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Diabetes: Diagnosis, Classification, Management Controversies and News

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1 Diabetes: Diagnosis, Classification, Management Controversies and News
Bianca Alfonso, MD Endocrinology Fellow, Year 1 Marina Krymskaya, ANP, CDE Diabetes Nurse Educator Jill Gregory Medical Illustrator Leonid Poretsky, MD Chief, Division of Endocrinology and Metabolism Director, Gerald J. Friedman Diabetes Institute Gerald J. Friedman Chair in Endocrinology Professor of Medicine, Albert Einstein College of Medicine

2 Diabetes Care Enhancement Initiative
Team: Leonid Poretsky, MD; Agustin Busta, MD; Morton Davidson, MD; Marina Krymskaya, RN, NP; Jason Park, MD; Carmen Schmidt, RN; Daniel Steinberg, MD; Goal: Improvement of diabetes care for both inpatients and outpatients throughout the Beth Israel System. The first event of the Initiative – Grand Rounds on June 16th, presented by Dr. Silvio E. Inzucchi,of Yale University: Successful Management of Inpatient Hyperglycemia. The Initiative includes educational and clinical components. Plan Educational aspects: To include physicians, nurses, house staff, patients and their significant others; The series of lectures, grand rounds, in-service events to be planned; The “discharge kit” with general and individualized instructions to be developed and piloted; Educational video materials for inpatient TV to be selected/created and used throughout BIMC; Clinical aspects: review of all existing diabetes protocols for general wards; review of current PRIZM orders; review of current diabetes-related protocols in CCU, MICU, CT ICU, SICU; Quality Improvement: jointly with GMA, develop program for house staff Open for suggestions. Please direct any comments to Marina Krymskaya at or

3 Diabetes: diagnosis, classification, management
Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

4 Diabetes: diagnosis, classification, management
Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

5 Definition Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.* The name 'diabetes mellitus' derives from: Greek: 'diabetes' – “siphon” or “to pass through” Latin: 'mellitus' – “honeyed” or “sweet”** * Diagnosis and Classification of Diabetes Mellitus. ADA 2009. **

6 Diabetes: diagnosis, classification, management
Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

7 Epidemiology 20.8 million Americans (7% of US population)
About 10% have Type 1 DM 14.6 million diagnosed 6.2 million remain undiagnosed 41 million have pre-diabetes Lifetime risk for developing DM (Type 1 or 2) is 33 % in males and 39% in females for individuals born in 2000 Up to 45% of newly diagnosed cases of DM in US children and adolescents are type 2 AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007;13(Suppl 1) 2007

8 Diabetes: diagnosis, classification, management
Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

9 Classification Type 1 diabetes Type 2 diabetes Other
Genetic defects of beta cell function Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug/ chemical - induced Infections Uncommon forms of immune-mediated diabetes Genetic syndromes sometimes associated with diabetes Gestational diabetes mellitus

10 Type 1 diabetes A. Immune-mediated B. Idiopathic
Type 1 diabetes is characterized by β-cell destruction, usually leading to absolute insulin deficiency.* * Diagnosis and Classification of Diabetes Mellitus. ADA 2009.

11 Atkinson MA and Eisenbarth GS. Lancet 2001;358:221-229.

12 Type 1 diabetes mellitus – immune mediated
Absolute insulin deficiency Usually due to autoimmune destruction of the pancreatic beta cells Islet-cell antibodies (ICA) or other autoantibodies (antibodies to glutamic acid decarboxylase [anti-GAD] and anti-insulin)

13 Type 2 diabetes Hyperglycemia Insulin resistance
Relative impairment in insulin secretion.

14 Decreased Glucose Transport & Activity (expression) of GLUT4
­cell dysfunction and insulin resistance produce hyperglycemia in type 2 diabetes Insulin Resistance ­Cell Dysfunction Increased Lipolysis Pancreas Liver Elevated Plasma FFA ↓Glucose Uptake ↑Glucose Production Islet ­Cell Degranulation; Reduced Insulin Content -Cell Dysfunction and Insulin Resistance Produce Hyperglycemia in Type 2 Diabetes Dual Impairment Impaired insulin action (Insulin Resistance) Impaired insulin secretion (Impaired -cell function) In adipose tissue resistant to the effects of insulin, there is increased lipolysis resulting in elevated level of plasma free fatty acids (FFA). Elevated FFA lead to an increase in hepatic glucose production and decrease in glucose uptake in the muscle. Impaired -cell function and -cell degranulation lead to a reduction in circulating insulin. This reduction in circulating insulin leads to hyperglycemia. Impaired insulin action or insulin resistance results in a decreased response to insulin in insulin sensitive tissues. In the liver, insulin resistance results in an increase in hepatic glucose production. Whether the impairment is to insulin secretion or action, the resulting hyperglycemia has a negative effect on muscle and adipose tissue by decreasing expression of GLUT4 which, in turn, limits glucose transport into insulin-sensitive tissues. Key words: Type 2 Defects Beta cell Insulin resistance Muscle Adipose Tissue Increased Glucose Output Reduced Plasma Insulin Decreased Glucose Transport & Activity (expression) of GLUT4 Hyperglycemia

