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Prof. Khalifa M. Abdallah Professor of Internal Medicine Unit of Diabetes & Metabolic Diseases Alexandria Faculty of Medicine Importance of early glycemic.

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Presentation on theme: "Prof. Khalifa M. Abdallah Professor of Internal Medicine Unit of Diabetes & Metabolic Diseases Alexandria Faculty of Medicine Importance of early glycemic."— Presentation transcript:

1 Prof. Khalifa M. Abdallah Professor of Internal Medicine Unit of Diabetes & Metabolic Diseases Alexandria Faculty of Medicine Importance of early glycemic control in management of type 2 diabetes

2 Overview The importance of early and sustained glycemic control The importance of early and sustained glycemic control The rationale for early insulinization The rationale for early insulinization Advantages of basal insulin therapy Advantages of basal insulin therapy Take home message Take home message

3 Diabetes Mellitus A Constellation of Complications Gastropathy Autonomic Neuropathy Renal Disease Peripheral Neuropathy Retinopathy/ Macular Edema Hypertension Cardiovascular Disease Dyslipidemia Peripheral Vascular Disease Erectile Dysfunction Diabetes

4 - A1c & Microvascular Complications 60 – 70 % Reduction of Complications - A1c & Microvascular Complications 60 – 70 % Reduction of Complications Relative Risk Retinopathy Nephropathy Neuropathy Microalbuminuria HbA 1c (%) Skyler JS. Endocrinol Metab Clin. 1996;25:243–254.

5 Risk Reduction in DCCT Risk Reduction DCCT Research Group. N Engl J Med. 1993;329: Neuropathy Albuminuria Retinopathy 76% 54% 60% 54% 39% Onset Progression albuminuria Effects of reduction of A1c by 1.9% in intensively treated group P=0.002 P=0.04

6 UKPDS 35. BMJ 2000; 321: A1c : Myocardial Infarction and Microvascular Complication Myocardial infarction Microvascular disease Mean HbA 1c (%) Incidence per 1000 patient-years

7 UKPDS: Glucose Control Study Summary The intensive glucose control policy maintained a lower HbA1c by a mean of 0.9% over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of: The intensive glucose control policy maintained a lower HbA1c by a mean of 0.9% over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of: 12% for any diabetes related endpoints p= % for any diabetes related endpoints p= % for microvascular endpoints p= % for microvascular endpoints p= % for myocardial infarction p= % for myocardial infarction p=0.052

8 UKPDS: Glucose Control Study Summary The intensive glucose control policy maintained a lower HbA1c by a mean of 0.9% over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of: The intensive glucose control policy maintained a lower HbA1c by a mean of 0.9% over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of: 12% for any diabetes related endpoints p= % for any diabetes related endpoints p= % for microvascular endpoints p= % for microvascular endpoints p= % for myocardial infarction p= % for myocardial infarction p=0.052

9 Ischemic heart disease Other heart disease Diabetes Malignant neoplasms Cerebrovascular disease Pneumonia/influenza All other Deaths (%) Causes of Death in People With Diabetes WHO Report World Health Organisation. Geneva 1997 of Diabetic Patients Deaths are from CV Causes 65%

10 Can long-term glycemic control reduce the risk of cardiovascular disease?

11 Summary of ACCORD, ADVANCE and VADT ACCORDADVANCEVADT No. of participants 10,25111, Participant age,years HbA1C at Baseline, % Significant Effect on Macrovascular Outcomes? NoNoNo Significant Effect on Microvascular Outcomes? NA Significant for nephropathy, not retinopathy No Rosiglitazone use, (intensive vs. standard) 90% vs. 58% 17% vs. 11% 85% vs. 78% Duration of follow-up, years

12 ACCORD ADVANCE and VADT- No Significant Effect on Macro or Micro Vascular Outcomes ACCORDADVANCEVADT No. of participants 10,25111, Participant age,years Duration of diabetes at study entry, years HbA1C at Baseline, % Participants with prior cardiovascular event, % Duration of follow-up, years

13 DCCT / EDIC: majority of patients receive intensive therapy and HbA 1C levels converge DCCT/EDIC: NEJM, 2005;353, No 25: HbA 1 c (%) Year DCCT Conventional Intensive DCCT end EDIC Conventional group encouraged to switch to intensive treatment HbA 1 c (%) Year DCCT Conventional Intensive Conventional Intensive DCCT end EDIC Conventional group encouraged to switch to intensive treatment EDIC Conventional group encouraged to switch to intensive treatment

