Download Type 2 Diabetes Management Goals

Management of Common
Comorbidities in Diabetes
1
Management of Common Comorbidities in Diabetes
OBESITY
2
3
4
More Than Two Thirds of US Adults
Are Overweight or Obese
NHANES Data
US Adults Age ≥20 Years
(Crude Estimate)
87.5
Population (%)
70.
30.5
52.5
35.
33.9
35.9
35.1
37.7
22.5
14.1
14.5
30.5
32.0
31.5
32.0
34.0
34.4
33.3
33.9
33.9
1962
1974
1980
1994
2000
2008
2010
2012
2014*
12.8
2.9-fold
increase in
obesity
since 1962
BMI ≥30
BMI 25-29
17.5
0.
*2014 rate of overweight not reported in Flegal et al 2016; 2012 rate carried over based on historic stability of overweight prevalence.
BMI, body mass index (in kg/m 2); NHANES, National Health and Nutrition Examination Survey (x-axis lists last year of each survey).
Flegal KM, et al. Int J Obes Relat Metab Disord. 1998;22:39-47; Flegal KM, et al. JAMA. 2002;288:1723-1727; Flegal KM, et al.
JAMA. 2010;303:235-241; Flegal KM, et al. JAMA. 2012;307:491-497. Ogden CL, et al. JAMA. 2014;311:806-814. Flegal KM, et al.
JAMA. 2016;315:2284-2291.
5
T2D Prevalence Parallels
Prevalence of Obesity
70
Obese
Diagnosed Diabetes
NHANES Data,
U.S. Adults ≥20 Years1-5
CDC Data,
U.S. Population6,7
Population (%)
60
12
10
50
8
40
6
30
4
20
10
2
0
0
White men
White women
Black men
Black women
Mexican American
men
Mexican American
women
Asian men
Asian women
1980 1994 2000 2008 2010 2012
BMI, body mass index (in kg/m 2); CDC, Centers for Disease Control and Prevention; NHANES, National Health and Nutrition Examination
Survey (x-axis lists last year of each survey).
*NHANES 1994 data.
1. Flegal KM, et al. Int J Obes Relat Metab Disord. 1998;22:39-47. 2. Flegal KM, et al. JAMA. 2002 ;288:1723-1727. 3. Flegal KM, et al. JAMA.
2010;303:235-241. 4. Flegal KM, et al. JAMA. 2012;307:491-497. 5. Ogden CL, et al. JAMA. 2014;311:806-814. 6. Harris MI, et al. Diabetes
Care. 1998;21:518-524. 7. CDC. Diabetes data & trends. Available at: https://www.cdc.gov/diabetes/statistics/prev/national/figraceethsex.htm
and http://www.cdc.gov/diabetes/statistics/prev/national/fighispanicthsex.htm.
6
Increase in Diabetes Parallels the
Increase in Obesity in the United States
Obesity*
Diabetes
12
111% increase
45
37.7
10
Population (%)
Population (%)
36
27
18
17.9
9
43% increase
9.3
8
6.5
6
4
2
0
0
1998
2014
1998
2014
*BMI ≥30 kg/m2.
CDC. National diabetes statistics report, 2014. Atlanta, GA: US Department of Health and Human Services, Centers for Disease
Control and Prevention, 2014. Mokdad AH, et al. JAMA. 1999;282:1519-1522; Mokdad AH, et al. Diabetes Care. 2000;23:1278-1283;
Flegal KM, et al. JAMA. 2016;315:2284-2291.
7
Prevalence of Overweight and
Obesity in Diabetes
Normal
BMI <25
kg/m2
12.9%
Overweight
Obese
BMI 25-<30
kg/m2
BMI ≥30 kg/m2
25.9%
61.2%
BMI, body mass index.
Selvin S, et al. Ann Intern Med. 2014;160:517-525. CDC. National diabetes statistics report, 2014. Atlanta, GA: US Department of Health and
Human Services, Centers for Disease Control and Prevention, 2014.
