Diabetes Complications Update

Transcription

1 Diabetes Complications Update George Grunberger, MD, FACP, FACE Chairman, Grunberger Diabetes Institute Clinical Professor, Internal Medicine and Molecular Medicine & Genetics Wayne State University School of Medicine Professor, Medicine Oakland University William Beaumont School of Medicine Visiting Professor First Faculty of Medicine, Charles University, Prague Past President, American Association of Clinical Endocrinologists President Elect, American College of Endocrinology

2 Disclosures research support: Eli Lilly, Novo Nordisk, Medtronic speakers bureau: Novo Nordisk, Janssen, Sanofi, Eli Lilly, BI

3 Cost of Diabetes Mellitus in the U.S. in 2012!Total estimated cost $245 billion!majority of the cost attributable for hospitalizations for diabetic complications!diabetes costs attributable to cardio-, cerebro-, peripheral vascular diseases:! 20,018,000 inpatient and outpatient visits! $47 billion! 28% of all cerebrovascular! 27% of all cardiovascular! 30% of all peripheral vascular expenditures in the U.S. Diabetes Care. 2013; 36:

4 Diabetes is a Vascular Disease 10 8 Men Women Risk ratio Total CVD CHD Cardiac Failure Intermittent Claudication Stroke Wilson PWF, Kannel WB. In: Ruderman N et al. eds. Hyperglycemia, Diabetes and Vascular Disease. 1992

5 Diabetic Complications Microvascular Complications Macrovascular Complications Retinopathy 12% of all new cases of blindness Nephropathy >40% new cases ESRD Neuropathy Cerebrovascular Disease Heart Disease Diagnosed in 37.2% patients with diabetes >35 years old Peripheral Vascular Disease Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329: Stratton IM et al. BMJ. 2000;321:

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7 Hyperglycemia damages tissues! Effects of hyperglycemia! Glycation of proteins (eg, hemoglobin, collagen)! Accumulation of sorbitol and fructose (eg, in nerves, lens)! Activation of protein kinase C (eg, on vascular cells)! Tissue changes! Altered protein function and turnover, cytokine activation! Osmotic and oxidative stress! Reduced motor and sensory nerve conduction velocity! Increased glomerular filtration rate and renal plasma flow Aronson D. Adv Cardiol. 2008;45:1-16. Setter SM, et al. Ann Pharmacother Dec;37(12): Graf RJ, et al. Ann Intern Med Mar;94(3):

8 Role of Nox oxidases in the development of diabetic complications Fundamental role for NADPH oxidases of the Nox family in the pathogenesis and pathophysiology of DN, DR, DCM and diabetes-associated macrovascular complications? Yves Gorin, and Karen Block Clin. Sci. 2013;125: by Portland Press Ltd

9 Changes in diabetes-related complications in the U.S. ESRD, end-stage renal disease. Adapted with permission from Gregg et al. N Engl J Med 2014;370:

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12 Risk of Complications in Type 2 Diabetes Any Endpoint Related to Diabetes* 5 4 Hazard Ratio A1C P< % risk decrease per 1% decrement in A1C *Reference category (hazard ratio 1.0) is HbA 1c <6% with log linear scales. Data adjusted for age at diagnosis of diabetes, sex, ethnic group, smoking, presence of albuminuria, systolic blood pressure, high and low density LDL and triglycerides. Stratton IM, et al. (UKPDS 35). BMJ. 2000;321:

13 Diabetic complications! What s our approach?!!! primary: prevent diabetes secondary: prevent diabetic complications tertiary: prevent progression of complications

14 Diabetic Retinopathy Leaky Blood Vessels Occluded Blood Vessels! Neovascularization! Vitreous hemorrhage! Tractional retinal detachment Classification! Nonproliferative retinopathy (mild, moderate, severe)! Proliferative retinopathy (early, high-risk)! Diabetic macular edema

15 Nonproliferative Diabetic Retinopathy!"#$%&'()*+,%&-'./012+3'40&&5'67'

16 Proliferative Diabetic Retinopathy!"#$%&'()*+,%&-'./012+3'40&&5'67'

17 Diabetic Macular Edema!"#$%&'()*+,%&-'./012+3'40&&5'67'

18 American Diabetes Association Updates on Diabetic Retinopathy Diabetes Care 2017 Mar; 40(3): !!!!! DR is explicitly a neurovascular complication of both T1 and T2 DM Rate of occurrence depends on the level of glycemic control and the duration of diabetes Risk factors associated with DR include hyperglycemia, nephropathy, hypertension, and dyslipidemia Reduction in BP decreases progression of retinopathy in people with T2DM Retinopathy progression slowed in patients with dyslipidemia by adding fenofibrate, mainly in NPDR at baseline Optimization of blood glucose, blood pressure, and serum lipid levels in conjunction with appropriately scheduled dilated eye examinations can decrease the risk of vision loss from DR complications, but many develop diabetic macular edema (DME) or proliferative changes that require intervention.