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17 Other specific types of diabetes – Genetic defects of beta cell function
Maturity–onset diabetes of the young (MODY) 6 subtypes

18 Maturity: Onset diabetes of the young (MODY)
MODY 1 - Mutation in HNF-4-alpha (transcription factor), chromosome 20 MODY 2 - Mutation in glucokinase gene, chromosome 7 MODY 3 - Mutation in HNF-1-alpha (transcription factor), chromosome 12 (most common form) MODY 4 - Mutation in insulin promoter factor-1 (IPF-1), chromosome 13 MODY 5 - Mutation in HNF-1-beta, chromosome 17 MODY 6 - Mutation in Neurogenic Differentiation Factor-1 (NEUROD1) , chromosome 2

19 Other specific types of diabetes: Genetic defects in insulin action
Type A insulin resistance Leprechaunism Rabson- Mendenhall syndrome Lipoatrophic diabetes Others

20 Latent Autoimmune Diabetes in Adults (LADA)
Adult-onset diabetes with circulating islet antibodies but not requiring insulin therapy initially Adults who should be considered for antibody testing*: age of onset <50 years acute symptoms BMI <25 kg/m2 personal or family history of autoimmune disease *A clinical screening tool identifies autoimmune diabetes in adults. Fourlanos S; Perry C; Stein MS; Stankovich J; Harrison LC; Colman PG. Diabetes Care May;29(5):970-5

21 Gestational DM Definition
Any degree of impaired glucose tolerance with onset or first recognition during pregnancy Gestational diabetes (GDM) occurs when pancreatic function is not sufficient to overcome the insulin resistance created by changes in diabetogenic hormones during pregnancy Most have impaired glucose tolerance that begins in pregnancy Some have previous undiagnosed type 2 diabetes mellitus 10% have circulating islet cell antibodies

22 Diabetes: diagnosis, classification, management
Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

23 Diagnosis Diabetes mellitus Impaired fasting glucose (IFG)
Impaired glucose tolerance (IGT) Gestational diabetes mellitus (GDM)

24 Diagnosis: Diabetes mellitus
Symptoms of diabetes (polydipsia, polyuria, unexplained weight loss) PLUS a random plasma glucose >200 mg/dL (11.1 mmol/L) or Fasting plasma glucose > 126 mg/dL (7.0 mmol/L) after overnight (at least 8 hours) fast Two-hour plasma glucose> 200mg/dL (11.1 mmol/L) during a standard 75g oral glucose tolerance test Any of these criteria establishes the diagnosis but needs to be confirmed on a later day

25 Diagnosis: Impaired fasting glucose (IFG)
Fasting plasma glucose (FPG) < 100 mg/dl (5.6 mmol/l) = normal FPG mg/dl ( mmol/l) = impaired fasting glucose (IFG)

26 Diagnosis: Impaired glucose tolerance (IGT)
Oral glucose tolerance test (OGTT) – glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water 2-h postload glucose < 140 mg/dl (7.8 mmol/l) = normal 2-h postload glucose mg/dl (7.8 – 11.1 mmol/l) = impaired glucose tolerance (IGT)

27 Diagnosis: Gestational Diabetes Mellitus (GDM)
Fasting plasma glucose > 126 mg/dL (7.0 mmol/L) Unequivocal hyperglycemia (confirmed on a subsequent day) Random plasma glucose >200 mg/dL (11.1 mmol/L) OR 100-g glucose load 2. Diagnostic OGTT mg/dl mmol/l Fasting 95 5.3 1-h 180 10.0 2-h 155 8.6 3-h 140 7.8

28 Diabetes: diagnosis, classification, management
Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

29 Treatment Lifestyle intervention Hypoglycemic drugs
oral hypoglycemic drugs insulin and insulin analogs others (incretins, pramlintide)

30 Treatment: Lifestyle Interventions
Weight loss Increased exercise

31 Treatment: Oral Antihyperglycemic Drugs
Biguanides Sulfonylureas Meglitinide analogs Thiazolidinediones -Glucosidase Inhibitors DPP-4 Inhibitors

