diabetes: diagnosis, classification, management

Diabetes:Diagnosis, Classification, Management

Controversies and News

Diabetes:Diagnosis, Classification, Management

Controversies and News

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

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

Bianca Alfonso, MD Bianca Alfonso, MD Endocrinology Fellow, Year 1Endocrinology Fellow, Year 1

Marina Krymskaya, ANP, CDE Diabetes Nurse Educator

Jill Gregory Medical Illustrator

Diabetes Care Enhancement InitiativeDiabetes 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 [email protected]

or 212-420-2062

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 [email protected]

or 212-420-2062

mailto:[email protected]

mailto:[email protected]

Diabetes:diagnosis, classification, management


Definition Epidemiology Classification Diagnosis Treatment Evidence Treatment goals


DefinitionDefinition

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. ** http://science.jrank.org/pages/2044/Diabetes-Mellitus.html

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. ** http://science.jrank.org/pages/2044/Diabetes-Mellitus.html

EpidemiologyEpidemiology

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

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

ClassificationClassification

Type 1 diabetes Type 2 diabetes Other

1. Genetic defects of beta cell function2. Genetic defects in insulin action3. Diseases of the exocrine pancreas4. Endocrinopathies5. Drug/ chemical - induced 6. Infections7. Uncommon forms of immune-mediated diabetes8. Genetic syndromes sometimes associated with diabetes

Gestational diabetes mellitus

Type 1 diabetes Type 2 diabetes Other

1. Genetic defects of beta cell function2. Genetic defects in insulin action3. Diseases of the exocrine pancreas4. Endocrinopathies5. Drug/ chemical - induced 6. Infections7. Uncommon forms of immune-mediated diabetes8. Genetic syndromes sometimes associated with diabetes

Gestational diabetes mellitus

Type 1 diabetesType 1 diabetes

A. Immune-mediated B. Idiopathic

Type 1 diabetes is characterized by β-cell destruction, usually leading to absolute insulin deficiency.*

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.* Diagnosis and Classification of Diabetes Mellitus. ADA 2009.

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

Type 1 diabetes mellitus – immune mediated 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)

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)

Type 2 diabetesType 2 diabetes

Hyperglycemia

Insulin resistance

Relative impairment in insulin secretion.

Hyperglycemia

Insulin resistance

Relative impairment in insulin secretion.

cell dysfunction and insulin resistance produce hyperglycemia in type 2 diabetes

cell dysfunction and insulin resistance produce hyperglycemia in type 2 diabetes

Pancreas

Insulin Resistance

Liver

HyperglycemiaHyperglycemia

Islet Cell Degranulation;Reduced Insulin Content

Muscle Adipose Tissue

Decreased Glucose Transport & Activity

(expression) of GLUT4

Increased Lipolysis

↑GlucoseProduction

↓GlucoseUptake

ReducedPlasma Insulin

Increased Glucose Output

Cell Dysfunction

Elevated Plasma FFA

Elevated Plasma FFA

Other specific types of diabetes – Genetic defects of beta cell functionOther specific types of diabetes –

Genetic defects of beta cell function

Maturity–onset diabetes of the young (MODY)

6 subtypes

Maturity–onset diabetes of the young (MODY)

6 subtypes

Maturity:Onset diabetes of the young (MODY)

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

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

Other specific types of diabetes: Genetic defects in insulin actionOther specific types of diabetes: Genetic defects in insulin action

Type A insulin resistance

Leprechaunism

Rabson- Mendenhall syndrome

Lipoatrophic diabetes

Others

Type A insulin resistance

Leprechaunism

Rabson- Mendenhall syndrome

Lipoatrophic diabetes

Others

*A clinical screening tool identifies autoimmune diabetes in adults. Fourlanos S; Perry C; Stein MS; Stankovich J; Harrison LC; Colman PG. Diabetes Care. 2006 May;29(5):970-5

Latent Autoimmune Diabetes in Adults (LADA)

