Type 2 Diabetes Glucose Management Goals 1 AACE Comprehensive Diabetes Care: Glucose Goals Parameter Treatment Goal for Nonpregnant Adults A1C (%) Individualize based on age, comorbidities, and duration of disease* • ≤6.5 for most • Closer to normal for healthy • Less stringent for “less healthy” FPG (mg/dL) <110 2- hour PPG (mg/dL) <140 *Considerations include • • • 2 Residual life expectancy Duration of T2DM Presence or absence of microvascular and macrovascular complications • • • • CVD risk factors Comorbid conditions Risk for severe hypoglycemia Patient’s psychological, social, and economic status Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Well-Recognized Risks for Hypoglycemia in T2DM • Use of insulin secretagogues and insulin therapy in any of the following settings: – – – – – – – – Missed or irregular meals Advanced age Longer duration of diabetes Impaired awareness of hypoglycemia Exercise Taking greater than the prescribed medication dose Excessive alcohol intake Preexisting impairment, or sudden worsening, of renal or hepatic function • Less well-recognized risks: female sex, African-American race, less education (ACCORD) 3 Amiel SA, et al. Diabet Med. 2008;25:245-254. ADA. Diabetes Care. 2005;28:1245-1249. Limitations of Management Goals: Potential Consequences of Hypoglycemia • Neurogenic symptoms – Tremor, palpitations, anxiety, sweating, hunger (weight gain), paresthesias • Neuroglycopenia morbidity – Cognitive impairment, psychomotor abnormalities, abnormal behavior, seizure, coma, mortality (brain death) • Rebound hyperglycemia, brittle diabetes • Barrier to glycemic control and adherence to treatment secondary to fear of hypoglycemia • Greater risk of dementia • Prolonged QT interval with increased risk of dysrhythmias, sudden death • Harm to property or to others (eg, if driving) 4 Cryer PE. J Clin Invest. 2007;117:868-870. Cryer PE. Diabetes Care. 2003;26:1902-1912. Glucose Control and Mortality: ACCORD Posthoc Analysis Adjusted Log (Hazard Ratio) by Treatment Strategy Relative to Standard at A1C of 6% Mortality Risk Intensive Risk increase with each 1% increase in A1C Log (Hazard Ratio) P Value 1 66% <0.0001 0 14% 0.17 Standard -1 Mortality Benefit 6 7 8 Average A1C (%) 9 5 Riddle MC, et al. Diabetes Care. 2010;33:983-990. Algorithm for Individualizing Glycemic Targets Most intensive 6.0% Less intensive 7.0% Least intensive 8.0% Psychosocioeconomic considerations Less motivated, nonadherent, limited insight, poor self-care capacities, and weak support systems Highly motivated, adherent, knowledgeable, excellent self-care capacities, and comprehensive support systems Hypoglycemia risk Moderate High Low 40 45 5 None None 6 50 55 60 10 Few or mild 65 Patient age, years 70 75 15 Disease duration, years 20 Other comorbid conditions Multiple or severe Established vascular complications Cardiovascular disease Early microvascular Advanced microvascular Ismail-Beigi F, Moghissi E, et al. Ann Intern Med. 2011;154:554-559. ADA-Recommended Approach to Management of Hyperglycemia More Stringent Less Stringent Patient attitude and expected treatment efforts Highly motivated, adherent, excellent self-care capacities Less motivated, nonadherent, poor self-care capacities Risks potentially associated with hypoglycemia, other adverse events Low Disease duration Life expectancy Important comorbidities Established vascular complications Resources, support system High Newly diagnosed Long-standing Long Short Absent Few/mild Severe Absent Few/mild Severe Readily available Limited 7 Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. Hyperglycemia and Microvascular Complications 8 Hyperglycemia-Induced Tissue Damage: General Features Genetic determinants of individual susceptibility Repeated acute changes in cellular metabolism Diabetic tissue damage Hyperglycemia Cumulative long-term changes in stable macromolecules Independent accelerating factors (eg, hypertension, dyslipidemia) 9 Brownlee M. Diabetes. 