32 Treatment: Oral Antihyperglycemic Drugs

33 Oral antihyperglycemic drugs: Biguanides
Metformin (Glucophage) Extended-release metformin (Glucophage-XR) decrease hepatic glucose output lower fasting glycemia reduce HbA1c by 1.5% adverse effects: lactic acidosis, gastro-intestinal disturbances

34 Oral antihyperglycemic drugs: Metformin
AMPK - adenosine monophosphate-activated protein kinase, ACC - acteyl-CoA carboxylase, SREPB-1 - sterol-regulatory-element-binding-protein-1. Diagram adapted from Alice Y.Y. Cheng, I. George Fantus, 'Oral antihyperglycemic therapy for type 2 diabetes mellitus' Canadian Medical Association Journal 172(2),2005 pp

35 Treatment: Oral Antihyperglycemic Drugs

36 Oral antihyperglycemic drugs: Sulfonylureas
1st generation : Tolbutamide (Orinase), Tolazamide (Tolinase), Acetohexamide (Dymelor), Chlorpropamide (Diabinese) 2nd generation : Glyburide (DiaBeta, Glynase) Glipizide (Glucotrol), Glimepiride (Amaryl) enhance insulin secretion lower HbA1c by 1.5 % side effects: hypoglycemia, weight gain

37 Treatment: Oral Antihyperglycemic Drugs

38 Oral antihyperglycemic drugs: Meglitinide analogs
Repaglinide (Prandin) Nateglinide (Starlix) enhance insulin secretion (early-phase insulin release) lower HbA1c by % (repaglinide) and by % (nateglinide) side effects: weight gain, hypoglycemia Black C, Donnelly P, McIntyre L et al. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev Apr 18;(2):CD  

39 Treatment: Oral Antihyperglycemic Drugs

40 Oral antihyperglycemic drugs: Thiazolidinediones (TZDs)
Rosiglitazone (Avandia) Pioglitazone (Actos) peroxisome proliferator-activated receptor γ modulators (PPAR γ) insulin sensitizers (increase the sensitivity of muscle, fat and liver to endogenous and exogenous insulin) lower HbA1c by % adverse effects: weight gain, fluid retention

41 Treatment: Oral Antihyperglycemic Drugs

42 Oral antihyperglycemic drugs: -Glucosidase Inhibitors
Acarbose (Precose) Miglitol (Glyset) reduce the rate of digestion of polysaccharides in the proximal small intestine, primarily lowering post-prandial glucose levels lower HbA1c by 0.5 – 0.8 % side effects: increased gas production and gastro-intestinal symptoms

43 Oral antihyperglycemic drugs: DPP-IV inibitors
Sitagliptin (Januvia) : DPP-IV inhibitor Dipeptidyl peptidase IV (DPP-IV) is a ubiquitous enzyme that deactivates a variety of bioactive peptides, including GIP and GLP-1

44 Oral antihyperglycemic drugs - Sitagliptin (Januvia)
Used alone or in combination with metformin or TZDs Reduces HbA1c by 0.5 – 0.7 % Side effects: increased rate of respiratory infections, headaches

45 "Januvia" by Byron Rubin Sculpture was installed at the West Point Pennsylvania Merck location.

46 Other antihyperglycemic drugs: Incretins
Exenatide (Byetta) glucagon-like peptide 1 (GLP-1) agonist

47 Antihyperglycemic drugs: Exenatide (Byetta)

48 Glucagon-like Peptide - 1
The majority of GLP-1 producing cells are in the terminal ileum and proximal colon. GLP-1 levels in the blood increase rapidly after a meal. Half-life being very short, approximately one minute. GLP-1 binding to its G-protein coupled receptor on ß-cells increases glucose stimulated insulin secretion GLP-1 infused into healthy subjects decreases gastric emptying, causes a sensation of satiety, and decreases appetite. Effects: enhances insulin secretion limits postprandial hyperglycemia.

49 Incretin Effect Figure 1. Insulin levels following oral vs IV glucose administration in healthy individuals. Despite identical glucose concentrations, plasma insulin levels peaked much earlier and were greater in response to an oral vs IV dose of glucose. Figure 2. Insulin levels following oral vs IV glucose administration in patients with type 2 diabetes. The markedly reduced early peak of insulin after oral glucose, along with the smaller differences in insulin levels in response to oral and IV glucose doses, illustrate the diminished incretin effect. Data extrapolated from Perley, et

50 Antihyperglycemic drugs: Exenatide (Byetta)
active ingredient in Exenatide (Byetta) is a synthetic version of a protein present in the saliva of the Gila monster