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

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

Gestational DMGestational DMDefinition 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

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

DiagnosisDiagnosis

Diabetes mellitus

Impaired fasting glucose (IFG)

Impaired glucose tolerance (IGT)

Gestational diabetes mellitus (GDM)

Diabetes mellitus

Impaired fasting glucose (IFG)

Impaired glucose tolerance (IGT)

Gestational diabetes mellitus (GDM)

Diagnosis: Diabetes mellitusDiagnosis: Diabetes mellitus

1. Symptoms of diabetes (polydipsia, polyuria, unexplained weight loss) PLUS a random plasma glucose >200 mg/dL (11.1 mmol/L)

or2. Fasting plasma glucose > 126 mg/dL (7.0 mmol/L) after overnight

(at least 8 hours) fastor

3. 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

1. Symptoms of diabetes (polydipsia, polyuria, unexplained weight loss) PLUS a random plasma glucose >200 mg/dL (11.1 mmol/L)

or2. Fasting plasma glucose > 126 mg/dL (7.0 mmol/L) after overnight

(at least 8 hours) fastor

3. 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

Diagnosis: Impaired fasting glucose (IFG)Diagnosis: Impaired fasting glucose (IFG)

Fasting plasma glucose (FPG) < 100 mg/dl (5.6 mmol/l) = normal

FPG 100-125 mg/dl (5.6-6.9 mmol/l) = impaired fasting glucose (IFG)

Fasting plasma glucose (FPG) < 100 mg/dl (5.6 mmol/l) = normal

FPG 100-125 mg/dl (5.6-6.9 mmol/l) = impaired fasting glucose (IFG)

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 140 - 199 mg/dl (7.8 – 11.1 mmol/l) = 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 140 - 199 mg/dl (7.8 – 11.1 mmol/l) = impaired glucose tolerance (IGT)

Diagnosis: Impaired glucose tolerance (IGT)Diagnosis: Impaired glucose tolerance (IGT)

Diagnosis: Gestational Diabetes Mellitus (GDM)

Diagnosis: Gestational Diabetes Mellitus (GDM)

1. Unequivocal hyperglycemia(confirmed on a subsequent day)

2. Diagnostic OGTT

Fasting plasma glucose > 126 mg/dL > 126 mg/dL (7.0 mmol/L)(7.0 mmol/L)

Random plasma glucose >200 mg/dL Random plasma glucose >200 mg/dL (11.1 mmol/L)(11.1 mmol/L)

OR

100-g glucose load

mg/dl mmol/l

Fasting 95 5.3

1-h 180 10.0

2-h 155 8.6

3-h 140 7.8

TreatmentTreatment

Lifestyle intervention

Hypoglycemic drugs oral hypoglycemic drugs insulin and insulin analogs others (incretins, pramlintide)

Lifestyle intervention

Hypoglycemic drugs oral hypoglycemic drugs insulin and insulin analogs others (incretins, pramlintide)

Treatment:Lifestyle Interventions

Treatment:Lifestyle Interventions

Weight loss

Increased exercise

Weight loss

Increased exercise

Treatment:Oral Antihyperglycemic Drugs


Biguanides Sulfonylureas Meglitinide analogs Thiazolidinediones -Glucosidase Inhibitors DPP-4 Inhibitors

Biguanides Sulfonylureas Meglitinide analogs Thiazolidinediones -Glucosidase Inhibitors DPP-4 Inhibitors

Oral antihyperglycemic drugs: Biguanides

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

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

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 pp213-226

Oral antihyperglycemic drugs: MetforminOral antihyperglycemic drugs: Metformin

Oral antihyperglycemic drugs: Sulfonylureas

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

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

Black C, Donnelly P, McIntyre L et al. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD004654.