2005;54:1615-1625. Microvascular Complications of Diabetes Nephropathy 10 Retinopathy Neuropathy Microvascular Complications Increase With Increasing A1C Diabetes Control and Complications Trial 20 Retinopathy 18 Nephropathy Relative Risk 16 Neuropathy 14 Microalbuminuria 12 10 8 6 4 2 0 6 7 8 9 A1C (%) 10 11 12 11 Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254. Reducing A1C Reduces Microvascular Risk Microvascular Complications Hazard Ratio United Kingdom Prospective Diabetes Study 10 P<0.0001 1 37% Decrease per 1% reduction in A1C 0.5 0 5 6 7 8 9 10 Updated Mean A1C 12 Stratton IM, et al. BMJ. 2000;321:405-412. Reducing A1C Reduces Nephropathy Risk in T2DM 13 UKPDS ADVANCE ACCORD A1C reduction (%)* 0.9 0.8 1.3 Nephropathy risk reduction (%)* 30 21 21 New onset microalbuminuria (P=0.033) New or worsening nephropathy (P=0.006) New microalbuminuria (P=0.0005) *Intensive vs standard glucose control. 1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. 2. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572. 3. Ismail-Beigi F, et al. Lancet. 2010;376:419-430. Prevalence of CKD in Diagnosed Diabetes Diabetic Kidney Disease Is the Leading Cause of Kidney Failure in the United States Stage 1, 10.4% NKF Description Stage Stage 2, 13.4% No kidney disease, 60.4% Stage 3, 14.1% GFR 1 Kidney damage* with normal or GFR ≥90 2 Kidney damage* with mild GFR 60-89 3 Moderate GFR 30-59 4 Severe GFR 15-29 5 Kidney failure or ESRD <15 or dialysis Stage 4, 1.1% 14 *Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. ESRD, end-stage renal disease; GFR, glomerular filtration rate (mL/min/1.73 m2); NKF, National Kidney Foundation. CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Plantinga LC, et al. Clin J Am Soc Nephrol. 2010;5:673-682. Development of Diabetic Nephropathy Hyperglycemia Hyperfiltration Hypertension Enlarged kidneys Angiotensin II Breakdown of glomerular filtration barrier Microalbuminuria Genetically susceptible individuals Protein reabsorption and accumulation in renal epithelial cells Capillary occlusion Decreasing GFR Macroalbuminuria Release of vasoactive and inflammatory cytokines Tubule and podocyte damage Tubular atrophy and fibrosis, podocyte destruction Renal failure 15 Radbill B, et al. Mayo Clin Proc. 2008;83:1373-1381. Remuzzi G, Bertani T. N Engl J Med. 1998;339:1448-1456. CV Risk Increases With Comorbid Diabetes and CKD Incidence per 100 Patient-Years No diabetes/no CKD Diabetes/CKD 60 x 2.8 x 2.0 50 40 30 x 2.1 x 1.7 x 2.5 20 10 x 2.3 0 CHF 16 Diabetes/no CKD AMI CVA/TIA PVD ASVD* Death AMI, acute myocardial infarction; ASVD, atherosclerotic vascular disease; CHF, congestive heart failure; CVA/TIA, cerebrovascular accident/transient ischemic attack; PVD, peripheral vascular disease. *ASVD was defined as the first occurrence of AMI, CVA/TIA, or PVD. Foley RN, et al. J Am Soc Nephrol. 2005;16:489-495. Appropriate Staging and Management of DKD GFR Stage Description Action* Diagnose and treat CKD, slow progression of CKD, treat comorbid conditions, reduce CVD risk factors 1 Kidney damage† with normal or GFR ≥90 2 Kidney damage† with mild GFR 60-89 Estimate progression 3 Moderate GFR 30-59 Evaluate and treat complications 4 Severe GFR 15-29 Prepare for kidney replacement therapy 5 Kidney failure ESRD 17 (mL/min/1.73 m2) <15 or dialysis Kidney replacement, if uremia present Renal replacement therapy DKD, diabetic kidney disease. *Includes actions from preceding stages. †Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. National Kidney Foundation. Am J Kidney Dis. 2002;39(suppl 1):S1-S266. KDIGO CKD Classification by Relative Risk Albuminuria stages (mg/g) A3 Optimal and high normal High Very high