14 DCCT / EDIC – incidence of all predefined cardiovascular outcome Patients previously receiving intensive treatment in the DCCT study had a 57% reduced incidence of nonfatal myocardial infarction, stroke or death from cardiovascular disease Patients previously receiving intensive treatment in the DCCT study had a 57% reduced incidence of nonfatal myocardial infarction, stroke or death from cardiovascular disease DCCT/EDIC: NEJM, 2005;353, No 25:

15 UKPDS: Post-Trial Changes in HbA 1c UKPDS results presented Mean (95%CI) UKPDS 80. N Eng J Med 2008; 359

16 After median 8.5 years post-trial follow-up Aggregate Endpoint Any diabetes related endpoint RRR: 12%9% P: Microvascular disease RRR: 25%24% P: Myocardial infarction RRR: 16%15% P: All-cause mortality RRR: 6%13% P: RRR = Relative Risk Reduction, P = Log Rank UKPDS: Legacy Effect of Earlier Glucose Control N Eng J Med 2008

17 Can long-term glycemic control reduce the risk of cardiovascular disease? Yes If early and sustained glycemic control started before atherosclerosis is established

18 At present, The question is not whether to intensively treat people with type 2 diabetes at onset of the disease to prevent long-term complications. At present, The question is not whether to intensively treat people with type 2 diabetes at onset of the disease to prevent long-term complications. The question rather is how to intensively treat patients with type 2 diabetes to consistently keep A1c < 7% all through the course of the disease The question rather is how to intensively treat patients with type 2 diabetes to consistently keep A1c < 7% all through the course of the disease

19 ADA: Position statement: Need for early treatment Patients with shorter duration of Type 2 diabetes and without established atherosclerosis might reap cardiovascular benefits from intensive glycaemic control 1 Patients with shorter duration of Type 2 diabetes and without established atherosclerosis might reap cardiovascular benefits from intensive glycaemic control 1 Skyler JS, et al. J Am Coll Cardiol. 2009;53(3):

20 Glycemic control & A1c Target AACEADA <6.5<7 A1c (%) < Preprandial (mg/dl) < Postprandial (mg/dl) Bedtime (mg/dl) ADA: American Diabetes Association AACE: American Association of Clinical Endocrinologists

21 Two-thirds of Type 2 Patients are not Achieving Glycemic Control NHANES = National Health and Nutrition Examination Survey. 1 Koro et al. Diabetes Care. 2004;27:17-20; 2 State of Diabetes in America, American Association of Clinical Endocrinologists, Available at: DiabetesAmericaReport.pdf. Accessed January 6, A1c 6.5% AACE survey N=157,000 type 2 patients 39 US states included 33%33% A1c <7% NHANES N= N= %44.5% 35.8%35.8%

22 Traditional Type 2 Diabetes Management: A Treat-to-Fail Approach HbA 1c Goal Duration of Diabetes OAD monotherapy Diet and exercise OAD combination OAD up-titration OAD + multiple daily insulin injections OAD + basal insulin Published Conceptual Approach Mean HbA 1c of patients OAD=oral antihyperglycemic agent. Adapted from Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7(10):625–631. Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355. Conventional stepwise treatment approach

23 Delays often occur between stepping up from monotherapy to combination therapy Months Metformin only n = months Sulfonylurea only n = months Length of time between first monotherapy HbA 1c > 8.0% and switch/addition in therapy (months) Brown, JB et al. Diabetes Care 2004; 27:1535–1540.

24 Brown JB et al. Diabetes Care 2004;27: % of Subjects Percentage of subjects advancing when A1C >7% < 8% Clinical Inertia: Failure to Advance Therapy When Required Diet 66.6% SulfonylureaMetformin 35.3% 44.6% Combination 18.6% At insulin initiation, the average patient had: 5 years with A1C > 8% 10 years with A1C > 7%

25 Diagnosis Lifestyle Intervention + Metformin No HbA1c 7% Yes Add Basal Insulin Add Sulfonylurea Add DPP-4 inhibitor Add Glitazone ADA-EASD-Consensus 2006