51 Antihyperglycemic drugs: Exenatide (Byetta)
Added to metformin or sulfonylureas will reduce HbA1c by % Side effects: nausea (dose-depended, declines with time) acute pancreatitis (some necrotizing or hemorrhagic pancreatitis cases reported as well)

52 Antihyperglycemic drugs: Exenatide (Byetta)

53 Antihyperglycemic drugs: Others
Pramlintide (Symlin) synthetic analog of amylin

54 Amylin Stored in insulin secretory granules in the ß-cells
Co-secreted with insulin Decreases glucagon Satiety signal? Decreases GI motility

55 Antihyperglycemic drugs: Pramlintide (Symlin)
Delays gastric emptying, suppresses glucagon secretion, decreases appetite Associated with weight loss ( kg over 6 months) Used only in conjunction with insulin treatment Reduces HbA1c by % Side effects: nausea, gastro-intestinal symptoms

56 Antihyperglycemic drugs: Pramlintide (Symlin)

57 AVAILABLE INSULIN PREPARATIONS
Product (Manufacturer) Form Rapid Acting (Onset min, duration hrs 3-4) Insulin Analog Aspart - Novolog (Novo Nordisk) Lispro - Humalog (Lilly) Glulisine – Apidra (Aventis) Analog** Short Acting (Onset hr, duration hrs 5-7)* Human Insulin Novolin R (Rugular) (Novo Nordisk) Humulin R (Regular) (Lilly) Human** Purified Insulin Regular Iletin II (Lilly) Pork Intermediate Acting (Onset 1-4 hrs, duration hrs 18-24)* Novolin N (NPH) (Lilly) Humulin N (NPH) (Lilly) Humulin L (Lente) (Lilly) NPH Iletin III (Lilly) Long Acting (Onset 4-6 hrs, duration hrs 24-34)* Humulin Ultralente (Lilly) Basal Peakless Insulin Glargine-Lantus (Aventis) Detemir – Levemir (Novo Nordisk) Mixed Insulins 70/30 Insulin Novolin 70/30 (Novo Nordisk) Humulin 70/30 (Lilly) Humulin 50/50 (Lilly) Humalog 50/50 Product (Manufacturer) Form Analog Mix Humalog 75/25 Mix Novolog Mix 70/30 (combination of fast and intermediate acting insulin with action similar to that of Humalog 75/25 mix) Analog** Insulin for Special Use Buffered Insulin (for pumps) Humulin BR Refills for Novolin Pen Novolin R PenFill Novolin N PenFill Novolin 70/30 PenFill Novolog Mix 70/30 PenFill Prefilled Pens Novolin R Novolin N Novolin 70/30 Novolog Novolog Mix 70/30 Humalog Humalog Mix 75/25 Humalog Mix 50/50 Humulin N Apidra Human** * Onset and duration are rough estimates. They can vary greatly within the range listed and from person to person ** Human insulin is made by recombinant DNA technology

58 ADA Treatment Algorithm
Initiation and adjustment of insulin regimens. Insulin regimens should be designed taking lifestyle and meal schedule into account. The algorithm can only provide basic guidelines for initiation and adjustment of insulin. See reference 90 for more detailed instructions. aPremixed insulins not recommended during adjustment of doses; however, they can be used conveniently, usually before breakfast and/or dinner, if proportion of rapid- and intermediate-acting insulins is similar to the fixed proportions available. bg, blood glucose.

59 Diabetes: diagnosis, classification, management
Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

60 Evidence

61 ACCORD ↑22%* 10,251 patients with DM2 Mean age – 62.2 yrs
Baseline A1C – 8.1% Intensive glucose control vs. standard control Median f/up 3.5 yrs primary outcome: nonfatal myocardial infarction nonfatal stroke death from CV causes Intensive Standard RR reduction A1C 6.4% 7.5% Primary outcome 6.9% 7.2% 10% Death from any cause 5.0% 4.0% ↑22%* Non-fatal MI 3.6% 4.6% 24%* Severe hypoglycemia 2.7% 1.5% had anatomical evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or at least two additional risk factors for cardiovascular disease (dyslipidemia, hypertension, current status as a smoker, or obesity). * P-value < 0.05 The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:

62 ACCORD Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial Designed primarily to examine the effects of glycemic control, lower than had previously been achieved, on CVD in subjects with long-standing diabetes 10,250 adults (mean age 62 years) with a median diabetes duration of ten years and at high risk for cardiovascular disease (diagnosed with CVD or two risk factors in addition to diabetes) Intensive treatment group with the aim of achieving A1C of < 6 % or a standard treatment group with a A1C goal of 7.0 to 7.9 %.

