Download Diabetes: 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
Bianca Alfonso, MD
Endocrinology Fellow, Year 1
Marina Krymskaya, ANP, CDE
Diabetes Nurse Educator
Jill Gregory
Medical Illustrator
Diabetes Care Enhancement Initiative
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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:
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Clinical aspects:
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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;
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:
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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
Diabetes:
diagnosis, classification, management
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Definition
Epidemiology
Classification
Diagnosis
Treatment
Evidence
Treatment goals
Diabetes:
diagnosis, classification, management
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Definition
Epidemiology
Classification
Diagnosis
Treatment
Evidence
Treatment goals
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.
**
http://science.jrank.org/pages/2044/Diabetes-Mellitus.html
Diabetes:
diagnosis, classification, management
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Definition
Epidemiology
Classification
Diagnosis
Treatment
Evidence
Treatment goals
Epidemiology
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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
Diabetes:
diagnosis, classification, management
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Definition
Epidemiology
Classification
Diagnosis
Treatment
Evidence
Treatment goals
Classification
Type 1 diabetes
Type 2 diabetes
Other
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1.
2.
3.
4.
5.
6.
7.
8.
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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
Type 1 diabetes
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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.
Atkinson MA and Eisenbarth GS. Lancet 2001;358:221-229.
Type 1 diabetes mellitus – immune mediated
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Absolute insulin deficiency
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Usually due to autoimmune destruction of the
pancreatic beta cells
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Islet-cell antibodies (ICA) or other autoantibodies
(antibodies to glutamic acid decarboxylase [antiGAD] and anti-insulin)
Type 2 diabetes
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Hyperglycemia
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Insulin resistance
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Relative impairment in insulin secretion.
cell dysfunction and insulin resistance produce hyperglycemia in
type 2 diabetes
Insulin Resistance
Cell Dysfunction
Increased
Lipolysis
Pancreas
Liver
Islet Cell Degranulation;
Reduced Insulin Content
Increased Glucose Output
Reduced
Plasma Insulin
Hyperglycemia
↑Glucose
Production
Elevated
Plasma FFA
↓Glucose
Uptake
Muscle
Adipose Tissue
Decreased Glucose
Transport & Activity
(expression)
of GLUT4
Other specific types of diabetes –
Genetic defects of beta cell function
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Maturity–onset diabetes of the young
(MODY)
6 subtypes
Maturity:
Onset diabetes of the young (MODY)
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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 action
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Type A insulin resistance
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Leprechaunism
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Rabson- Mendenhall syndrome
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Lipoatrophic diabetes
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Others
Latent Autoimmune Diabetes in Adults
(LADA)
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Adult-onset diabetes with circulating islet antibodies
but not requiring insulin therapy initially
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Adults who should be considered for antibody
testing*:
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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. 2006 May;29(5):970-5
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
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Most have impaired glucose tolerance that begins in pregnancy
Some have previous undiagnosed type 2 diabetes mellitus
10% have circulating islet cell antibodies
Diabetes:
diagnosis, classification, management
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Definition
Epidemiology
Classification
Diagnosis
Treatment
Evidence
Treatment goals
Diagnosis
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Diabetes mellitus
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Impaired fasting glucose (IFG)
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Impaired glucose tolerance (IGT)
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Gestational diabetes mellitus (GDM)
Diagnosis: Diabetes mellitus
1.
2.
3.
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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
or
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)
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Fasting plasma glucose (FPG) < 100 mg/dl
(5.6 mmol/l) = normal
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FPG 100-125 mg/dl (5.6-6.9 mmol/l) =
impaired fasting glucose (IFG)
Diagnosis: Impaired glucose tolerance (IGT)
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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:
Gestational Diabetes Mellitus (GDM)
Fasting plasma glucose > 126 mg/dL
(7.0 mmol/L)
1. Unequivocal hyperglycemia
(confirmed on a subsequent day)
Random plasma glucose >200 mg/dL
(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
2. Diagnostic OGTT
Diabetes:
diagnosis, classification, management
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Definition
Epidemiology
Classification
Diagnosis
Treatment
Evidence
Treatment goals
Treatment
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Lifestyle intervention
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Hypoglycemic drugs
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oral hypoglycemic drugs
insulin and insulin analogs
others (incretins, pramlintide)
Treatment:
Lifestyle Interventions
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Weight loss
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Increased exercise
Treatment:
Oral Antihyperglycemic Drugs
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Biguanides
Sulfonylureas
Meglitinide analogs
Thiazolidinediones
-Glucosidase Inhibitors
DPP-4 Inhibitors
Treatment:
Oral Antihyperglycemic Drugs
Oral antihyperglycemic drugs:
Biguanides
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Metformin (Glucophage)
Extended-release metformin (Glucophage-XR)
decrease hepatic glucose output
lower fasting glycemia
reduce HbA1c by 1.5%
adverse effects: lactic acidosis, gastrointestinal disturbances
Oral antihyperglycemic drugs: Metformin
AMPK - adenosine monophosphate-activated protein kinase, ACC - acteyl-CoA carboxylase, SREPB-1 - sterolregulatory-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
Treatment:
Oral Antihyperglycemic Drugs
Oral antihyperglycemic drugs:
Sulfonylureas
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1st generation : Tolbutamide (Orinase), Tolazamide
(Tolinase), Acetohexamide (Dymelor),
Chlorpropamide (Diabinese)
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2nd generation : Glyburide (DiaBeta, Glynase)
Glipizide (Glucotrol), Glimepiride (Amaryl)
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enhance insulin secretion
lower HbA1c by 1.5 %
side effects: hypoglycemia, weight gain
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Treatment:
Oral Antihyperglycemic Drugs
Oral antihyperglycemic drugs:
Meglitinide analogs
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Repaglinide (Prandin)
Nateglinide (Starlix)
enhance insulin secretion (early-phase insulin release)
lower HbA1c by 0.1- 2.1 % (repaglinide) and by 0.20.6% (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. 2007 Apr
18;(2):CD004654.
Treatment:
Oral Antihyperglycemic Drugs
Oral antihyperglycemic drugs:
Thiazolidinediones (TZDs)
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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
Treatment:
Oral Antihyperglycemic Drugs
Oral antihyperglycemic drugs:
-Glucosidase Inhibitors
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Acarbose (Precose)
Miglitol (Glyset)
reduce the rate of digestion of polysaccharides in the
proximal small intestine, primarily lowering postprandial glucose levels
lower HbA1c by 0.5 – 0.8 %
side effects: increased gas production and gastrointestinal symptoms
Oral antihyperglycemic drugs:
DPP-IV inibitors
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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)
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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
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Sculpture was installed at the West Point
Pennsylvania Merck location.
Other antihyperglycemic drugs:
Incretins
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Exenatide (Byetta)
glucagon-like peptide 1 (GLP-1) agonist
Antihyperglycemic drugs: Exenatide (Byetta)
Glucagon-like Peptide - 1
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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:
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enhances insulin secretion
limits postprandial hyperglycemia.
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 al. @ http://www.byettahcp.com/hcp/hcp_incretin_effect.jsp
Antihyperglycemic drugs:
Exenatide (Byetta)
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active ingredient in Exenatide (Byetta) is a synthetic
version of a protein present in the saliva of the Gila
monster
Antihyperglycemic drugs:
Exenatide (Byetta)
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Added to metformin or sulfonylureas will reduce
HbA1c by 0.4-0.6 %
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Side effects:
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nausea (dose-depended, declines with time)
acute pancreatitis (some necrotizing or hemorrhagic
pancreatitis cases reported as well)
Antihyperglycemic drugs:
Exenatide (Byetta)
Antihyperglycemic drugs: Others
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Pramlintide (Symlin)
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synthetic analog of amylin
Amylin
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Stored in insulin secretory granules in the ßcells
Co-secreted with insulin
Decreases glucagon
Satiety signal?
Decreases GI motility
Antihyperglycemic drugs:
Pramlintide (Symlin)
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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
Antihyperglycemic drugs:
Pramlintide (Symlin)
AVAILABLE INSULIN PREPARATIONS
Product (Manufacturer)
Form
Product (Manufacturer)
Form
Analog**
Analog**
Analog**
Analog**
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)
Rapid Acting (Onset 15-30 min, duration hrs 3-4)
Insulin Analog
Aspart - Novolog (Novo Nordisk)
Lispro - Humalog (Lilly)
Glulisine – Apidra (Aventis)
Insulin for Special Use
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**
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
Mixed Insulins
70/30 Insulin
Novolin 70/30 (Novo Nordisk)
Humulin 70/30 (Lilly)
Humulin 50/50 (Lilly)
Humalog 50/50
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**
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 rapidand intermediate-acting insulins is similar to the fixed proportions available. bg, blood glucose.
Diabetes:
diagnosis, classification, management
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Definition
Epidemiology
Classification
Diagnosis
Treatment
Evidence
Treatment goals
Evidence
ACCORD
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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:
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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%
* P-value < 0.05
The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559
ACCORD
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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 %.
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 0.78-1.04).
* hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04
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).
ADVANCE
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
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
A1C
Intensive
Standard
6.5%
7.3%
RR
reduction
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%
* P-value < 0.05
The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572
ADVANCE

