Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
MEASURES TO PREVENT DIABETIC NEPHROPATHY AND END-STAGE RENAL DISEASE AND IMPLICATIONS FOR INSULIN THERAPY R Wright-Pascoe DM, FACP, FACE, FRCP (Edin) The University of the West Indies Mona Outline of Presentation • Epidemiology of Diabetes mellitus in Jamaica • Epidemiology of end-stage renal disease in diabetic subjects • Define diabetic nephropathy and the stages of chronic kidney disease (CKD) • Review the evidence for the role of hyperglycaemia in diabetic nephropathy Outline of Presentation • Discuss the targets of glycaemic control • Discuss the legacy effect • Control of glycaemia in Jamaicans with diabetes mellitus • Discuss bolus insulin • Outline the contribution of fasting hyperglycaemia to HbA1c • Introduce to ADA ?EASD algorithm • Review how to use bolus insulin in Type 2 diabetes mellitus Outline of Presentation • Discuss the premixed insulins • Discuss the biphasic insulin • Outline the use of algorithms to use biphasic insulins • Discuss insulin therapy in Type 1 diabetes mellitus and starting regimes Prevalence of Diabetes Mellitus in Jamaica % 17.9 20 13.4 15 8.1 10 5 1.3 0 1959-60 1969-70 1995 1999 Sargeant et al, 2002 WHO estimates that there will be 155,000 diabetics in Jamaica in 2025 No. of people with diabetes (000) 120 101 100 80 40 60 40 15 20 0 20-44 45-64 Age (years) >= 65 King et al, 1998 Age Distribution of Diabetics Attending the DAJ Clinics in Kingston and St Ann’s Bay Hospital % 34.4 35 30 25 19.7 17.2 20 19.0 15 10 6.1 6.1 < 29 30-39 5 0 40-49 50-59 Age (years) Wright-Pascoe R et al, Diabetes Rev 2000 60-69 >70 Number of people with Diabetes by age-group in developing countries 120 100 80 1995 2025 60 40 20 0 20 - 44 45-64 King H et al. Diabetes Care,1998,21;1414-1431 65+ At the Primary Care Clinics in Jamaica Diabetes account for 4-7 % of patient attendees and 2 % of all admissions to all general hospitals in the island Richard-George One complication associated with diabetes mellitus • End-Stage Renal Disease • Diabetes mellitus is one of the leading cause of End-Stage Renal Disease requiring dialysis in the Caribbean Diabetic nephropathy is one of the commonest causes of end-stage renal disease in the world 29TH January 2011 NHANES II: Annual incidence of diabetes-associated complications among USA patients Complication Cases per year Risk % * Ischemic Herat disease 101,000 1.58 Amputation 47,000 0.73 Cerebrovascular accident 27,000 0.42 Blindness 6,900 0.11 Renal insufficiency 5,900 0.09 * Anual risk of development of complications, calculation based on 6.4 million diabetic patients Adaptado de: McMillan D.E. Vasc Med 2 (2):132- 42, 1997. Hyperglycaemia increases risk for diabetes –related complications 20 Retinopathy Nephropathy Neuropathy Microalbuminuria 15 Relative Risk 13 11 9 7 5 3 1 6 7 8 9 10 11 12 A1C (%) DCCT, Diabetes Control and Complications Trial. 1. Adapted from 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. Glycaemic control is associated with a reduction in diabetes –related complications : UKPDS Risk Reduction (%) Risk reduction in complications per each 1% reduction in mean A1C 50 40 Type 2 DM 43 37 30 21 21 20 14 10 0 Microvascular Any Endpoint Death Related Related to Diabetes to Diabetes Fatal and Nonfatal MI UKPDS, United Kingdom Prospective Diabetes Study; MI, myocardial infarction; PVD, peripheral vascular disease. Stratton IM et al. Br Med J. 2000;321:405-412. Amputation or Death From PVD The Evidence for Hyperglycaemia and Diabetic Nephropathy • • • • DCCT UKPDS Kumamoto ADVANCE DCCT: Results after