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Welcome and Introduction
This presentation will:
• Define obesity, prediabetes, and diabetes
• Discuss the diagnoses and management of obesity, prediabetes, and diabetes
• Explain the early risk factors for diabetes and the rationale for aggressive treatment to delay or prevent diabetes onset
Defining Obesity – A Disease• Body Mass Index (BMI)
– Evaluates weight relative to height (kg/m2)
– Correlates highly with body fat, morbidity, and mortality
• Categories:
Handelsman Y et al. Endocr Pract. 2016;22(Suppl 1):34.
Table 6. Classification of Ov erweight and Obesity by BMI and Waist Circumference (31[EL 4; NE])
Classification
BMI Waist
BMI (kg/m2)Comorbidity
Risk
Waist Circumference andComorbidity Risk
Men < 40 in (102cm)Women < 35 in (88cm)
Men > 40 in (102cm)Women > 35 in (88cm)
Underweight <18.5 Low but other problems
Normal weight 18.5-24.9 Average
Overweight 25-29.9 Increased Increased High
Obese class I 30-34.9 Moderate High Very high
Obese class II 35-39.9 Severe Very high Very high
Obese class III >40 Very severe Extremely high Extremely high
Abbreviation s : BMI = body ma ss inde x; in = inches
BMI = body mass index.
Overweight and Obesity Prevalence Increasing Among U.S. Adults
Flegal KM et al. JAMA 2002;288:1723-27; Hedley AA et al. JAMA 2004;291:2847-50; Ogden CL et al. JAMA2006;295:1549-55; Flegal KM et al. JAMA 2012;307(5):491-7.
0.
17.5
35.
52.5
70.
87.5
1960-62 1971-74 1976-80 1988-94 1999-2002 2003-2004 2009-2010
Pre
va
len
ce
(%
) .
NHANES Data Collection Period
Overweight Obesity
NHANES = National Health and Nutrition Examination Survey.
Age-adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults
Obesity (BMI ≥30 kg/m2)
Diabetes
1994
1994
2000
2000
No Data <14.0% 14.0%–17.9% 18.0%–21.9% 22.0%–25.9% > 26.0%
No Data <4.5% 4.5%–5.9% 6.0%–7.4% 7.5%–8.9% >9.0%
CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics
2013
2013
BMI = body mass index; CDC = U.S. Center for Disease Control and Prevention.
An Expensive Epidemic
• Currently, 69% of American adults are overweight and nearly 38% are obese
• Compared to non-obese individuals, obesity adds $3,559 per patient to total annual health care costs
– This includes $1,130 per patient to annual pharmacy costs
• As much as 27.5% of annual medical spending in the U.S. is obesity-related
• In the U.S., medical costs for obesity are at least $190.2 billion per year
– Some studies estimate current obesity-related costs as high as $315.8 billion
Garvey W et al. Endocrine Practice 2016;22 (Suppl 3):1-203; Cawley J et al. PharmacoEconomics 2015;33:707-722; 2014
AACE/ACE Consensus Conference on Obesity. Executive Summary.
Available at: http://mms.businesswire.com/media/20140325006164/en/408761/1/aace.pdf
Medical Complications of Obesity
Coronary heart disease
Pulmonary diseaseabnormal functionobstructive sleep apneahypoventilation syndrome
Gall bladder disease
Gynecologic abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome
Gout
Stroke
Diabetes
Osteoarthritis
Cancerbreast, uterus, cervixcolon, esophagus, pancreaskidney, prostate
Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis
Hypertension
Dyslipidemia
Cataracts
Skin
Idiopathic intracranial hypertension
Severe pancreatitis
Phlebitisvenous stasis
Health Benefits of Modest Weight Loss
• Loss of 5% to 10% of body weight can result in:
– Decreased cardiovascular risk, blood glucose and insulin levels, blood pressure, LDL cholesterol and triglycerides, sleep apnea severity, and degenerative joint disease symptoms
– Increased HDL cholesterol
– Improvement in multiple cardiovascular risk factors, and other complications, including gynecologic conditions
Handelsman Y et al. Endocr Pract. 2016;22(Suppl 1):34.The Practical Guide to the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults;
HDL = high density lipoprotein; LDL = low density lipoprotein.
Relationship Between BMI and Risk of Type 2 Diabetes Mellitus
Chan J et al. Diabetes Care 1994;17:961.; Colditz G et al. Ann Intern Med 1995;122:481.
Age
-Ad
just
ed R
elat
ive
Ris
k
<23 24–24.9 25–26.9 27–28.9 33–34.9
0
25
50
75
100
1.0
2.9 4.3 5.08.1 15.8
27.6
40.3
54.0
93.2
<22 23–23.9 29–30.9 31–32.9 35+
1.0 1.52.2
4.4
6.711.6
21.3
42.1
1.0
Men
Women
BMI (kg/m2)
BMI = body mass index.