26

27 Nathan DM et al. Diabetes Care 2009;32: Consensus Algorithm Update 2009 Check A1C every 3 months until <7%. Change treatment if A1C is 7% Step 3 Tier 1: Well-validated core therapies At diagnosis: Lifestyle + Metformin plus Basal Insulin Lifestyle + Metformin plus Sulfonylurea a Lifestyle + Metformin plus Intensive Insulin Step 1 Step 2 Lifestyle + Metformin plus Pioglitazone No hypoglyceamia Oedema / CHF Bone Loss Lifestyle + Metformin plus GLP-1 agonist No hypoglyceamia Weight loss Nausea / vomiting Tier 2: Less well-validated therapies Lifestyle + Metformin plus Pioglitazone plus Sulfonylurea Lifestyle + Metformin plus Basal Insulin

28 Sulphonylureas failed to maintain glycemic control Gliclazide Tan (n=297) Glyburide Hanefeld (n=250) Chicago (n=230) Glimpiride Glyburide Periscope (n=181) Glibenclamide ADOPT (n=1441) Glyburide UKPDS (n=1573) HBA1c % Reduction Time (years) 0

29 Islet -cell function (% of normal by HOMA ) HOMA = homeostasis model assessment Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25; UKPDS. Diabetes. 1995;44: Years Time of diagnosis UKPDS: Islet -cell function and the progressive nature of diabetes Pancreatic function = 50% of normal

30 Advantages of insulin It lowers mean blood glucose in a predictable dose-dependent manner It lowers mean blood glucose in a predictable dose-dependent manner Can be tailored to individual needs on a unit-to-unit basis Can be tailored to individual needs on a unit-to-unit basis It has the longest experience than any other drug (90 years) It has the longest experience than any other drug (90 years) No contraindications to its use No contraindications to its use

31 Insulin is the only drug that directly reduces lipolysis and free fatty acid concentrations in blood, thus reducing lipotoxicity Insulin is the only drug that directly reduces lipolysis and free fatty acid concentrations in blood, thus reducing lipotoxicity Insulin improves lipoprotein metabolism, decreases LDL cholesterol and triglycerides, and increases HDL cholesterol Insulin improves lipoprotein metabolism, decreases LDL cholesterol and triglycerides, and increases HDL cholesterol Insulin improves endothelial dysfunction Insulin improves endothelial dysfunction Advantages of insulin

32 thoughts/concerns about starting insulin Common Fears: Common Fears: Needles Needles Hypoglycemia Hypoglycemia Weight gain Weight gain Common Beliefs: Common Beliefs: Insulin is the last option Insulin is the last option Insulin causes complications Insulin causes complications Insulin is a personal failure Insulin is a personal failure Adverse impact on relationships/lifestyle Adverse impact on relationships/lifestyle

33 What should I tell people with Type 2 diabetes about insulin? Most people with Type 2 diabetes eventually need insulin because their own production of insulin falls off with time and they therefore inevitably become insulin deficient

34 What should I tell people with Type 2 diabetes about insulin? If you need insulin, it doesnt mean you failed. Tablets cannot control blood glucose forever, because they dont stop the problem of your own declining insulin production getting worse Islet -cell dysfunction worsens over time, regardless of therapy Islet -cell dysfunction worsens over time, regardless of therapy

35 What should I tell the person with Type 2 diabetes who needs insulin, but doesnt want to take it? Insulin will not make your diabetes worse. In fact, it will help control your glucose, so youll have fewer complications and youll feel better. Strict glycaemic control reduces the risks of both microvascular and macrovascular complications Strict glycaemic control reduces the risks of both microvascular and macrovascular complications

36 Insulin Regimens 1. Basal insulin ( NPH or long-acting insulin analogue) + OAD 1. Basal insulin ( NPH or long-acting insulin analogue) + OAD 2. Total insulin replacement therapy 2. Total insulin replacement therapy - Premixed insulins - Premixed insulins - Basal-bolus - Basal-bolus

37 24-hour Plasma Glucose Curve: Rationale for Adding Basal Insulin Time of Day Adapted from Polonsky KS et al. N Engl J Med. 1988;318: Glucose (mg/dL) Diabetes Normal

38 hour Plasma Glucose Curve: Rationale for Adding Basal Insulin Normal Diabetic Time of Day Glucose (mg/dL) Adapted from Polonsky KS et al. N Engl J Med. 1988;318:

39 Starting With Basal Insulin in DM 2 – Advantages 1 injection with no mixing 1 injection with no mixing Insulin pens for increased acceptance Insulin pens for increased acceptance Slow, safe, simple titration Slow, safe, simple titration Low dosage Low dosage Effective improvement in glycemic control Effective improvement in glycemic control Limited weight gain Limited weight gain