and nephrotic 10-29 30-299 300-1999 ≥2000 Very low Very low Low Moderate Very high Very low Very low Low Moderate Very high Mild to 45-59 moderate Low Low Moderate High Very high Moderate 30-44 to severe Moderate Moderate High High Very high High High High High Very high Very high Very high Very high Very high Very high High and optimal G2 Mild G5 A2 <10 G1 GFR stages (mL/min G3a per 1.73 m2 body surface G3b area) G4 A1 >105 90-104 75-89 60-74 Severe 15-29 Kidney failure <15 18 Levey AS, et al. Kidney Int. 2011;80:17-28. DKD Risk Factor Management Risk Factor Goal Hyperglycemia Individualized A1C goals Avoid biguanide in moderate to severe CKD ≤6.5% for most (AACE) Consider need for dose reductions and/or risk of hypoglycemia and other renal-related AEs with other <7.0% (NKF) antidiabetic agents Hypertension BP <130/80 mmHg Proteinuria Dyslipidemia Management Recommendation Use ACE inhibitor or ARB in combination with other antihypertensive agents as needed Use ACE inhibitor or ARB as directed LDL-C <100 mg/dL, <70 mg/dL an option for high risk Statin therapy recommended Fibrate dose reduction may be required 19 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179. Use of Noninsulin Antidiabetic Therapies in Patients With Kidney Disease 20 Class Agent(s) Kidney Disease Recommendation Amylin analog Pramlintide No dosage adjustment Thiazolidinediones Pioglitazone, rosiglitazone No dosage adjustment Bile acid sequestrant Colesevelam No dosage adjustment DPP-4 inhibitors Linagliptin, saxagliptin, sitagliptin Dopamine-2 agonist Bromocriptine Glinides Nateglinide, repaglinide Insulin Aspart, detemir, glargine, glulisine, lispro, NPH, regular Sulfonylureas Glimepiride, glipizide, glyburide GLP-1 receptor agonists Exenatide, exenatide XR, liraglutide -Glucosidase inhibitors Acarbose, miglitol Biguanide Metformin Reduce dosage for saxagliptin and sitagliptin if CrCl <50 mg/dL Use with caution Use lowest effective dose of nateglinide for stage ≥3 CKD Dosage reduction needed in stage 4-5 CKD Glimepiride preferred, use lowest effective dose; avoid other SUs Use with caution in stage 3 CKD; avoid in stage 4-5 CKD Not recommended if SCr >2 mg/dL; avoid in dialysis Contraindicated if SCr >1.5 in men or 1.4 in women Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179. Dietary Guidelines for DKD CKD Stage Macronutrient 1-2 1-4 Sodium <2.3 Total fat, % calories* <30 Saturated fat, % calories <10 Cholesterol, mg/day <200 Carbohydrate, % calories 50-60 Protein, g/kg/day (% calories) 3-4 0.8 (~10) 0.6-0.8 (~8-10) Phosphorus 1.7 0.8-1.0 Potassium >4 2.4 *Adjust so total calories from protein, fat, and carbohydrate are 100%. Emphasize such whole-food sources as fresh vegetables, whole grains, nuts, legumes, low-fat or nonfat dairy products, canola oil, olive oil, cold-water fish, and poultry. Tailor dietary counseling to cultural food preferences. 21 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179. Reducing A1C Reduces Retinopathy Progression in T2DM A1C reduction (%) Retinopathy risk reduction (%)* 22 UKPDS ACCORD 0.9 1.3 29 17 33 Retinopathy onset (P=0.003) Retinopathy progression (P=0.017) Retinopathy progression (P=0.003) *Intensive vs standard glucose control. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. Ismail-Beigi F, et al. Lancet. 