Mean glycated hemoglobin level was lower in the intensivecontrol 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)
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)
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
DCCT
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
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
A1C
7.4%
9.1%
New retinopathy
1.2 per 100
4.7 per
pt-yr
100 pt-yr
2.2 per 100
3.4 per
pt-yr
100 pt-yr
3.1 per 100
9.8 per
pt-yr
100 pt-yr
0.5 per 100
0.8 per
pt-yr
100 pt-yr
Microalbuminuria
Clinical neuropathy
Macrovascular
disease
RR
reduction
76%*
34%*
68%*
41%
* P-value < 0.05
The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986
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
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
RR
reduction
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: 99- 111.
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):837-53.
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
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
UKPDS: results

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


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. NEJM 2008;359:1577-89
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;359:1577-89
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;360:129-139
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)
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. 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
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. 2008 Feb 7;358(6):580-91.
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)
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
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
Effect of Rosiglitazone on the Risk of Myocardial
Infarction and Death from Cardiovascular Causes


Meta-analysis
Searches




Inclusion criteria







published literature,
FDA website,
GlaxoSmithKline clinical trial registry
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 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; 356:2457-2471
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;355:2427-43
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
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
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
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
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
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, 360:2503-2515
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
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
Diabetes:
diagnosis, classification, management







Definition
Epidemiology
Classification
Diagnosis
Treatment
Evidence
Treatment goals
Glycemic 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
* 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 - 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: 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
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
www.medscape.com/viewarticle/559463
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.
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
Coming Attractions
Medical Nutrition Therapy for Diabetes
Does 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
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
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
Coming Attractions
What do these pictures have in common?