphysematous pyelonephritisPerinephric abscessFungal cystitisNecrotizing fasciitisInvasive otitis externaRhinocerebral mucormycosisEmphysematous cholecystitisCAP: Pneumococcal infection carries a higher risk of death in diabetic than non diabetic patients; S pneumoniae, S aureus, H influenzaeAcute bacterial cystitis: Bacteriuria more common in diabetic women; E coli, ProteusEmphysematous pyelonephritis: emergency nephrectomy often required; E coli, gr- bacilliPerinephric abscess: surgical drainage usually required; E coli, Gr- bacilliNecrotizing fasciitis: High mortality; emergency surgery required; Gr- bacilli, anaerobes, Group A streptococciMucormycosis: Strong association with DKA; emergency surgery requiredInvasive otitis externa: Prompt ENT consultation required; Pseudomonas aeruginosaEmphysematous cholecystitis: High mortality; gallstones in 50%; emergency cholecystectomy required; Gr- bacilli, anaerobes
58Screening and Management Strategy for Diabetes Complications
59Screening for Macrovascular Complications 1. Examine pulses and for cardiovascular disease2. Lipogram3. ECG4. Blood pressure1-3 annually4 every visit (quarterly)
60Screening for Eye disease AnnuallyVisual acuity (corrected with pinhole or lenses)Careful eye examination (noting the clarity of the lens and any retinal changes (Ophthalmoscopy through dilated pupils)
61Screening for Eye disease When to refer?Severe non-proliferative/proliferative retinopathyMacular edema or exudates in close proximity to the maculaCataractUnexplained reduction in visual acuity
62Screening for Nephropathy AnnuallyDo one of the following:u Albumin:Creatinine ratio (spot sample)24h u Albumin excretion rateEarly morning Albumin concentration(spot sample)Dipstick for MicroalbuminuriaIf positive the test must be repeated twice in the ensuing 3 months. Microalbuminuria with incipient nephropathy is diagnosed if 2 or more of the tests are within the microalbumin range
63Microalbuminuria Increased risk for overt nephropathy Increased cardiovascular mortalityIncreased risk of RetinopathyIncreased all-cause mortalityThusMicroalbuminuria is an indication for screening for possible vascular disease and aggressive intervention to reduce all cardiovascular risk factorsMicroalbuminuria indicates an increased risk for progression to overt nephropathy. Patients with microalbuminuria are between 9 and 20 more likely to progress to ESRD.All-cause mortality increase 148% and CV mortality increase 15-fold.In a 11-year follow up study, nearly 70% of diabetes patients with microalbuminuria developed retinopathy as opposed to none of the patients without microalbuminuria.
64Screening Tests for Microalbuminuria Category24h u collection(mg/24h)Timed collection(mg/min)Spot collection(mg/mg creat)Normal 30 20MicroalbuminuriaAlbuminuria Overt 300 200Screening for microalbuminuria can be performed by three methods: 1) measurement of the albumin-to-creatinine ratio in a random spot collection; 2) 24-h collection with creatinine, allowing the simultaneous measurement of creatinine clearance; and 3) timed (e.g., 4-h or overnight) collection. The first method is often found to be the easiest to carry out in an office setting and generally provides accurate information; first-void or other morning collections are preferred because of the known diurnal variation in albumin excretion, but if this timing cannot be used, uniformity of timing for different collections in the same individual should be employed. Specific assays are needed to detect microalbuminuria because standard hospital laboratory assays for urinary protein are not sufficiently sensitive to measure such levels. Microalbuminuria is said to be present if urinary albumin excretion is >30 mg/24 h (equivalent to 20 µg/min on a timed specimen or 30 mg/g creatinine on a random sample).False Positive Tests: Short-term hyperglycaemia, exercise, urinary tract infections, marked hypertension, heart failure, and acute febrile illness can cause transient elevations in urinary albumin excretion. If assays for microalbuminuria are not readily available, screening with reagent tablets or dipsticks for microalbumin may be carried out, since they show acceptable sensitivity (95%) and specificity (93%) when carried out by trained personnel. Because reagent strips only indicate concentration and do not correct for creatinine as the spot urine albumin-to-creatinine ratio does, they are subject to possible errors from alterations in urine concentration. All positive tests by reagent strips or tablets should be confirmed by more specific methods. There is also marked day-to-day variability in albumin excretion, so at least two of three collections done in a 3–6 month period should show elevated levels before designating a patient as having microalbuminuria.
65Who to Screen For Microalbuminuria Type 1 DiabetesBegin with pubertyAfter 5 years duration of diseaseShould be done annually there afterType 2 DiabetesStart screening at the Diagnosis of diabetesShould be done annually there afterSCREENING FOR ALBUMINURIA — A routine urinalysis should be performed at diagnosis in patients with type 2 diabetes. If the urinalysis is positive for protein, a quantitative measure is frequently helpful in the development of a treatment plan. If the urinalysis is negative for protein, a test for the presence of microalbumin is necessary. Microalbuminuria rarely occurs with short duration of type 1 diabetes or before puberty; therefore, screening in individuals with type 1 diabetes should begin with puberty and after 5 years' disease duration. Because of the difficulty in precise dating of the onset of type 2 diabetes, such screening should begin at the time of diagnosis. After the initial screening and in the absence of previously demonstrated microalbuminuria, a test for the presence of microalbumin should be performed annually
66Management of Nephropathy Improvement of glycemic controlTreatment of hypertensionTreatment with angiotensin converting enzyme inhibitorsRestriction of dietary intake of proteinOnce persistent elevation in u-Albumin isfound refer to a Internist or NephrologistTight glucose control prevents the development of and ameliorates established diabetic nephropathyLowering blood pressure slows the progression of decline in renal function and improves patient survivalACE inhibitors preserve renal structure and function independent of their effect on systemic blood pressureHigh dietary protein intake accelerates the deterioration of renal function
67Screening for Neuropathy 128 Hz tuning fork for testing of vibration perception10g Semmers monofilamentThe main reason is toidentify patients at riskfor development ofdiabetic foot
68Using of the Monofilament A standardized filament is pressed against part of the foot. When the filament bends, its tip is exerting a pressure of 10 grams (therefore this monofilament is often referred to as the 10gram monofilament). If the patient cannot feel the monofilament at certain specified sites on the foot, he/she has lost enough sensation to be at risk of developing a neuropathic ulcer. The monofilament has the advantage of being cheaper than a biothesiometer, but to get results which can be compared to others, the monofilament needs to be calibrated to make sure it is exerting a force of 10 grams
69Management of Neuropathy Burning pain – TADs / CapsaicinLancinating pain – Anticonvulsants / TAD / CapsaicinPainful cramps – Quinidine sulphateRestless legs - ClonazepamOther causes should be excluded especially: alcohol, vit B12 deficiency and uremiaUKPDS, DCCT – good glycemic control can largely prevent neuropathy
70Do’s and Don'ts of foot care Patient shouldcheck feet dailyWash feet dailyKeep toenails shortProtect feetAlways wear shoesLook inside shoes before putting them onAlways wear socksBreak in new shoes gradually
71ConclusionThis is just an outline of the major diabetic complications, and doesn't aim to be comprehensiveAll complications are preventable with good glycaemic controlThe progression of most complications can be halted if detected early and appropriate therapy instituted