Oral antihyperglycemic drugs: Meglitinide analogs

Oral antihyperglycemic drugs: Meglitinide analogs

Repaglinide (Prandin) Nateglinide (Starlix)

enhance insulin secretion (early-phase insulin release) lower HbA1c by 0.1- 2.1 % (repaglinide) and by 0.2-

0.6% (nateglinide) side effects: weight gain, hypoglycemia

Repaglinide (Prandin) Nateglinide (Starlix)

enhance insulin secretion (early-phase insulin release) lower HbA1c by 0.1- 2.1 % (repaglinide) and by 0.2-

0.6% (nateglinide) side effects: weight gain, hypoglycemia

Oral antihyperglycemic drugs: Thiazolidinediones (TZDs)

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 0.5 - 1.4 % adverse effects: weight gain, fluid retention

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 0.5 - 1.4 % adverse effects: weight gain, fluid retention

Oral antihyperglycemic drugs:-Glucosidase Inhibitors

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

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

Oral antihyperglycemic drugs: DPP-IV inibitors

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

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

Oral antihyperglycemic drugs - Sitagliptin (Januvia)

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

Used alone or in combination with metformin or TZDs

Reduces HbA1c by 0.5 – 0.7 %

Side effects: increased rate of respiratory infections, headaches

"Januvia" by Byron Rubin"Januvia" by Byron Rubin

Sculpture was installed at the West Point Pennsylvania Merck location.

Sculpture was installed at the West Point Pennsylvania Merck location.

Other antihyperglycemic drugs: Incretins

Other antihyperglycemic drugs: Incretins

Exenatide (Byetta) glucagon-like peptide 1 (GLP-1) agonist

Exenatide (Byetta) glucagon-like peptide 1 (GLP-1) agonist

Antihyperglycemic drugs: Exenatide (Byetta)Antihyperglycemic drugs: Exenatide (Byetta)

Glucagon-like Peptide - 1Glucagon-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.

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.

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 al. @ http://www.byettahcp.com/hcp/hcp_incretin_effect.jsp

Incretin EffectIncretin Effect

Antihyperglycemic drugs:Exenatide (Byetta)


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

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



Added to metformin or sulfonylureas will reduce HbA1c by 0.4-0.6 %

Side effects: nausea (dose-depended, declines with time) acute pancreatitis (some necrotizing or hemorrhagic

pancreatitis cases reported as well)

Added to metformin or sulfonylureas will reduce HbA1c by 0.4-0.6 %

Side effects: nausea (dose-depended, declines with time) acute pancreatitis (some necrotizing or hemorrhagic

pancreatitis cases reported as well)

Antihyperglycemic drugs: OthersAntihyperglycemic drugs: Others

Pramlintide (Symlin) synthetic analog of amylin

Pramlintide (Symlin) synthetic analog of amylin

AmylinAmylin

Stored in insulin secretory granules in the ß-cells

Co-secreted with insulin Decreases glucagon Satiety signal? Decreases GI motility

Stored in insulin secretory granules in the ß-cells

Co-secreted with insulin Decreases glucagon Satiety signal? Decreases GI motility

Antihyperglycemic drugs:Pramlintide (Symlin)


Delays gastric emptying, suppresses glucagon secretion, decreases appetite

Associated with weight loss (1 - 1.5 kg over 6 months)

Used only in conjunction with insulin treatment Reduces HbA1c by 0.5 - 0.7 % Side effects: nausea, gastro-intestinal symptoms

Delays gastric emptying, suppresses glucagon secretion, decreases appetite

Associated with weight loss (1 - 1.5 kg over 6 months)

Used only in conjunction with insulin treatment Reduces HbA1c by 0.5 - 0.7 % Side effects: nausea, gastro-intestinal symptoms

Product (Manufacturer) Form

Rapid Acting (Onset 15-30 min, duration hrs 3-4)

Insulin Analog

Aspart - Novolog (Novo Nordisk)

Lispro - Humalog (Lilly)

Glulisine – Apidra (Aventis)

Analog**

Analog**

Short Acting (Onset 0.5-1 hr, duration hrs 5-7)*

Human Insulin

Novolin R (Rugular) (Novo Nordisk)