8
Incidence Diabetes by Waist
Circumference and Race/Ethnicity
The Multi-Ethnic Study of Atherosclerosis
(2000–2007)
8.00
Chinese
Hispanic
Incidence of Diabetes
Per 100 Person-Years
7.00
Black
6.00
5.00
4.00
White
3.00
2.00
1.00
0.00
70
80
90
100
110
120
130
Waist Circumference (cm)
Solid lines pertain to values between the race-specific 5th and 95th percentiles of waist circumference. Dotted lines are extrapolated
values outside the aforementioned race-specific ranges. Adjusted for age, sex, education, and income.
Lutsey PL, et al. Am J Epidemiol. 2010;172:197-204.
9
Consequences of Obesity in
Diabetes
• Increases risk of cardiovascular comorbidities
– Hypertension
– Dyslipidemia
– Atherosclerosis
• May limit ability to engage in physical activity
• Increases insulin resistance
– Worsens glucose tolerance
– Necessitates higher exogenous insulin doses
• Changes neuroendocrine signaling and
metabolism
• Reduces quality of life
Goal: 5% to 10% weight loss
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
10
Energy Homeostasis
Body Weight
Increase
Decrease
Energy intake
Energy
expenditure
Ingestion of:
Physical activity
Proteins
Fats
Diet-induced
thermogenesis
Carbohydrates
Basal metabolic rate
Mechanick JI, et al. Endocr Pract. 2012;18:642-648.
11
Peripheral and Central Regulation of
Energy Intake
Bray GA, et al. Lancet. 2016;387:1947-1956.
12
Obesity Impairs Appetite and
Energy Balance Regulation
Key Hormone Changes Associated with Weight Gain and Regain
Hormone
Source
Normal function
Alteration
Cholecystokinin
(CCK)
Duodenum
Suppress appetite
Levels decrease during dieting and
weight loss
Glucose-dependent
insulinotropic
polypeptide (GIP)
Duodenum,
jejunum
Energy storage
Levels increase during dieting and
weight loss
Ghrelin
Gastric fundus
Stimulate appetite,
particularly for high-fat, highsugar foods
Levels increase during dieting and
weight loss
Glucagon-like
peptide 1 (GLP-1)
Ileum
Suppress appetite and
increase satiety
Decreased functionality
Insulin
Pancreas
Regulate energy balance
Signal satiety to brain
Insulin resistance in obese persons
Reduced insulin levels after dieting
Leptin
Adipocytes
Regulate energy balance
Suppress appetite
Levels decrease during weight loss
Peptide YY (PYY)
Distal small
intestine
Suppress appetite
Levels decreased in obese persons
Sumithran P, Proietto J. Clin Sci (Lond). 2013;124:231-241.
13
Small Amounts of Weight Gain or Loss
Have Important Effects on CHD Risk
Framingham Offspring Study 16-year Follow-up*
Change in Risk Factor Sum (%)
Loss ≥2.25 kg
Gain ≥2.25 kg
60
**
37
40
**
20
20
0
-20
-40
-40
-60
-48
** Men
**
Women
*Patients with low HDL-C, high cholesterol, high BMI, high systolic BP, high triglyceride, high glucose.
**P<0.002 vs baseline.
BMI, body mass index; BP, blood pressure; HDL-C, high density lipoprotein cholesterol.
Wilson PW, et al. Arch Intern Med. 1999;159:1104-1109.
14
Abdominal Obesity and Increased
Risk of Cardiovascular Events
The HOPE Study
Waist Circumference (cm)
Men
Women
Tertile 1
<95
<87
Tertile 2
95-103
87-98
Tertile 3
>103
>98
1.4
1.35
Relative risk*
1.29
1.17
1.2
1
1.27
1
1.16
1
1.14
1
0.8
CVD death
MI
All-cause deaths
*Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-cholesterol, total-C; CVD: cardiovascular disease; MI: myocardial infarction;
BMI: body mass index; DM: diabetes mellitus; HDL: high-density lipoprotein cholesterol.
Dagenais GR, et al. Am Heart J. 2005;149:54-60.