sustained glycaemic separation for 4-9 years Intensively treated group Conventionally treated group • Mean HBA1c 7.2 • Mean HBA1c 9.1% % • Mean blood glucose 155mg/dl (8.6 mmol/l) • Mean blood glucose 230 mg/dl • (12.8 mmol/l) Those with a HBa1c of 7.2% • Microalbuminuria – • 60% Clinical grade nephropathy – 54% Skyler JS. Microvascular Complications : Retinopathy and Nephropathy In Endocrn and Metab Clinics of North Am 2001;30:833-856 Those with a HBa1c of 7.2% • Microalbuminuria – • 39% Advanced microalbuminuria – 51% • (Albumin excretion rate >28 ug/min or 40 mg/24 hr) • (Albumin excretion rate >70 ug/min or 100mg/ 24 hr) Skyler JS. Microvascular Complications : Retinopathy and Nephropathy In Endocrn and Metab Clinics of North Am 2001;30:833-856 Those with a HBa1c of 7.2% – Renal damage • 54% – AER > 208 ug/min or 300mg/24hr Skyler JS. Microvascular Complications : Retinopathy and Nephropathy In Endocrn and Metab Clinics of North Am 2001;30:833-856 Those with a HBa1c of 7.2% and previous Diabetic Nephropathy • Microalbuminuria – 43% • Severe advanced microalbuminuria – 56% Skyler JS. Microvascular Complications : Retinopathy and Nephropathy In Endocrn and Metab Clinics of North Am 2001;30:833-856 Those with a HBa1c of 7.2% and previous Diabetic Nephropathy • Clinical grade albuminuria – 56% Advanced nephropathy 6.5 % per year increase in the conventional group vs. the intensive group Skyler JS. Microvascular Complications : Retinopathy and Nephropathy In Endocrn and Metab Clinics of North Am 2001;30:833-856 Epidemiology of Diabetes Interventions and Complications (EDIC) Study • Patients in the DCCT • Seen now by their own physicians • Enrolled in this observational study AIM • To compare the long-term effects of intensive or conventional glycaemic control on the development of retinal and renal complications 6 years later Steffes MW, Molitch ME, Chavers BM et al, and the DCCT/EDIC Study Group: Sustained reduction in albuminuria six years after the Diabetes Control and Complications Trial (Abstract). Diabetes 2001: 50: 254 Results in EDIC Intensively treated group Conventionally treated group • Mean HBA1c 7.9 % • Mean HBA1c 8.2% Steffes MW, Molitch ME, Chavers BM et al, and the DCCT/EDIC Study Group: Sustained reduction in albuminuria six years after the Diabetes Control and Complications Trial (Abstract). Diabetes 2001: 50: 254 Incidence of: • Microalbuminuria and albuminuria significantly lower in the intensive-therapy group compared to the conventionaltherapy group despite the similar HBA1c (p<0.001) Steffes MW, Molitch ME, Chavers BM et al, and the DCCT/EDIC Study Group: Sustained reduction in albuminuria six years after the Diabetes Control and Complications Trial (Abstract). Diabetes 2001: 50: 254 The United Kingdom Prospective Diabetes Study (UKPDS) • • • • • • Type 2 diabetes Newly diagnosed N=5102 Aged 25-63 years Median age 53 years Duration of follow-up 10 years UK Prospective Diabetes Study Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998: 352: 854-865 UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications In patients with type 2 diabetes (UKPDS 33). Lancet 1998: 352: 837-853 The United Kingdom Prospective Diabetes Study (UKPDS) • Half intensive therapy – Sulphonylureas, insulin, metformin • Half conventional therapy – Diet and exercise Results of UKPDS Intensively treated group Conventionally treated group • Mean HBA1c 7.0 % • Mean HBA1c 7.9 % • (P<0.001) Results : Intensive vs. the Conventional group • Risk reduction in the appearance of microalbuminuria • At 9 years – • by 24% At 12 years – • by 33% At 