Humulin R (Regular) (Lilly)

Human**

Human**

Purified Insulin

Regular Iletin II (Lilly) Pork

Intermediate Acting (Onset 1-4 hrs, duration hrs 18-24)*

Human Insulin

Novolin N (NPH) (Lilly)

Humulin N (NPH) (Lilly)

Humulin L (Lente) (Lilly)

Human**

Human**

Human**

Purified Insulin

NPH Iletin III (Lilly) Pork

Long Acting (Onset 4-6 hrs, duration hrs 24-34)*

Human Insulin

Humulin Ultralente (Lilly) Human**

Basal Peakless Insulin

Glargine-Lantus (Aventis)

Detemir – Levemir (Novo Nordisk)

Analog**

Analog**

Mixed Insulins

70/30 Insulin

Novolin 70/30 (Novo Nordisk)

Humulin 70/30 (Lilly)

Humulin 50/50 (Lilly)

Humalog 50/50

Human**

Human**

Human**

Analog**

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**

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**

Human**

Human**

Analog**

Human**

Human**

Human**

Analog**

Analog**

Analog**

Analog**

Analog**

Human**

Analog**

* 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

AVAILABLE INSULIN PREPARATIONS

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.

ADA Treatment AlgorithmADA Treatment Algorithm

EvidenceEvidence

ACCORDACCORD

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

10,251 patients with DM2 Mean age – 62.2 yrs Baseline A1C – 8.1% Intensive glucose


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%

The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559

* P-value < 0.05

ACCORDACCORD 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 %.

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 %.

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 0.78-1.04).

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 0.78-1.04).

* hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04* hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04

ACCORDACCORD

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).

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).

ACCORDACCORD

ADVANCEADVANCE

11,140 patients with DM2

Mean age – 66 yrs Baseline A1C - 7.5% Intensive glucose


Median f/up 5 yrs 1º end-points: major

macro- and micro vascular events

11,140 patients with DM2

Mean age – 66 yrs Baseline A1C - 7.5% Intensive glucose


Median f/up 5 yrs 1º end-points: major

macro- and micro vascular events


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%

The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572

* P-value < 0.05

ADVANCEADVANCE

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)

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)

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)

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)

ADVANCEADVANCE

ADVANCEADVANCE

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

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

The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986

* P-value < 0.05

DCCTDCCT

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

1441 patients with DM1 Age: 13-39 No history of

cardiovascular disease IIT vs. conventional IT

for 6.5 yrs 1º prevention group:



A1C 7.4% 9.1%New retinopathy 1.2 per 100

pt-yr4.7 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%

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 totheir own health careproviders for diabetes care)

No hx of cardiovascular disease IIT vs. conventional IT for 6.5

yrs 1º prevention group:


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 totheir own health careproviders for diabetes care)

No hx of cardiovascular disease IIT vs. conventional IT for 6.5

yrs 1º prevention group:


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%*

Epidemiology of diabetes interventions and Complications (EDIC, 1994- 2006) follow-up study

EDICEDIC

(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: 99- 111.

EDICEDIC 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

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

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):837-53.

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

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



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

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

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

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

UKPDS: resultsUKPDS: results

UKPDS: resultsUKPDS: results

No reduction in macrovascular disease

More hypoglycemic episodes and weight gain in the intensive therapy group

No reduction in macrovascular disease

More hypoglycemic episodes and weight gain in the intensive therapy group

10 year follow-up of intensive glucose control in type 2 diabetes. R Holman et al. 10 year follow-up of intensive glucose control in type 2 diabetes. R Holman et al. NEJMNEJM 2008;359:1577-89 2008;359:1577-89

10 year follow-up of intensive glucose control in type 2 diabetes


United Kingdom Prospective Diabetes Study (UKPDS)- 4209 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

United Kingdom Prospective Diabetes Study (UKPDS)- 4209 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. 10 year follow-up of intensive glucose control in type 2 diabetes. R Holman et al. NEJMNEJM 2008;359:1577-89 2008;359:1577-89



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)

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)

Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. Duckworth W et al. NEJM 2009;360:129-139

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

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



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)

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)


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. 13.8 % in a standard group, P=0.04).*

* N ENGL J MED 361;10, September 3, 2009

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes.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. 2008 Feb 7;358(6):580-91.