2010;376:419-430. Chew EY, et al. N Engl J Med. 2010;363:233-244. Prevalence of Diabetic Retinopathy Diabetic Retinopathy Is the Leading Cause of Adult Blindness in the United States NHANES 2005-2008 Adults Age ≥40 Years (N=1006) None, 71.5% Visionthreatening*, 4.4% NPDR, 24.1% 23 *Severe NPDR, PDR, or clinically significant macular edema. NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; T2DM, type 2 diabetes mellitus. CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Zhang X, et al. JAMA. 2010;304:649-656. Diabetic Retinopathy Management • Goal: detect clinically significant retinopathy before vision is threatened • Annual dilated eye examination by experienced ophthalmologist, starting at diagnosis for all T2DM patients Lesion Type Management Recommendation Background or • nonproliferative retinopathy Optimal glucose and blood pressure control Macular edema • • • Optimal glucose and blood pressure control Ranibizumab injection therapy Focused laser photocoagulation guided by fluorescein angiography Preproliferative retinopathy • • Optimal glucose and blood pressure control Panretinal scatter laser photocoagulation Proliferative retinopathy • • • Optimal glucose and blood pressure control Panretinal scatter laser photocoagulation Vitrectomy for patients with persistent vitreous hemorrhage or significant vitreous scarring and debris 24 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Reducing A1C Reduces Neuropathy Risk in T2DM ACCORD A1C reduction (%) 1.3 Neuropathy risk reduction (%)* 12 Loss of sensation to light touch (P=0.045) 25 *Intensive vs standard glucose control. Ismail-Beigi F, et al. Lancet. 2010;376:419-430. Prevalence of Diabetic Neuropathy Diabetic Peripheral Neuropathy Is the Leading Cause of Nontraumatic Amputations in the United States NHANES 1999-2004 Adults With Diabetes, Age ≥40 (N=559) Years3 • Neuropathy is a heterogenous disorder • 70% to 100% of T2DM patients may have at least mild damage to DPN, 18.5% – Proximal nerves – Distal nerves – Somatic nerves – Autonomic nerves • Neuropathy may be – Acute and self-limiting – Chronic and indolent None, 81.5% 26 CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Gregg EW, et al. Diabetes Res Clin Pract. 2007;77:485-488. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Diabetic Neuropathies: Key Characteristics and Management Recommendations • Optimize glucose, lipid, and blood pressure control for all T2DM patients Type Condition(s) Clinical Features Focal Mononeuritis Single nerve involvement Inflammatory demyelinating conditions Entrapment Carpal tunnel syndrome Proximal lumbosacral Thoracic Cervical radiculoplexus neuropathies involving the proximal limb girdle Treatment Immunotherapy 27 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Diabetic Neuropathies: Key Characteristics and Management Recommendations • Optimize glucose, lipid, and blood pressure control for all T2DM patients Type Condition(s) Clinical Features Treatment Large-fiber sensorimotor polyneuropathy Symmetric, glove and stocking distribution with Loss of sensation Poor coordination Ataxia Low-impact activities that improve muscular strength and coordination and challenge the vestibular system Pilates Yoga Tai Chi Symmetric, glove and stocking distribution with Loss of sensation Pain Autonomic features Protect insensate feet from ulceration Padded socks Daily inspection by patient Moisturizing lotions Treat neuropathic pain Amitriptyline Gabapentin Pregabalin Duloxetine Topical lidocaine Distal neuropathy Small-fiber neuropathy 28 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Diabetic Neuropathies: Key Characteristics and Management Recommendations • Optimize glucose, lipid, and blood pressure control for all T2DM patients Type Condition(s) Clinical Features Treatment Autonomic Cardiac Symptoms Tachycardia Exercise intolerance Orthostatic hypotension, weakness, fatigue, syncope Associated with significant mortality and possibly also Silent myocardial ischemia Coronary artery disease Stroke Diabetic nephropathy progression Perioperative morbidity Intensive control of CV risk factors For tachycardia, exercise intolerance Supervised exercise ACE inhibitors -adrenergic blockers For hypotension, weakness, etc Mechanical measures Clonidine Midodrine Octreotide Erythropoietin 29 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Diabetic