15 years – by 34% Skyler JS. Microvascular Complications : Retinopathy and Nephropathy In Endocrn and Metab Clinics of North Am 2001;30:833-856 Results : Intensive vs. the Conventional group • Risk reduction in the doubling of the serum creatinine • At 9 years – • by 60% At 12 years – by 74% Skyler JS. Microvascular Complications : Retinopathy and Nephropathy In Endocrn and Metab Clinics of North Am 2001;30:833-856 31 UKPDS: legacy effect of earlier glucose control End of randomised intervention1 1997 Any diabetes related endpoint RRR pvalue Microvascular disease RRR pvalue Myocardial infarction RRR pvalue All-cause mortality RRR pvalue End of 10-year observational follow-up2 2007 12% 0.029 9% 0.040 25% 0.0099 24% 0.001 16% 0.052 15% 0.014 6% 0.44 13% 0.007 RRR = relative risk reduction associated with intensive glucose control 1UKPDS 2Holman Group. Lancet 1998;352:837–853. R, et al. N Engl J Med 2008;359:1577–1589. Conclusions Clear and unequivocal evidence that meticulous glycaemic control has a profound and beneficial effect on the: 1. development of diabetic nephropathy 2. progression of diabetic nephropathy Intensive glycaemic control in diabetes is important ADVANCE: intensive glucose control significantly reduced nephropathy but not retinopathy Hazard ratio Definitions New or worsening nephropathy: macroalbuminuria, renal replacement, or death due to renal disease New or worsening retinopathy: proliferative retinopathy, macular oedema, diabetes-related blindness or retinal photocoagulation therapy 33 ADVANCE Collaborative Group. N Engl J Med 2008;358:2560–2572. Does intensive glucose control reduce microvascular complications in type 2 diabetes? UKPDS1 ADVANCE2 VADT3 ACCORD (n=3867) (n=11,140) (n=1791) (n=10,251) HbA1c (%)* 7.0 vs 7.9 6.5 vs 7.3 6.9 vs 8.4 6.4 vs 7.5 Combined microvascular 25% RRR 14% RRR Not available (p=0.0099) (p=0.01) Nephropathy No difference: death from renal disease or renal failure 21% RRR Retinopathy Retinal photocoagulation (p=0.0031) & cataract extraction (p=0.046) No difference: new or worsening retinopathy Neuropathy No difference: absent ankle/knee reflexes No difference: new or worsening neuropathy 34 achieved HbA1c, intensive vs standard * Mean RRR: relative risk reduction New or worsening nephropathy (p=0.006) & newonset microalbuminuria (p=0.02) Any worsening albuminuria (p=0.05) No difference: kidney function, advanced/end stage Not yet reported renal disease, proteinuria No difference: hard eye endpoints/ retinopathy No difference: new neuropathy 1UKPDS 2ADVANCE Group. Lancet 1998;352:837–853. Collaborative Group. N Engl J Med 2008;358:2560–2572. 3Duckworth W, et al. N Engl J Med 2009;360:129–139. • The beneficial effect of tight glycaemic control itself on diabetic nephropathy in CKD stages 3 -5 has not yet been established unequivally • If blood pressure is controlled however, glycaemic control has been shown to decrease the rate of decrease in GFR1 Alaveras AE, Thomas SM, Sagariotis A et al. Promoters of progression of diabetic nephropathy: the relative role of blood glucose and blood pressure control. Nephrol Dial Transplant 1997; 12(Suppl 2):71-74 Additional Years of Derived Benefits Benefits of Improved Glycaemic Control 2.0 1.5 1.0 0.5 0 Life Sight ESRD-free LEA-free QALYs Benefit Parameter ESRD, end-stage renal disease; LEA, lower-extremity amputation; QALYs, quality-adjusted life-years. Adapted from Klonoff DC et al. Diabetes Care. 2000;23:390-404. Target HbA1c to prevent Diabetic Nephropathy • HbA1c • <7% • <6.5% How Well Controlled Are They GlyHb (N=66) Normal or < normal > 1% above normal > 2% but < 3% >3% but < 5% >5% but <10% > = 10% % 27.3 16.7 10.6 13.6 24.2 5.0 53.4% Wright-Pascoe et al , 1999 What are the messages we must take back to our practices? Chronic renal failure in diabetes mellitus is associated with hyperglycaemia What are the messages we must take back to our practices? • Treating hyperglycaemia aggressively will decrease appearance of each component of diabetic nephropathy in persons without established diabetic nephropathy What are the messages we must take back to our practices? • Treating hyperglycaemia aggressively will result in delay in the progression of diabetic nephropathy in persons with established diabetic nephropathy What are the messages we must take back to our practices? • The time to treat to goal is NOW • This as there is “memory” in euglycaemia • Protection against “ Diabetic Nephropathy” will be seen 10 years after even if the persons becomes hyperglycaemic later in life • THE LEGACY EFFECT Jamaican diabetics are poorly controlled and are therefore at risk for diabetic nephropathy What are the messages we must take back to our practices? The goal for metabolic control and prevention of disease is a HbA1C < 7% < 6.5% • Insufficient data and trials regarding the ideal glucose target in patients with CKD stage 3 or worse. • A1c levels >9 % and < 6.5 % were associated with increased mortality in the presence of nondialysis dependent CKD stage 3 or worse • ESRD patients with diabetes benefit from maintaining their A1c between 7–8 %, as A1c levels above 8 % or below 7 % carry increased risks of all-cause and cardiovascular death • Accuracy of HbA1C in CKD Hyperglycaemia drives diabetic kidney disease Three mechanisms have been postulated that explain how hyperglycaemia causes tissue damage in the kidney:1-3 1. Activation of protein kinase C1 2. Acceleration of the reninHyperglycaemia angiotensin-aldosterone Protein kinase C and Advanced glycation system (RAAS)1 growth factors end products (AGEs) Acceleration 3. Non-enzymatic glycation of RAAS that generates advanced glycation end products1 Tubulointerstitial Overproduction of – Circulating levels are Hypertension injury mesangial cell matrix raised in people with diabetes, particularly those with renal insufficiency, Glomerular damage since they are normally excreted in the urine1 • Oxidative stress seems to be a Nephron loss Proteinuria theme common to all three pathways3 Reference: 1.Cade WT. Diabetes-Related Microvascular and macrovascular diseases in the physical therapy setting. Phys Ther. 2008;88(11):1322–1335. 2.Wolf G et al. (2005) From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes 54: 1626-1634. 3.Dronavalli S, Duka I and Bakris GL. Nat Clin Pract Endocrinol Metab. 2008;4(8):444-52. 46 Stages of Diabetic Nephropathy • Normoalbuminuria • Microalbuminuria • Incipient diabetic nephropathy • Albumin Excretion Rate (AER) <20 ug/min • Increased albumin excretion rate (AER 20200ug/min • Persistent microalbuminuria (2 out of 3 over 6 months, +/hyperfiltration • BP elevation Stages of Diabetic Nephropathy contd • Early overt diabetic nephropathy Clinical- grade proteinuria (AER >200 ug/min in 2 of 3 within 6 months or dipstick +proteinuria Hypertension • Advanced diabetic nephropathy • • • Progressive proteinuria Hypertension Declining glomerular filtration rate (decreased CrCl, Increased BUN and creatinine) • • • Uremia Nephrotic syndrome Need for renal replacement therapy • End-stage Renal disease Staging of Chronic Kidney Disease Persistent albuminuria categories Description and range GFR categories (mL/min/1.73 m2) Description and range Previous NKF CKD stage Guide to frequency of monitoring (number of times per year) by GFR and albuminuria category A1 A2 A3 Normal to mildly increased Moderately increased Severely increased <30 mg/g <3 mg/mmol 30-300 mg/g 3-30 mg/mmol >300 mg/g >30 mg/mmol 1 G1 Normal or high ≥90 1 if CKD 1 2 2 G2 Mildly decreased 60-89 1 if CKD 1 2 G3a Mild to moderately decreased 45-59 1 2 3 G3b Moderately to severely decreased 30-44 2 3 3 4 G4 Severely decreased 15-29 3 3 4+ 5 G5 Kidney failure <15 4+ 4+ 4+ 3 CKD = chronic kidney disease; GFR = glomerular filtration rate; NKF = National Kidney Foundation. Levey AS, et al. Kidney Int. 2011;80:17-28. Approach to the Management • Inhibition of the renin-angiotensin aldosterone system (RAS) – ACE inhibitors – ARB’s • Protein restriction • Blood pressure control • Optimal glycaemic control SGLT-2 Inhibitors are not recommended in patients with GFR < 60ml/min How to achieve this-the role of insulin therapy The Insulin molecule Insulin • stimulates glucose uptake from the systemic circulation • suppresses hepatic gluconeogenesis • primary role in glucose homeostasis Current and new antidiabetic medications: benefits and risks Intervention Advantages Disadvantages Metformin1 • Weight neutral • May improve lipid profile • GI side effects • Lactic acidosis (rare) Sulphonylureas1 • Well established • Weight gain • Hypoglycaemia Thiazolidinediones1 • Durable glycaemic control • Fluid retention, congestive heart failure • Weight gain, bone fractures Meglitinides1 • Short duration • Weight gain • Frequent dosing Insulin2 • No dose limit • Improves lipid profile • Injections • Weight gain • Hypoglycaemia -Glucosidase inhibitors1 • Weight neutral • Do not cause hypoglycaemia • Frequent GI side effects • Dosing 3 times/day Amylin analogues3 • Weight loss • Injections, frequent GI side effects • Limited experience DPP-4 inhibitors4 • Weight neutral • Limited experience GLP-1 agonists4 • Weight loss • Injections, frequent GI side effects • Limited experience 54 A and Bailey C. Drugs 2005;65:385–411. 2Carver C. Diabetes Educ 2006;32:910–917. 4 A, et al. Drugs 2008;68:2131–2162. Bosi E, et al. Diabetes Res Clin Pract 2008;82:S102–S107. 1Krentz 3Krentz BASAL INSULIN • Insulin which regulates glucose betweenmeals and during the night and which also suppresses hepatic glucose production Insulin PharmacodynamicsBasal insulin Insulin NPH Insulin Detemir Levemir Insulin Glargine Lantus Onset (hr) Peak (hr) Duration (hr) Appearance 1-2 4-10 14+ Cloudy 3-4 6-8 6-23 Clear 1.5 flat 24 Clear Insulin Glargine and Detemir Insulin analogues produced using recombinant DNA technology. http://www.endotext.org/diabetes/diabetes14/diabetesframe14.html Insulin PharmacodynamicsBasal insulin Insulin NPH Insulin Detemir Levemir Insulin Glargine Lantus Onset (hr) Peak (hr) Duration (hr) Appearance 1-2 4-10 14+ Cloudy 3-4 6-8 6-23 Clear 1.5 flat 24 Clear How to Use Basal Insulin in Type 2 Diabetes mellitus Contribution of fasting hyperglycaemia to overall glycaemia increases with worsening diabetes • • 290 patients with T2DM treated with diet or OHAs Baseline (normal) PG defined as 6.1 mmol/l (110 mg/dl) ― threshold defined by ADA as the upper limit of normal PG at fasting or preprandial times Relative contribution (%) 100 70% 50 Fasting 30% 0 <7.3 7.3―8.4 8.5―9.2 9.3―10.2 HbA1c (%) quintiles ADA=American Diabetes Association; OHA=oral hypoglycaemic agent; PG=plasma glucose. Adapted from Monnier L, et al. Diabetes Care 2003;26:881―5. >10.2 Treat Fasting Hyperglycaemia First ADA/EASD consensus algorithm