15
Medical Complications of Obesity
Obesity
Biomechanical
Dismotility/disability
GERD
Lung function
defects
Osteoarthritis
Sleep apnea
Urinary
incontinence
Cardiometabolic
Dyslipidemia
Hypertension
Prediabetic states
NAFLD
PCOS
Diabetes
Cardiovascular
Disease
Other
Androgen
deficiency
Cancer
Gallbladder
disease
Psychological
disorders
GERD, gastroesophageal reflux disease; NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome.
Pi-Sunyer X. Postgrad Med. 2009;121:21-33.
16
Weight Loss With Intensive
Lifestyle Intervention in T2D
Look AHEAD Trial
(N=5145)
Reduction in initial weight (%)
0
-1.1%
-2
P<0.0001
Diabetes support and education
Intensive lifestyle intervention
-4
-4.7%
-6
Retention at 4 years:
ILI = 94.1%
DSE = 93.1%
-8
-10
0
1
2
3
4
Years
Differences between groups were statistically significant (P˂0.0001) at all 4 years.
DSE, diabetes support and education; ILI, intensive lifestyle intervention; T2D, type 2 diabetes.
Look AHEAD Research Group. Arch Intern Med. 2010;170:1566-1575.
17
Effect of Weight Loss in T2D on CV
Risk Factors and Diabetes Measures
Look AHEAD Trial
(N=5145)
1 Year
4 Years
DSE
ILI
DSE
ILI
Weight loss (%)
-0.7
-8.6
-0.88
-6.15*
A1C (%)
-0.14
-0.64*
-0.09
-0.36*
FPG (mg/dL)
-7.2
-21.5*
—
—
% on diabetes medications
2.2
-7.8*
—
—
Systolic BP (mm Hg)
-2.8
-6.8*
-2.97
-5.33*
Diastolic BP (mm Hg)
-1.8
-3.0*
-2.48
-2.92†
LDL-C (mg/dL)
-5.7
-5.2
-12.84
-11.27
HDL-C (mg/dL)
1.4
3.4*
1.97
3.67*
-14.6
-30.3*
-19.75
-25.56*
TG (mg/dL)
*P≤0.001, †P=0.01 vs customary support.
BP, blood pressure; CV, cardiovascular; DSE, diabetes support and education; ILI, intensive lifestyle intervention; T2D, type 2 diabetes.
Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383. Look AHEAD Research Group. Arch Intern Med. 2010;170:1566-1575.
18
Long-term Limitations of Weight
Loss Benefits in T2D
Main effect: -4 (95% CI -5 to -3)
P<0.001
Estimated mean A1C (%)
Estimated mean weight (kg)
Look AHEAD Trial
(N=5145)
Main effect:
-0.22 (95% CI -0.28 to -0.16)
P<0.001
*P<0.05 for between-group comparison.
Main effect is the average of post-baseline differences.
CI, confidence interval; T2D, type 2 diabetes.
Look AHEAD Research Group. N Engl J Med. 2013;369:145-154.
19
Long-Term Effects of Lifestyle Change on
Cardiovascular Risk in T2D
Look AHEAD Trial
Patients experiencing
death from cardiovascular
causes, nonfatal myocardial
infarction, nonfatal
stroke, or hospitalization for
angina (%)
HR 0.95 (95% CI, 0.80 to 1.09)
P=0.51
Lack of difference between treatment groups may be due to:
• Educational sessions in control group, contributing to weight loss
• Increased use of statins in control group
• Intensification of CV risk control in routine clinical care
T2D, type 2 diabetes mellitus.
Look AHEAD Research Group. N Engl J Med. 2013;369:145-154.