40 Mean A1C Levels During Study Mean A1C (%) Time (weeks) Insulin glargine NPH insulin Target A1C (%) Insulin Glargine vs. NPH Insulin Added to Oral Therapy Riddle MC et al. Diabetes Care. 2003;26:

41 Mullins P et al. Clin Ther 2007;29: Less Hypoglycemia with Insulin Glargine vs NPH HbA 1c Hypoglycemia events per 100 patient-years NPHInsulin glargine HbA 1c Hypoglycemia events per 100 patient-years T1DM T2DM p=0.004 between treatments p=0.021 between treatments

42 Insulin Glargine vs. NPH Insulin Added to Oral Therapy Hypoglycemia defined as PG 72 mg/dL, by hour Glargine NPH insulin Time of Day (hour) Events per Patient-Year * * * * * * Basal insulin Riddle MC et al. Diabetes Care. 2003;26: * Symptomatic Hypoglycemia by Time of Day *P < 0.05 vs. glargine.

43 Insulin Glargine Trials Showing Effective Reduction in HbA 1c HbA 1c (%) APOLLOLAPTOPTriple Therapy LANMET Treat-To- Target INITIATE Baseline Study endpoint

44 Target: FPG 100 mg/dL Subjects (n=364) were randomly assigned to: Insulin glargine once daily + continued OADs Premixed human insulin 70/30 BID Baseline End Point Time (wk) 0 24 Treatment Regimen *Sulfonylurea + metformin OAD=oral antidiabetic drug Janka HU, et al. Diabetes Care. 2005;28: Insulin Glargine Plus OADs vs Twice-daily Premixed 70/30 Human Insulin OADs*

45 Change in A1C from Baseline to Study End Point * *Intent-to-treat analysis OAD=oral antidiabetic drug OAD=oral antidiabetic drug Janka HU, et al. Diabetes Care. 2005;28: P= A1C Insulin Glargine Plus OADs vs Twice-daily Premixed Human Insulin Baseline 24 week

46 LAPTOP: Insulin Glargine Versus 70/30 Premixed Insulin in OHA Failures Janka H et al. Diabetes Care 2005;28: *Confirmed symptomatic hypoglycaemia (blood glucose <60 mg/dl [<3.3 mmol/l]) N=371 insulin-naïve patients Insulin glargine + OADs vs twice-daily human NPH insulin (70/30) Follow-up: 24 weeks Hypoglycaemia* (events/patient year) p= HbA 1c (%) 7.5% 7.2% 1.3% 1.7% p= Twice-daily premixed insulin Insulin glargine + OADs

47 Documented Hypoglycemic Episodes Per Patient-Year Less Hypoglycemia With Glargine Plus OADs vs Twice-daily Premixed 70/30 Human Insulin Average dose = 28.2 IU with G + OAD vs 64.5 IU with premixed insulin Weight Gain: 1.4 ± 3.4 kg with G + OAD vs 2.1 ± 4.2 kg with pre mixed insulin Janka HU, et al. Diabetes Care. 2005;28: # of Episodes Per Patient-Year P< Insulin Glargine + OAD Premixed

48 Conclusions Due to declining -cell function, insulin therapy will be necessary for most patients with Type 2 diabetes Due to declining -cell function, insulin therapy will be necessary for most patients with Type 2 diabetes Insulin therapy should be initiated early when glycemic control exceeds the recommended targets Insulin therapy should be initiated early when glycemic control exceeds the recommended targets Insulin effectively lowers HbA 1c, thereby reducing the risks of both micro- and macrovascular complications Insulin effectively lowers HbA 1c, thereby reducing the risks of both micro- and macrovascular complications

49 Diabetes Care 2003, 26: A1c <7%A1c >10% PPG FPG Contribution % Relative Contributions of Fasting and Postprandial Glycemia(%) to The Overall Diurnal Hyperglycemia Over Quintiles of A1C A1c 9%A1c 8%

50 Insulin glargine when used as a basal insulin has the following advantages: It effectively lowers fasting and mean blood glucose It effectively lowers fasting and mean blood glucose Easily initiated and titrated Easily initiated and titrated Low risk of hypoglycemia Low risk of hypoglycemia Conclusions-cont.

51 Thank You

52 Insulin glargine offers long-term efficacy without the need for intensification Gordon J, et al. Int J Clin Pract. 2010;64(12): Insulin glargine provides superior long term efficacy vs. NPH. 52


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