Call to action if HbA1c is 7% Tier 1: well-validated therapies Lifestyle + Metformin + Basal insulin At diagnosis: Lifestyle + Metformin STEP 1 Lifestyle + Metformin + Intensive insulin Lifestyle + Metformin + Sulfonylurea STEP 2 STEP 3 Tier 2: Less well validated therapies Lifestyle + Metformin + Pioglitazone No hypoglycaemia Oedema/CHF Bone loss Lifestyle + metformin + GLP-1 agonist No hypoglycaemia Weight loss Nausea/vomiting Nathan DM, et al. Diabetes Care 2009;32 193-203. Lifestyle + Metformin + Pioglitazone + Sulfonylurea Lifestyle + metformin + Basal insulin 63 ADA/EASD Consensus Algorithm: Step 2 If step 1 fails to achieve or sustain HbA1c <7%, another medication should be added within 2-3 months Basal insulin if HbA1c >8.5% or symptoms of hyperglycemia * Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide Nathan DM, et al. Diabetes Care 2009;32:193-203. Initiation and titration of insulin glargine: practical advice In insulin-naïve patients: • Titrate using an algorithm • Decide on a target e.g. FBG <5.6 mmol/l (<100 mg/dl) ** • Make no increase in insulin dosage if blood glucose <4 mmol/l (<72 mg/dl) • Monitor the blood glucose regularly • Teach self-adjustment of insulin dose using algorithm • Follow the patient carefully 1. Davies M, et al. Diabetes Care 2005;28:1282―8. 2. Riddle M, et al. Diabetes Care 2003;26:3080―6. 3. Yki-Jarvinen H, et al. Diabetes 2004;53(suppl 2). Abstract 2181-PO. *Individualise Initiation and titration of insulin glargine: practical advice • Either start with an insulin dose of 10 U nocte or in the morning • Or start with an insulin dose numerically equivalent to the highest plasma glucose in mmol/l over the previous 7 days • The fasting glucose is done daily for 3 days • The average plasma fasting glucose over 3 consecutive days is calculated Initiation and titration of insulin glargine: practical advice • The dose of the long-acting insulin analogue is changed or kept as per the algorithm • Do this every week • Or do this every three days Initiation and titration of insulin glargine: practical advice Mean FBG mmol/l (mg/dl) for previous consecutive 3 days Titrate weekly** Titrate every 3 days** (AT.LANTUS,1 Treat-toTarget2 studies) Start dose 10 units daily (AT.LANTUS,1 LANMET3 studies) Start dose numerically equivalent to the highest FBG value in mmol/l over the previous 7 days ≥5.6 (≥100) ― <6.7 (<120) 0–2 0–2 ≥6.7 (≥120) ― <7.8 (<140) 2 2 ≥7.8 (≥140) ― <10 (<180) 4 2 6–8 2 ≥10 (≥180) 1. Davies M, et al. Diabetes Care 2005;28:1282―8. 2. Riddle M, et al. Diabetes Care 2003;26:3080―6. 3. Yki-Jarvinen H, et al. Diabetes 2004;53(suppl 2). Abstract 2181-PO. *Individualise Insulin initiation can be easy with the use of an insulin pen Easy to teach: simple & quick Easy to use: dial & dose Easier to inject: smooth & gentle Mean final daily insulin glargine doses in studies using forced-titration algorithms in type 2 diabetics on OHAs Mean daily insulin dose (units) 80 Treat-to-Target1 (insulin glargine ± OHAs) 60 LANMET2 (insulin glargine + metformin) AT.LANTUS3 (insulin glargine ± OHAs) Clinic-driven algorithm 40 AT.LANTUS3 (insulin glargine ± OHAs) Patient-driven algorithm 20 0 48U 68U 44U 46U 1. Riddle M, et al. Diabetes Care 2003;26:3080―6. 