63 ACCORD After 3.5 years, the intensive arm was halted due to a higher number of total deaths: 257 deaths in subjects assigned to intensive therapy versus 203 deaths in patients assigned to standard treatment group.* The primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) occurred in 352 and 371 patients in the intensive and standard therapy groups, respectively (HR 0.90, 95% CI ). * hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04

64 ACCORD Preliminary information : extensive analyses have not identified a specific cause for the excess mortality in the intensive treatment group. Subjects in the intensive group rapidly achieved target A1C values and experienced a greater number of severe hypoglycemic events (annualized rate of 3.1 versus 1.0 percent) and more weight gain (mean 3.5 versus 0.4 kg at three years) than the standard group (median A1C 7.5 percent).

65 The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572
11,140 patients with DM2 Mean age – 66 yrs Baseline A1C - 7.5% Intensive glucose control vs. standard control Median f/up 5 yrs 1º end-points: major macro- and micro vascular events Intensive Standard RR reduction A1C 6.5% 7.3% Major microvascular 9.4% 10.9% 14% * New/worsening nephropathy 4.1% 5.2% 21%* New onset microalbuminuria 23.7% 25.7% 9% * Major macrovascular 10.0% 10.6% 6% Mean duration of DM – 8 yrs * P-value < 0.05 The ADVANCE Collaborative Group. N Engl J Med 2008;358:

66 ADVANCE Mean glycated hemoglobin level was lower in the intensive- control group (6.5%) than in the standard-control group (7.3%) Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1% vs 20.0% with standard control; hazard ratio 0.90, 95% confidence interval (CI), 0.82 to 0.98; p=0.01) reduced the incidence of major microvascular events (9.4% vs 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; p=0.01) This occurred primarily because of a reduction in the incidence of the nephropathy (4.1% vs 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; p=0.006) with NO effect on retinopathy (p=0.50)

67 ADVANCE NO significant effects of the type of glucose control for:
major macrovascular events (hazard ratio with intensive control 0.94; 95% CI, 0.84 to 1.06; p=0.32) death from CV causes (hazard ratio with intensive control 0.88; 95% CI, 0.74 to 1.04; p=0.12) death from any cause (hazard ratio with intensive control 0.93; 95% CI, 0.83 to 1.06; p=0.28)

68 ADVANCE Intensive control that resulted in HbA1c of 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy

69 DCCT 1441 patients with DM1 Age: 13-39
No history of cardiovascular disease IIT vs. conventional IT for 6.5 yrs 1º prevention group: Retinopathy Neuropathy Nephropathy Intensive Standard RR reduction A1C 7.4% 9.1% New retinopathy 1.2 per 100 pt-yr 4.7 per 100 pt-yr 76%* Microalbuminuria 2.2 per 100 pt-yr 3.4 per 100 pt-yr 34%* Clinical neuropathy 3.1 per 100 pt-yr 9.8 per 100 pt-yr 68%* Macrovascular disease 0.5 per 100 pt-yr 0.8 per 100 pt-yr 41% ½ w/o and ½ with clinical retinopathy * P-value < 0.05 The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:

70 EDIC 93% of DCCT patients f/up for additional 11 yrs
At the end of the DCCT: the conventional-treatment group intensive treatment (all participants returned to their own health care providers for diabetes care) No hx of cardiovascular disease IIT vs. conventional IT for 6.5 yrs 1º prevention group: Retinopathy Neuropathy Nephropathy Year 11th of EDIC Intensive Standard RR reduction A1C 7.9% 7.8% Microalbuminuria 9% 17% 38%* Cr>2.0 0% 2.0% 46%* Progressive retinopathy 6% 21% 75%* Major CV events 0.38 per 100 pt-yr 0.8% per 100 pt-yr 42%* Non-fatal MI CVA, death from CVD 11 25 57%* Glycosylated hemoglobin values were measured quarterly and fasting lipid levels, serum creatinine values, and other risk factors for cardiovascular disease were measured annually in a central laboratory. Microalbuminuria and albuminuria were defined by urinary albumin excretion of at least 40 mg in a 24-hour period and of at least 300 mg in a 24-hour period, respectively. Renal disease was defined by the development of a serum creatinine level of at least 2 mg per deciliter (177 µmol per liter) or the need for dialysis or kidney transplantation. Electrocardiograms were obtained and examined annually by readers who were unaware of patients' treatment assignments. During the EDIC follow-up study, the methods used in the DCCT were continued, but glycosylated hemoglobin was measured annually and fasting lipid levels and renal function were measured in alternate years. Epidemiology of diabetes interventions and Complications (EDIC, ) follow-up study