Adipose Tissue in Obesity
Lean
Gustafson: Arterioscler Thromb Vasc Biol, 27(11): 2276-2283, 2007
Obese
Prediabetes
Impaired Fasting Glucose (IFG):
FPG 100-125 mg/dL (5.6-6.9 mmol/l)
or
Impaired Glucose Tolerance (IGT):
2-h plasma glucose in the 75-g OGTT140-199 mg/dL (7.8-11.0 mmol/l)
or
A1C 5.7% to 6.4%
Handelsman Y et al. Endocrine Practice 2015;21 (Suppl 1)
A1C = glycated hemoglobin; FPG = fasting plasma glucose; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; OGTT = oral glucose tolerance test.
Overall incidence: 4% to 10%/year
American Diabetes Association. Diabetes Care. 2003;26:917-932.; Nathan D, et al. Diabetes Care. 2007;30(3):753-759.
Progression to Diabetes
• Over 3 to 5 years, 25% of patients with prediabetes will develop diabetes, while 50% will remain in the category of IFG or IGT; 25% will have normal glucose tolerance.
IFG = impaired fasting glucose; IGT = impaired glucose tolerance; UK = United Kingdom.
5% per year with metforminvs 10% per year by lifestyle intervention
58%
Diabetes Prevention Program: An Example of Effectiveness
Outcomes of Modest Weight Loss and Lifestyle Changes
DPP Research Group. N Engl J Med 2002;346:393-403.
Placebo
Metformin
Lifestyle
Effect of Treatment on Incidence of Diabetes
Placebo Metformin Lifestyle
Incidence of diabetes 11.0% 7.8% 4.8%
(% per year)
Reduction in incidence ---- 31% 58%
vs. placebo
Number needed to treat ---- 13.9 6.9
to prevent 1 case in 3 years
The DPP Research Group. NEJM 2002; 346:393-403
Diabetes
• Diabetes is defined as:
– Fasting blood glucose ≥ 126 mg/dL
– 2-hour postprandial glucose ≥ 200 mg/dL
– A1C ≥ 6.5%
Handelsman Y et al. Endocrine Practice 2015;21 (Suppl 1)
A1C = glycated hemoglobin.
Main Pathophysiological Defects in T2DM “The Ominous Octet”
Islet b-cell
Impaired
insulin secretion
Neurotransmitter
dysfunction
Decreased glucose
uptake
Islet a-cell
Increased
glucagon secretion
Increasedlipolysis
Increased glucose
reabsorption
Increased
hepatic
glucose
production
Decreasedincretin effect
Defronzo RA. Diabetes. 2009 Apr;58(4):773-95.
T2DM = type 2 diabetes mellitus.
LoweringA1C
Preventing Hypoglycemia
Glycemic Management of Type 2 Diabetes: Treatment Goals
Individualized Algorithm
A1C = glycated hemoglobin.
Approach To Management of Hyperglycemia
ADA. V. Diabetes Care. Diabetes Care. 2014;37(suppl 1):S25. Figure 1.
Adapted with permission from Ismail-Beigi F, et al. Ann Intern Med 2011;154:554-559
DCCT Research Group. N Engl J Med. 1993;329:977.Skyler J. Endocrinol Metab Clin North Am. 1996;25:243.
A1C and Microvascular Complications: DCCT R
ela
tive R
isk
Retinopathy
Nephropathy
Neuropathy
Microalbuminuria
A1C (%)
15
13
11
9
7
5
3
1
6 7 8 9 10 11 12
A1C = glycated hemoglobin; DCCT = Diabetes Control and Complications Trial.
A1C and Complications: UKPDS
UKPDS Group. Lancet. 1998;352:837-853.
A1C = glycated hemoglobin; UKPDS = United Kingdom Prospective Diabetes Study Group.
Mortality and Causes of Death in Diabetes
0
10
20
30
40
50
60
T1DMMale T1DMFemale T2DMMale T2DMFemale
Un
der
lyin
gca
use
of
dea
th(
%)
CVD
Cancer
Diabetes
Renal
Others
Morrish NJ, et al. Diabetología. 2001;44:S14-S21.
CVD = cardiovascular disease; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.
The ABCs of Diabetes Care:Recommended Goals
• A1C
– ADA and IDF recommend < 7.0% in general, < 6.0% in selected individuals.
– AACE/ACE recommend ≤ 6.5% in patients without concurrent serious illness and at low hypoglycemia risk, and > 6.5% in patients with concurrent serious illness and at risk for hypoglycemia.
• Blood Pressure
– AACE/ACE and IDF recommend < 130/80 mm Hg
– ADA recommends <140/90 mm Hg
• Cholesterol
– AACE/ACE and ADA recommend
• LDL-C: < 100 mg/dL (< 70 mg/dL in very high risk patients)
• HDL-C: > 40 mg/dL in men and > 50 mg/dL in women
• Non–HDL-C: < 130 mg/dL (< 100 mg/dL in high-risk patients)
• Triglycerides: < 150 mg/dL
American Diabetes Association. Diabetes Care. 2016;39 Suppl 1:S1-102; Handlesman Y et al. Endocr Pract. 2015; 21 Suppl 1:1-87; IDF Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes. Available at: http://www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-Diabetes.pdf
A1C = glycated hemoglobin; AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; ADA = American Diabetes Association; HDL-C = high density lipoprotein-cholesterol; IDF = International Diabetes Federation; LDL-C = low density lipoprotein-cholesterol.