2. Yki-Jarvinen H, et al. Diabetes 2004;53(suppl 2). Abstract 2181-PO. 3. Davies M, et al. Diabetes Care 2005;28:1282―8. Bolus Insulin Addresses postprandial hyperglycaemia Insulin Pharmacodynamics- Bolus Insulin Insulin Type Insulin Lispro Onset (hr) Peak (hr) Duration (hr) Appearance within 15 min ½-1½ 3-5 Clear within 15 min 1-3 3-5 Clear Apidra 0.25-.5 hr 0.5-1 4 Clear Regular ½-1 hr 2-4 5-8 Clear Humalog Insulin Aspart Novorapid Insulin Glulisine Ultra-short-acting Insulin Analogues vs Human Insulin • • • • Less hexamers Dissociate quickly when injected Absorbed rapidly Peak values <1 hour Ultra-short-acting Insulin analogues Insulin aspart vs Soluble Insulin • Twice as fast an absorption rate • Achieves twice as high a peak • Provides a gentle return to baseline • Improves HBA1c • Maintains lower HbA1c • 72% lower risk of nocturnal hypoglycaemia Heller SR et al Diabetes Med 2004 http://www.endotext.org/diabetes/diabetes14/diabetesframe14.html Insulin Pharmacodynamics- Bolus Insulin Insulin Type Insulin Lispro Onset (hr) Peak (hr) Duration (hr) Appearance within 15 min ½-1½ 3-5 Clear within 15 min 1-3 3-5 Clear Apidra 0.25-.5 hr 0.5-1 4 Clear Regular ½-1 hr 2-4 5-8 Clear Humalog Insulin Aspart Novorapid Insulin Glulisine Insulin Pharmacodynamics- Premixed Insulins Insulin preparations Onset of Action Peak Action Maximal Duration (h or min) (h) (h) 0.5–1 h 0.5–1 h 4 – 12 5 – 10 18–24 18–24 0.5–1 h 5 – 10 18–24 0.5–1 h 0.5–1 h 5– 9 1– 3 18–24 18–24 Intermediate-acting • • • • • Premixed insulin 10/90 Premixed insulin 20/80 Premixed insulin 30/70 Premixed insulin 40/60 Premixed insulin 50/50 How to Start PreMixed Insulin in Type 2 Diabetes mellitus Insulin PharmacodynamicsBiphasic Insulin Insulin Onset (hr) Peak (hr) Duration (hr) Appearance Lispro Mix 50/50 .25-.5 .5-3 14-24 Cloudy Lispro Mix 75/25 .25-5 .5-2.5 14-24 Cloudy Cloudy Aspart Mix 70/30 .1-.2 1-4 18-24 When to Administer • NovoLog® Mix® 70/30 [NovoMix 30] : • once daily (QD) before supper • twice (BID), daily before breakfast and supper • three times (TID), daily before breakfast, lunch and supper Jain et al, ADA 2005 Treat-to-target: Phase 1- OD at suppertime • Dose of insulin at inclusion: -Insulin naïve: 12 U -Insulin on <30 U: previous dose (ratio 1:1) -Insulin on 31-60 U: dose Jain et al, ADA 2005 same dose as 70% of previous Treat-to-target: Phase 1 The dose was titrated using the average fasting plasma glucose values from 3 previous days Blood glucose (mg/dl) <80 80110 111140 141180 >180 < 4.4 4.4-6.1 6.2-7.7 7.8-10.0 >10.0 Dose change (U) -3 No change +3 +6 Jain et al, ADA 2005 +9 Treat-to-target: Phase 2 ProtocolBreakfast and Supper Insulin – Patients with FBG ≤ 110 mg/dl (6.1 mmol/l) add 3 units before breakfast – Patients with FBG > 110 mg/dl (6.1 mmol/l) add 6 units before breakfast FBG, or predinner SMBG (mg/dl) (mmol/l) Dose change (U) Jain et al, ADA 2005 <80 80110 111140 141180 >180 <4.4 4.4- 6.1 6.16-7.7 7.8-10.0 >10. -3 No change +3 +6 +9 Treat-to-target: titration schedule in Phase 3 –Breakfast, Lunch and Supper Insulin • • • • Dose adjustments Average post-lunch SMBG values for the preceding 3 days TID therapy only one dose per day was titrated. The choice was based on SMBG levels, anticipated diet and activity Post-lunch <100 SMBG (mg/dl) <4.4 100140 141180 >180 4.4- 6.1 6.16-7.7 >10. Dose change (U) No change +3 +6 Jain et al, ADA 2005 -3 Investigating NovoLog Mix® 70/30 QD, BID and TID Withdrawals 1. Novo Log Mix®70/30 QD (12U) Completers (reaching HbA1c≤6.5%) 100 patients 11 15 68 21 2. NovoLogMix® 70/ 30 BID 25 28 3. NovoLogMix® 70/30 TID 0 Jain et al, ADA 2005 17 8 58% The Insulin doses needed to achieve target 3 Insulin Dose U/Kg 2.5 2 1.5 A1C<6.5% All patients 1 0.5 0 Phase Phase Phase 1QD 2BID 3TID 0.5 U/Kg OD. 1.0 U/Kg BID. 1.5 U/Kg TID Insulin Therapy in Type 1 Diabetes Total Daily Dose Average dose 0.5-1.0 units per kg of body weight per day of insulin Starting dose 0.5-0.75 