71 EDIC Goal : examine the longer term effects of the original DCCT interventions (applied to cardiovascular, retinal and renal complications) Discovered the long term “imprinting” effects (metabolic memory) of the previous intensive and standard treatments Established (first time) the role of intensive therapy and chronic glycemia with regard to atherosclerosis (DCCT/EDIC Research Group. Epidemiology of Diabetes Interventions and Complications (EDIC). Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort. Diabetes Care 1999; 22:

72 United Kingdom Prospective Diabetes Study (UKPDS)
3867 patients with newly diagnosed DM2 Randomized to conventional-therapy group (diet alone) or intensive-therapy group: sulfonylurea (chlorpropamide, glibenclamide, glipizide) or insulin Metformin added to sulfonylurea if optimal control not achieved Insulin initiated if combination of oral agents was ineffective Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998 Sep 12;352(9131):

73 United Kingdom Prospective Diabetes Study (UKPDS)
Drugs added to conventional group if symptoms of hyperglycemia or FPG>270 mg/dl Goal of therapy: FPG<108 mg/dl Microvascular and Macrovascular complications examined

74 UKPDS: results 11 percent reduction in A1C ( 7.0% vs. 7.9%)
25 percent risk reduction in microvascular disease (P = 0.001) defined as renal failure, death from renal failure, retinal photocoagulation, or vitreous hemorrhage

75 UKPDS: results No reduction in macrovascular disease
More hypoglycemic episodes and weight gain in the intensive therapy group

76 10 year follow-up of intensive glucose control in type 2 diabetes
United Kingdom Prospective Diabetes Study (UKPDS) patients in conventional or intensive therapy Post-trial monitor – 3277 patients followed up: first 5 years: annual UKPDS clinic visits (no attempts to maintain previously assigned therapy) years 6 – 10: annual questionnaires 10 year follow-up of intensive glucose control in type 2 diabetes. R Holman et al. NEJM 2008;359:

77 10 year follow-up of intensive glucose control in type 2 diabetes
Results HbA1c: differences between groups in were lost after the first year Sulfonylurea-insulin group: any diabetes-related end point- relative risk reduction persisted at 10 years (9%, p=0.04) microvascular disease - relative risk reduction persisted at 10 years (24%, p=0.001) myocardial infarction - risk reduction emerged over time (15%, p=0.01) death from any cause - risk reduction emerged over time (13%, p=0.007) Metformin group: any diabetes-related end point - significant risk reductions persisted (21%, p=0.010) myocardial infarction - significant risk reductions persisted (33%, p=0.005) death from any cause - significant risk reductions persisted (27%, p=0.002) 10 year follow-up of intensive glucose control in type 2 diabetes. R Holman et al. NEJM 2008;359:

78 Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes
1791 military veterans with suboptimal response to therapy for type 2 DM mean age: 60.4 years Mean number of years since diagnosis with diabetes: 11.5 40% had already had one CV event 2 groups intensive glucose control standard glucose control Goal: absolute reduction of 1.5 percentage points in HbA1c in intensive treatment group compared to the standard treatment Primary outcome: time from randomization to first major CV event Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. Duckworth W et al. NEJM 2009;360:

79 Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes
Follow-up: 5.6 years Primary outcome occurred in 264 patients in the standard treatment group vs 235 patients in the intensive therapy group (HR: 0.88; 95%CI, 0.74 to 1.05; p=0.14) Median glycated hemoglobin levels were 8.4% in the standard therapy group vs 6.9% in the intensive-treatment group. Rate of adverse events were 17.6% in the standard therapy group and 24.1% in the intensive therapy group (p=0.05). Hypoglycemia (most common side effect) occurred significantly more in the intensive treatment group than in the standard treatment group (p<0.001)

80 Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes
Results NO significant difference between the 2 groups in any component of the primary outcome (the time from randomization to a major CV event) or in the rate of death from any cause. NO difference between the 2 groups was observed for microvascular complications Note! Correction: progression of microalbuminuria favors intensive therapy group (9.1% vs % in a standard group, P=0.04).* * N ENGL J MED 361;10, September 3, 2009

81 Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes
160 patients with type 2 diabetes mellitus and persistent microalbuminuria Intensive, target-driven treatment Conventional multifactorial treatment Targets: - HbA1c < 6.5% - fasting serum total cholesterol < 175 mg/dl (4.5 mmol/l) - fasting serum triglyceride < 150 mg/dl (1.7 mmol per liter) - blood pressure: systolic <130 mm Hg, diastolic < 80 mm Hg. Followed for a mean of 5.5 years Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes. Gæde P, M.D., D.M.Sc., Lund-Andersen H, M.D., D.M.Sc., Parving H, M.D., D.M.Sc., and Pedersen O, M.D., D.M.Sc. N Engl J Med Feb 7;358(6):