Prediabetes Treatment Algorithm
T2DM = type 2 diabetes mellitus
BP = blood pressure
CVD = cardiovascular disease
TZD = thiazolidinedione
GLP-1 RA= glucagon-like peptide-1 receptor agonist
• Weight-loss agents orlistat, lorcaserin, phentermine/topiramate and liraglutide can prevent progression to T2DM
– Improve BP, triglycerides, and insulin sensitivity
• Metformin and acarbose can reduce progression to T2DM by 25% - 30%
– Use for prediabetes is off-label
– Both are safe, confer CVD risk benefit; metformin is well tolerated
• TZDs prevented progression to T2DM in 60% - 75% of patients in clinical trials
– Associated with adverse outcomes
• GLP-1 receptor agonists may be as effective as TZDs
– Promote weight loss, but inadequate safety data
Garber A et al. Endocr Pract. 2008;14 (7)933-946AACE/ACE Diabetes Algorithm Endocr Pract.
2017,doi:10.4158/EP161682.CS; AACE/ACE Obesity Algorithm Part 2
The Ticking Clock
Increased risk for both microvascular and macrovasculardisease begins early in the prediabetic state
– Insulin resistance is already present in patients with NGT who later develop T2DM
– Patients with prediabetes already have insulin resistance and significantly decreased beta-cell function
– Diabetic retinopathy, peripheral neuropathy, and nephropathy occur in patients with prediabetes
– Patients with prediabetes have a 2- to 3-fold increase in CHD risk, similar to patients with diabetes
CHD = coronary heart disease; NGT = normal glucose tolerance; T2DM = type 2 diabetes mellitus
AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2016. Endocr Pract. 2016;22(1):84-113;
DeFronzo RA et al. Am J Cardiol. 2011;108(3 Suppl):3B-24B
AACE Diabetes Algorithm
• Guide therapy based on A1C level– Focus on lifestyle intensification at all levels
• Important tenets:
– Target A1C is ≤6.5%• For patients without concurrent serious illness and at low hypoglycemic risk
• Based on associated lower risk of micro- and macrovascular complications
• Recommend monitoring A1C quarterly, along with fasting and postprandial blood glucose, with intensification of therapy until goal A1C is achieved
• Individualize A1C target based on comorbidities
• Patient should monitor fasting and postprandial blood glucose levels
– Use agents with maximal efficacy, associated with lowest risk of hypoglycemia• Sulfonylureas are therefore much lower in algorithm
• Earlier use of incretin mimetics and DPP-4 inhibitors to stimulate insulin secretion without hypoglycemia
A1C = glycated hemoglobin; DPP-4 = dipeptidyl-peptidase 4
AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2017. Endocr Pract.
2017,doi:10.4158/EP161682.CS.
Current Antihyperglycemic Medications
Sulfonylureas
Generalized
insulin
secretagogue
12 Groups with Different Mechanisms of Action
-Glucosidase
Inhibitors
Delay CHO
absorption
Biguanide
Reduce hepatic
insulin
resistance
TZDs
Reduce
peripheral insulin
resistance
Amylin Analog
Suppress
glucagon
GLP-1 Analogs
Stimulate cells,
suppress
glucagon
Colesevelam
Bile acid
sequestrant
Bromocriptine
Hypothalamic
pituitary reset
Insulin
Replacement
Therapy
SGLT-2
Inhibitors
Block renal
glucose
reabsorption
Glinides
Restore
postprandial
insulin
patterns
DPP-4 Inhibitors
Restore
GLP-1 Level
Clinical Considerations
• Combining therapeutic agents with different modes of action may be advantageous
• Use insulin sensitizers such as metformin and/or TZDs as part of the therapeutic regimen in most patients (unless contraindicated or intolerance to these agents has been demonstrated)
• Insulin and secretagogues are the only medications that cause significant hypoglycemia– Therefore, dosage of secretagogues or insulin should be adjusted as
blood glucose levels decline, when used in combination with metformin, TZD, DPP-4 inhibitors, and/or incretin mimetics (GLP-1 agonists)
DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; TZD = thiazolidinediones.
AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2016. Endocr Pract. 2016;22(1):84-113.
Sitagliptin [package insert]. Whitehouse Station, NJ; Merck Co. Inc.; 2010. Saxagliptin [package insert]. Princeton, NJ; Bristol Meyers Squibb;
2009; Linagliptin [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals. 2011.
Summary
• Obesity as a disease• Obesity and medical complications• Relationship to diabetes• Prediabetes• Early intervention: prevention or delay of diabetes• Diabetes and related complications
• Treating the ABCs of diabetes
The purpose of AACE Primary Care Day:
We can do better
We must do better
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