units/kg/day Early in the diabetic course 0.1-0.6 units per kg per day 50% basal insulin 50% bolus insulin 1-2 units of insulin will lower the blood glucose by 1.66-2.77 mmol/l. Hirsch IB 1999 Type 1 diabetes mellitus and the use of flexible insulin regimens. Am Fam Physician 60:2343-52, 2355-6 Hirsch IB 1999 Type 1 diabetes mellitus and the use of flexible insulin regimens. Am Fam Physician 60:2343-52, 2355-6 ADA 1998 Medical Management of Insulin-Dependent (Type I) Diabetes Mellitus, 3rd edition ed. American Diabetes Association, Alexandria, VA 2002 Practical insulin: A handbook for prescribing providers. American Diabetes Association, Alexandria, VA Insulin Regimes in Type 1 diabetes A Twice Daily Injection Regime NPH, Soluble Breakfast + Dinner B Three-times Daily Injection Regime NPH, Soluble Soluble Soluble NPH Breakfast Lunch Dinner Bedtime C Multiple Injection Regime Soluble NPH (30-40%) Breakfast + Lunch + Dinner Bedtime Regime B Normal Normal Normal Normal Normal Insulin Regimes in Type 1 diabetes A Twice Daily Injection Regime NPH, Soluble Breakfast + Dinner B Three-times Daily Injection Regime NPH, USAI USAI USAI NPH Breakfast Lunch Dinner Bedtime C Multiple Injection Regime Soluble NPH (30-40%) Breakfast + Lunch + Dinner Bedtime Regime B Insulin Regimes in Type 1 diabetes A Twice Daily Injection Regime Glargine /Detemir + Breakfast + Dinner B Three-times Daily Injection Regime Glargine/ Detemir +, Soluble/USAI Breakfast Soluble/USAI Lunch Soluble/USAI Dinner C Multiple Injection Regime Soluble/USAI Breakfast + Lunch + Dinner NPH (30-40%) Bedtime Insulin Regimes in Type 1 Diabetes A Twice Daily Injection Regime Detemir/ Glargine /Bedtime Ultra-rapid insulin Breakfast Breakfast + dinner B Three-times Daily Injection Regime Detemir/ Glargine +/Bedtime Ultra-rapid insulin Ultra-rapid insulin Ultra-rapid insulin Breakfast Breakfast Lunch Dinner C Multiple Injection Regime Ultra -rapid insulin + Detemir / Glargine (50%) Breakfast + Lunch Dinner Bedtime Regime B Normal Normal Normal Normal Normal AACE / ACE diabetes algorithm for glycaemic control HbA1c 7.6-9.0 % Call to action if HbA1c is 6.5% DPP- 4 / GLP-1 or TZD Dual Therapy Metformin and Insulin therapy +/Other agents SU / Glinide Triple Therapy Metformin and GLP-1 / DPP4 and TZD or SU TZD and SU Glycemic Control Algorith, Endocr Pract. 2009; 15(No. 6) AACE / ACE diabetes algorithm for glycaemic control HbA1c>9.0% Call to action if HbA1c is 6.5% TRIPLE THERAPY Symptoms Drug Naive Insulin and / other agents No symptoms Metformin +GLP-1 / DPP- 4 + TZD + / - SU Metformin +GLP-1 /DPP4 + SU + / - TZD Glycemic Control Algorith, Endocr Pract. 2009; 15(No. 6) Insulin + or - other agents Type 2 Diabetic subjects with CKD Stages 3 -5 Chronic Kidney Disease Stage 3 • eGFR of 30-59 mL/min/1.73 m2 Chronic Kidney Disease Stage 4 • eGFR of 15-29 mL/min/1.73 m2 Chronic Kidney Disease Stage 5 • eGFR of <15 mL/min/1.73 m2 National Kidney Foundation. K/DOQ1 clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Part 4. Definition and classification of stages of chronic kidney disease. Am J Kidney Dis 2002; 39 (Suppl 1): S46-S75 Strategies for the Use of Insulin in CKD 3-5 • Where the GFR less than 50ml but greater than 10 ml/min i.e. Stage 4 • Decrease insulin starting dose by 25% • Where the GFR less than 10 ml/min i.e. Stage 5 • Decrease insulin starting dose by 50 % • Use SMBG to aid in achieving control without hypoglycaemia Aronoff GR et al. Dosing Guidelines for Adults. 4th edn. Philadelphia: American College of Physicians; 1999. Drug prescribing in renal failure;p. p 84 THANK YOU