160 patients with type 2 diabetes mellitus and persistent microalbuminuria 160 patients with type 2 diabetes mellitus and persistent microalbuminuria

Intensive, target-driven treatment Conventional multifactorial treatment

Followed for a mean of 5.5 years

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.

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes: End points

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes: End points

1. Primary end point: time to death from any cause

2. 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)

3. Tertiary end points: incident diabetic nephropathy development or progression of diabetic retinopathy or neuropathy

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)

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)



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 0.0.67; 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

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 0.0.67; 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

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; 356:2457-2471

Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular CausesEffect 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%

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; 356:2457-2471

Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular CausesEffect 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)

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)

Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. S E Kahn et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. S E Kahn et al. NEJMNEJM 2006;355:2427-43 2006;355:2427-43

Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy

ADOPT - A Diabetes Outcome Progression Trial


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

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



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

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



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

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

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

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



4447 people with type 2 diabetes with mean HbA1c: 7.9%, who were already taking metformin or sulfonylurea alone

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



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

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

A Randomized Trial of Therapies for Type 2 Diabetes and Coronary Artery Disease.The BARI 2D Study Group. NEJM, 360:2503-2515

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

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



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

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



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

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

* 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.

Glycemic goals: non-pregnant adults with diabetesGlycemic goals: non-pregnant adults with diabetes HbA1c < 7.0% Preprandial capillary plasma glucose 70-130 mg/dl (3.9-7.2 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

HbA1c < 7.0% Preprandial capillary plasma glucose 70-130 mg/dl (3.9-7.2 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

Glycemic goals - pregnant adults with diabetesGlycemic 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 GDM


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


premeal, bedtime, and overnight: 60-99mg/dl

Peak postprandial: 100-129 mg/dl

HbA1c <6.0%

Women with preexisting diabetes who become pregnant


premeal, bedtime, and overnight: 60-99mg/dl

Peak postprandial: 100-129 mg/dl

HbA1c <6.0%

Road Maps to Achieve Glycemic Control

In Type 2 Diabetes Mellitus

ACE/AACE Diabetes Road Map Task Force

ChairpersonsPaul S. Jellinger, MD, MACE, Co-Chair

Jaime A. Davidson, MD, FACE, Co-Chair

Task Force MembersLawrence 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, reproducedor distributed in any form without the express permission of AACE.

Revision April 2008

www.medscape.com/viewarticle/559463

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.

ADA Treatment AlgorithmADA Treatment Algorithm

Coming Attractions

• Insulin therapy in outpatient and inpatient settings

• Glycemic control and inpatient outcomes

Agustin Busta,MDAssistant ProfessorAlbert Einstein College of Medicine2009

Medical Nutrition Therapy for DiabetesDoes a perfect eating plan exist?

Jennifer Regester, RD, CDN

Medical Nutrition Therapy for DiabetesDoes a perfect eating plan exist?

Jennifer Regester, RD, CDN

Coming Attractions

Medical Nutrition Therapy

Review goals and outcomes of MNT Discuss basic recommendations for MNT Review specific recommendations for patient

population groups

Medical Nutrition Therapy

Review goals and outcomes of MNT Discuss basic recommendations for MNT Review specific recommendations for patient

population groups

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

“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

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

Diabetes Technology Update Glucose Monitoring Systems - Glucose Meters

- CGMS Insulin Delivery Modes - Syringes

- Insulin Pens

- Jet Injectors

- Insulin Pumps

Marina Krymskaya, ANP, CDE

Coming Attractions

Coming Attractions

What do these pictures have in common?

diabetes: diagnosis, classification, management

Health & Medicine