82 Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes: End points
Primary end point: time to death from any cause Secondary end points: death from cardiovascular causes a composite of cardiovascular disease events (death from cardiovascular causes, nonfatal stroke, nonfatal myocardial infarction, coronary-artery bypass grafting, percutaneous coronary intervention or revascularization for peripheral atherosclerotic arterial disease, and amputation because of ischemia) Tertiary end points: incident diabetic nephropathy development or progression of diabetic retinopathy or neuropathy

83 Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes: Results
Intensive group 24 patients died (30%) vs 40 patients (50%) in the conventional treatment group (hazard ratio for death in the intensive group vs conventional group: 0.54; 95% confidence interval, 0.32 to 0.89; p=0.02)

84 Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes: Results
Lower risk of death from cardiovascular causes (HR 0.43; 95% CI, 0.19 to 0.94; p=0.04) compared to conventional treatment group Lower risk of cardiovascular events (HR 0.41; 95% CI, 0.25 to ; p<0.001) vs conventional treatment group 1 patient had progression to end-stage renal disease vs 6 patients in the conventional treatment group (p=0.04) Fewer patients required retinal photocoagulation (relative risk, 0.45; 95% CI, 0.23 to 0.86; p=0.02) compared to the other group

85 Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes
Meta-analysis Searches published literature, FDA website, GlaxoSmithKline clinical trial registry Inclusion criteria study duration > 24 weeks, use of a control group not receiving rosiglitazone, availability of outcome data for myocardial infarction and death from cardiovascular causes Included: 42 trials (out of 116 potentially relevant trials) Tabulated all occurrences of myocardial infarction and death from any cardiovascular causes Mean age of subjects: 56 years Mean baseline HbA1c: 8.2% S.E. Nissen, M.D., and K. Wolski, M.P.H. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. NEJM 2007; 356:

86 Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes
Results Myocardial infarction: OR=1.43 in the rosiglitazone group compared with the control group (95% CI, 1.03 to 1.98; p=0.03) Death from cardiovascular causes: OR=1.64 in the rosiglitazone group compared with the control group (95% CI, 0.98 to 2.74; p=0.06) S.E. Nissen, M.D., and K. Wolski, M.P.H. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. NEJM 2007; 356:

87 Double-blind, randomized, controlled clinical trial
Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy ADOPT - A Diabetes Outcome Progression Trial Evaluate rosiglitazone, metformin and glyburide as initial treatment for recently diagnosed type 2 diabetes Double-blind, randomized, controlled clinical trial 4360 patients enrolled Median treatment time: 4.0 years Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. S E Kahn et al. NEJM 2006;355:

88 Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy
Outcomes Primary outcome: time to monotherapy failure (FPG> 180 mg/dl) for rosiglitazone, as compared to metformin or glyburide Secondary outcomes: FPG levels, glycated hemoglobin, insulin sensitivity, and beta-cell function

89 Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy
Results 5 years cumulative incidence of monotherapy failure: 15% with rosiglitazone, 21% with metformin, 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone as compared with metformin and 64% as compared with glyburide (p<0.01 for both) Risk of cardiovascular (CV) events: glyburide was associated with lower CV risk than rosiglitazone (p<0.05) and risk was similar between the rosiglitazone group and metformin group Rosiglitazone was associated with more weight gain and edema than either glyburide or metformin; less hypoglycemia than glyburide and less GI effects than metformin (p<0.001 for all) Rosiglitazone was associated with a higher rate of fractures in women

90 Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD)
Design To evaluate long-term impact of rosiglitazone on cardiovascular outcomes and blood glucose control, compared to the conventional medications metformin and sulfonylureas 338 centers in 23 countries, 5.5 years duration randomized 4447 people with type 2 diabetes who were already taking metformin or sulfonylurea alone

91 Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD)
4447 people with type 2 diabetes with mean HbA1c: 7.9%, who were already taking metformin or sulfonylurea alone 1. Add-on rosiglitazone 2. Combination of metformin and sulfonylurea Goal: HbA1c: 7.0 or less If HbA1c >8.5 Add a third oral glucose-lowering agent Add insulin

92 Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD)
On the composite outcomes of cardiovascular death, stroke and heart attack the result was slightly but not statistically significant in favor of rosiglitazone Rosiglitazone was shown to be superior in controlling blood glucose than older metformin and sulfonylurea therapies Found a double risk for heart failure Found an increased risk of arm and lower leg fractures in women