Neuropathies: Key Characteristics and Management Recommendations • Optimize glucose, lipid, and blood pressure control for all T2DM patients Type Condition(s) Clinical Features Treatment Autonomic Gastrointestinal Gastroparesis, erratic glucose control Frequent small meals Prokinetic agents Metoclopramide Domperidone Erythromycin Abdominal pain, early satiety, nausea, vomiting, bloating, belching Antibiotics Antiemetics Bulking agents Constipation High-fiber diet Bulking agents Osmotic laxatives Lubricating agents Diarrhea (often nocturnal, alternating with constipation) Soluble dietary fiber Gluten and lactose restriction Anticholinergic agents Tricyclic antidepressants Pyloric Botox Gastric pacing Cholestyramine Antibiotics Somatostatin Pancreatic enzyme supplements 30 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Diabetic Neuropathies: Key Characteristics and Management Recommendations • Optimize glucose, lipid, and blood pressure control for all T2DM patients Type Condition(s) Clinical Features Treatment Autonomic Sexual dysfunction Erectile dysfunction Sex therapy Psychological counseling 5′-phosphodiesterase inhibitors Prostaglandin E1 injections Devices Prostheses Vaginal dryness Vaginal lubricants Bladder dysfunction Frequency, urgency, nocturia, urinary retention, incontinence Bethanechol Intermittent catheterization Sudomotor dysfunction Emollients and skin lubricants Scopolamine Glycopyrrolate Botulinum toxin Vasodilators Anhidrosis Heat intolerance Dry skin Hyperhidrosis 31 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Hyperglycemia and Macrovascular Complications 32 7-Year Incidence of MI (%) Diabetes Is a Cardiovascular Disease Risk Equivalent P<0.001 50 45 40 30 P<0.001 18.8 20.2 Prior MI No prior MI 20 10 3.5 0 No prior MI Nondiabetic (n=1373) 33 Prior MI Diabetic (n=1059) MI, myocardial infarction. Grundy SM, et al. Circulation. 2004;110:227-239. Haffner SM, et al. N Engl J Med. 1998;339:229-234. Lower A1C Is Associated With Lower Risk of Myocardial Infarction United Kingdom Prospective Diabetes Study Myocardial Infarction Hazard Ratio 10 P<0.0001 1 14% Decrease per 1% reduction in A1C 0.5 0 5 6 7 8 9 10 Updated Mean A1C 34 Stratton IM et al. BMJ. 2000;321:405-412. Intensive Glycemic Control Reduces Long-term Macrovascular Risk in Younger Patients With Shorter Duration of Disease UKPDS T2DM, newly diagnosed (N=4209) DCCT T1DM, 5-6 years duration (N=1441) 42% risk reduction 0.10 0.08 Conventional Randomized treatment 0.06 0.04 0.02 P=0.01 1.0 Proportion With MI 0.12 CV Outcome Cumulative incidence 15% risk reduction P=0.02 Intensive 0.00 0.8 0.6 Randomized treatment 0.4 0.2 Intensive 0.0 0 5 10 15 20 0 5 No. at Risk Conventional Intensive 714 705 688 683 10 15 20 25 221 577 20 66 Years Years 35 Conventional 618 629 92 113 1138 2729 1013 2488 857 2097 578 1459 CV, cardiovascular; DCCT, Diabetes Control and Complications Trial; MI, myocardial infarction; UKPDS, United Kingdom Prospective Diabetes Study. Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Holman RR, et al. N Engl J Med. 2008;359:1577-1589. Intensive Glycemic Control Does Not Reduce Macrovascular Risk in Older Patients With Longer Duration of Disease ACCORD ADVANCE VADT T2DM duration (years) 10 8 12 A1C reduction (%)* 0.9 0.8 1.3 Macrovascular risk (%)* 10 6 12 P=0.16 P=0.32 P=0.14 Mortality increased in intensively treated patients (P=0.04) 36 *Intensive vs standard glucose control. ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572. Duckworth W, et al. N Engl J Med. 2009;360:129-139. Macrovascular Risk Reduction in T2DM • • • • • • Individualized glucose control Hypertension control Dyslipidemia control Smoking cessation Aspirin therapy Diagnosis and management of: – Autonomic cardiac neuropathy – Kidney disease 37 Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.