19 DCCT Cumulative incidence of DR progression (three-step or greater by ETDRS criteria) in the DCCT primary prevention cohort Diabetes Care 2014 Jan; 37(1): 17-23

20 The cumulative incidence of any major eye disease end point in relation to diabetes duration DCCT CON (open squares) and INT (solid circles) groups the observational Pittsburgh Epidemiology of Diabetes Complications (EDC) study (solid triangles)

21 Diabetic Retinopathy! Annual dilated fundoscopic examination by trained individual!first exam at time of diagnosis (T2DM) or within 5 years after diagnosis (T1DM)!Individuals with diabetic retinopathy should have a minimum of twice a year fundoscopic exams! Moderately severe or worse non-proliferative diabetic retinopathy: refer to retina specialist! Stereoscopic fundus photography! Ultra-wide field angiography: detects leakage and vessel proliferation! Optical coherence tomography: cross-sectional view of the retina, detects cystic changes

22 Evolution of Treatments for DME Focal Laser For >25 years, had been standard of care for center-involving DME Useful in select circumstances Intravitreal Steroids Useful in select circumstances 2 new options for DME since 2014: dexamethasone implant fluocinolone acetonide implant Intravitreal An3- VEGF Standard of care for center-involving DME Expanded indication for DR in patients with DME in 2015

23 How PanRetinalPhotocoagulation Treatment Works! Apply laser to entire midperipheral fundus! Works by decreasing growth factors! Reduces risk of severe vision loss by 50%! Complications (usually mild):! Discomfort! Decreased night and peripheral vision! Worsened DME!"#$%'()*+,%&-')8'.*90+':;'<#+$5'67'

24 Along Came Steroids Intraocular/intravitreal steroids Triamcinolone a (DRCR.net study) 1 Dexamethasone intravitreal implant (MEAD study) 2,3 Fluocinolone intravitreal implant (FAME study) 4 Likely work by reducing cytokines and inflammation a Off-label 1. Diabetic Retinopathy Clinical Research Network. Arch Ophthalmol. 2009;127: Boyer D et al. Ophthalmology. 2014;121(10): Ciulla TA et al. Expert Opin Pharmacother. 2014;15(7): Cunha-Vaz J et al. Ophthalmology. 2014;121(10):

25 Pre-steroid injection!"#$%&'()*+,%&-')8'.*90+':;'<#+$5'67' =>'

26 Post-steroid injection!"#$%&'()*+,%&-')8'.*90+':;'<#+$5'67;' =?'

27 Anti-VEGF (Vascular Endothelial Growth Factor: Aflibercept, bevacizumab, and ranibizumab) Bilateral PDR Baseline! Neovascularization! Ischemia/nonperfusion! Vetreous hemorrhage! Macular edema!"#$%&'()*+,%&-'./012+3'40&&5'67'

28 Response to Anti-VEGF: Bilateral PDR Following 4 monthly bilateral intravitreal anti-vegf 9%)A#&(*1#+0/#B)9'!!"C+)A%3'C%+0CD%+#1' C%+8*&0)9'! E)9B9*%3'"#(*1#+'%3%"#'!"#$%&'()*+,%&-'./012+3'40&&5'67'

29 Diabetic Nephropathy Diabetic nephropathy is a clinical syndrome characterized by: Persistent albuminuria (>300 mg/d or >200 μg/min) confirmed 3-6 months apart Progressive decline in the glomerular filtration rate (GFR) Elevated arterial blood pressure Cause of diabetic nephropathy is unknown postulated mechanisms hyperglycemia (causing hyperfiltration and renal injury) advanced glycation products activation of cytokines Diabetes is an autoimmune disorder, with overlapping pathophysiologies contributing to both T1 and T2 DM?pivotal role of innate immunity (toll-like receptors) and regulatory T-cells (Treg) Updated: Apr 21, 2017 Medscape Vecihi Batuman, MD, FASN

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32 Nephropathy Rates of Death and Cardiovascular Events vs. egfr Up to 50% of Deaths in CKD Due to Cardiovascular Disease (CVD) * Rate of Death From Any Cause ! < egfr (ml/min/1.73 m 2 ) 5 0 Rate of CV Events ! <15 N=1,120,295 adults. * Data from Kaiser Permanente! Age-standardized rates per 100 person-years CV event defined as hospitalization for coronary heart disease, heart failure, ischemic stroke, and peripheral arterial disease per 100 person-years Go AS, et al. N Engl J Med. 2004;351:

33 Diabetic Nephropathy Epidemiology ~50% of patients with DM of more than 20 years duration Rarely develops before 10 years duration of T1DM ~3% of newly diagnosed patients with T2DM have overt nephropathy Peak incidence (3%/y) if DM for years, after which the rate declines Prognosis Proteinuria is a predictor of morbidity and mortality Microalbuminuria independently predicts cardiovascular morbidity Microalbuminuria and macroalbuminuria increase mortality from any cause

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36 Nephropathy Role of antihypertensive drugs! ACE-I and ARBs equally effective in prevention of progression of diabetic nephropathy! ACE-I and ARBs have renoprotective effect that exceeds that seen with BP reduction by other antihypertensives! ACE-I: effective in preventing onset of microalbuminuria! RENAAL losartan decreased risk of ESRD by 35.3% in highest tertile of Cr ( mg/dl)! IDNT irbesartan was effective in patients with serum creatinine up to 3.0 mg/dl Segura J, et al. J Am Soc Nephrol. 2006;17:S90; De Zeuw D, et al. Circulation. 2004;110(8):921.! Parving HH, et al. N Engl J Med. 2001; 345(12):870.

37 Diabetic Nephropathy Renal Replacement options Refusal of further treatment for uremia, ultimately leading to death Peritoneal dialysis (e.g. machine-assisted intermittent or continuous peritoneal dialysis) Hemodialysis (facility or home) Renal transplantation (e.g. cadaver donor kidney, living related-, living unrelated-donor kidney) Dietary Changes Meta-analysis examined effects of dietary protein restriction ( g/kg/d) Beneficial effect on the GFR, creatinine clearance, and albuminuria However, a large, long-term prospective study is needed When nephropathy is advanced, the diet should reflect the need for phosphorus and potassium restriction, with the use of phosphate binders

38 Diabetic Neuropathy!Heterogeneous group of conditions affecting somatic and autonomic nerves!~50% of patients with diabetes develop neuropathy after 25 years!~10% of patients with diabetes develop symptomatic neuropathy!major morbidities: pain, numbness, foot ulceration!leads to ~75% of all non-traumatic foot amputations Casellini CM et al. Endocrine Pract. 2007; 13:

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40 Diabetic Neuropathy: A Position Statement by the American Diabetes Association 1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable by specific measures. " Diabetes Care 2017;40: A number of treatment options exist for symptomatic diabetic neuropathy. " 3. Up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk " for injuries to their insensate feet. " 4. Recognition and treatment of autonomic neuropathy may improve symptoms, " reduce sequelae, and improve quality of life. " Recommendations Optimize glucose control as early as possible to prevent or delay the development of distal symmetric polyneuropathy and cardiovascular autonomic neuropathy in people with T1DM. A Optimize glucose control to prevent or slow the progression of distal symmetric polyneuropathy in people with T2DM. B Consider a multifactorial approach targeting glycemia among other risk factors to prevent cardiovascular autonomic neuropathy in people with T2DM. C

41 Diabetic Polyneuropathy distal symmetric

42 Diabetic Polyneuropathy distal symmetric

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44 Diabetic Polyneuropathy distal symmetric

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46 Can We Impact on Cardiovascular Complications? 2017 Update

47 Primary outcome: 3-point MACE Empagliflozin HR 0.86 (95.02% CI 0.74, 0.99) p=0.0382* Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p )

48 Canagliflozin DOI: /NEJMoa

49 Liraglutide Primary outcome! CV death, non-fatal myocardial infarction, or non-fatal stroke

50 Steno-2 Effects of Multifactorial Intervention on CV Outcomes 160 Patients With Type 2 Diabetes and Microalbuminuria Conventional Primary composite outcome* (%) % relative risk reduction p=0.01 Intensive Months of follow-up. *CV death, MI, stroke, revascularization, amputation Gæde P et al. N Engl J Med 2003;348:383

51 Kaplan-Meier Estimates of the Risk of Death from Any Cause and from Cardiovascular Causes and the Number of Cardiovascular Events, According to Treatment Group Gaede P et al. N Engl J Med 2008;358:580

52 Take Home Messages How do we prevent complications? microvascular meticulous attention to glycemic control from the time of diagnosis or even before (?) macrovascular attention to cardiovascular risk factors (insulin resistance, obesity, dyslipidemia, hypertension, hypercoagulability)

53 Thank You!