93 Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) study
Evaluated the cardiovascular treatment approach compared to a diabetes control approach in persons with type 2 diabetes and stable coronary artery disease to reduce deaths or deaths and cardiovascular events (MI, stroke) combined 2368 people with stable heart disease and type 2 diabetes 5 years average follow up A Randomized Trial of Therapies for Type 2 Diabetes and Coronary Artery Disease.The BARI 2D Study Group. NEJM, 360:

94 Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) study
Prompt bypass surgery or angioplasty does NOT lower mortality risk compared to drug therapy in people with type 2 diabetes and stable heart disease. No difference in mortality risk between drugs that reduce insulin resistance and drugs that provide insulin

95 Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) study
No increase in heart attacks was observed in the rosiglitazone group Prompt CABG had significantly better outcomes when compared to medical treatment alone when CV events were considered in addition to death (non-fatal MI) Among the subgroup of patients pre-identified as candidates for CABG, the subgroup that received prompt surgery had fewer heart attacks or strokes compared to those receiving intensive medical therapy alone

96 Diabetes: diagnosis, classification, management
Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals

97 Glycemic goals: non-pregnant adults with diabetes
HbA1c < 7.0% Preprandial capillary plasma glucose mg/dl ( mmol/l) Peak postprandial capillary plasma glucose < 180 mg/dl (< 10.0 mmol/l)* Key concepts in setting glycemic goals HbA1c is the primary target for glycemic control Goals should be individualized based on: duration of diabetes age/life expectancy comorbid conditions known CVD or advanced microvascular complications hypoglycemia unawareness individual patient considerations More or less stringent glycemic goals may be appropriate for individual patients Postprandial glucose may be targeted if HbA1c goals are not met despite reaching preprandial glucose goals * Postprandial measurements should be made 1-2 h after the beginning of the meal, generally peak levels in patients with diabetes. Standards of Medical Care in Diabetes–2009. ADA Position Statement. Diabetes Care;32:S13-S61.

98 Glycemic goals - pregnant adults with diabetes
Women with GDM Maternal capillary glucose concentrations: preprandial:≤95 mg/dl (5.3 mmol/l) and either 1-h postmeal: ≤140 mg/dl (7.8 mmol/l) Women with preexisting diabetes who become pregnant Maternal capillary glucose concentrations: premeal, bedtime, and overnight: 60-99mg/dl Peak postprandial: mg/dl HbA1c <6.0%

99 Road Maps to Achieve Glycemic Control In Type 2 Diabetes Mellitus
ACE/AACE Diabetes Road Map Task Force Chairpersons Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Task Force Members Lawrence Blonde, MD, FACP, FACE Daniel Einhorn, MD, FACP, FACE George Grunberger, MD, FACP, FACE Yehuda Handelsman, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Harold Lebovitz, MD, FACE Philip Levy, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE © 2008 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE. Revision April 2008

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101 ADA Treatment Algorithm
Algorithm for the metabolic management of type 2 diabetes; Reinforce lifestyle interventions at every visit and check A1C every 3 months until A1C is <7% and then at least every 6 months. The interventions should be changed if A1C is ≥7%. a)Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide. b)Insufficient clinical use to be confident regarding safety.

102 Coming Attractions Insulin therapy in outpatient and inpatient settings Glycemic control and inpatient outcomes Agustin Busta,MD Assistant Professor Albert Einstein College of Medicine 2009

103 Coming Attractions Medical Nutrition Therapy for Diabetes Does a perfect eating plan exist? Jennifer Regester, RD, CDN

104 Coming Attractions Medical Nutrition Therapy
Review goals and outcomes of MNT Discuss basic recommendations for MNT Review specific recommendations for patient population groups

105 Coming Attractions “What Do I Eat?”
Discuss lifestyle changes including diet and exercise Review basic nutrition recommendations and how to give nutrition advice Provide follow-up resources

106 Coming Attractions Diabetes Technology Update
Glucose Monitoring Systems - Glucose Meters - CGMS Insulin Delivery Modes - Syringes - Insulin Pens - Jet Injectors - Insulin Pumps Marina Krymskaya, ANP, CDE In the last few decades, there has been much progress in diabetes management. Due to technological advancements, patients whose lives are affected by diabetes are able to take advantage of more comfortable methods in checking their glucose and administering insulin.

107 (Answer: detect sugar)
Coming Attractions What do these pictures have in common? Glucose monitoring systems have come a long way. In the past, ants were utilized to detect diabetes. High concentration of sugar spilled into the urine would attract these insects. So, we can call it the ANTcient method. Currently, there are faster and more effective methods, which include continuous wireless transmission of the blood glucose readings from the sensor on the skin to the portable receiver. The quality of this modern technology has significantly improved diabetes management. (Answer: detect sugar)

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