20
AACE Recommendations:
Therapeutic Lifestyle Changes
Parameter
Treatment Goal
Weight loss
(for overweight and
obese patients)
Reduce by 5% to 10%
Physical activity
150 min/week of moderate-intensity exercise (eg, brisk walking)
plus flexibility and strength training
•
•
Diet
•
•
•
•
Eat regular meals and snacks; avoid fasting to lose weight
Consume plant-based diet (high in fiber, low
calories/glycemic index, and high in
phytochemicals/antioxidants)
Understand Nutrition Facts Label information
Incorporate beliefs and culture into discussions
Use mild cooking techniques instead of high-heat cooking
Keep physician-patient discussions informal
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
21
AACE Recommendations:
Healthful Eating
Carbohydrate
Specify healthful carbohydrates (fresh fruits and vegetables, legumes, whole
grains); target 7-10 servings per day
Preferentially consume lower-glycemic index foods (glycemic index score <55 out
of 100: multigrain bread, pumpernickel bread, whole oats, legumes, apple, lentils,
chickpeas, mango, yams, brown rice)
Fat
Specify healthful fats (low mercury/contaminant-containing nuts, avocado, certain
plant oils, fish)
Limit saturated fats (butter, fatty red meats, tropical plant oils, fast foods) and trans
fat; choose fat-free or low-fat dairy products
Protein
Consume protein in foods with low saturated fats (fish, egg whites, beans); there is
no need to avoid animal protein
Avoid or limit processed meats
Micronutrients
Routine supplementation is not necessary; a healthful eating meal plan can
generally provide sufficient micronutrients
Chromium; vanadium; magnesium; vitamins A, C, and E; and CoQ10 are not
recommended for glycemic control
Vitamin supplements should be recommended to patients at risk of insufficiency or
deficiency
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
22
AACE Physical Activity
Recommendations
• Evaluate for contraindications • ≥150 minutes per week of
and/or limitations to increased
moderate-intensity exercise
physical activity before patient
– Flexibility and strength training
begins or intensifies exercise
– Aerobic exercise (eg, brisk
program
walking)
• Develop exercise
• Start slowly and build up
recommendations according to
gradually
individual goals and limitations
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
23
Antidiabetic Agents and Weight
Class
Amylin analog
Biguanide
GLP1 receptor agonists
SGLT-2 inhibitors
-Glucosidase inhibitors
Bile acid sequestrant
DPP4 inhibitors
Dopamine-2 agonist
Glinides
Sulfonylureas
Insulin
Thiazolidinediones
•
Agent(s)
Pramlintide
Metformin
Albiglutide, dulaglutide, exenatide, exenatide XR,
liraglutide
Canagliflozin, dapagliflozin, empagliflozin
Acarbose, miglitol
Colesevelam
Alogliptin, linagliptin, saxagliptin, sitagliptin
Bromocriptine
Nateglinide, repaglinide
Glimepiride, glipizide, glyburide
Aspart, detemir, glargine, glulisine, lispro, NPH, regular,
inhaled
Pioglitazone, rosiglitazone
Weight Effect
↓
↓
↓
↓
↔
↔
↔
↔
↑
↑
↑↑
↑↑
Risk of additional weight gain must be balanced against the benefits of the agent
– Sulfonylureas may negate weight loss benefits of GLP1 receptor agonists or
metformin
– Insulin should not be withheld because of the risk of weight gain
Garber AJ, et al. Endocr Pract. 2017;23:207-238.
ADA. Diabetes Care. 2017;40:S64-S74.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
24
Effect of Phentermine/Topiramate ER on
A1C and Number of Diabetes Medications
SEQUEL Type 2 Diabetes Subgroup
LS Mean A1C (%)
Baseline
Mean A1C (%)
0
-0.1
Placebo
(n=55)
6.9
Phen/TPM Phen/TPM
7.5/46 mg 15/92 mg
(n=26)
(n=64)
7.3
6.9
-0.04
-0.2
-0.23
-0.3
-0.4
-0.42
-0.5
Change in Diabetes Medications
(Overall safety population†)
Patients With Net Change* in
Concomitant Antihyperglycemics (%)
Change in A1C
*Percent increase minus percent decrease.
†The safety population was defined as all subjects who received at least 1 dose of study drug.
‡ P=0.013 for between-group differences.
8
7.1
7
6
5
4
‡
3
1.9
2
‡
1
0
0
Placebo
(n=227)
Phen/TPM Phen/TPM
7.5/46 mg 15/92 mg
(n=153)
(n=295)
Phen/TPM, phentermine/topiramate.
Garvey WT, et al. Am J Clin Nutr. 2012;95:297-308.
25
Effects of Phentermine/Topiramate ER on
Glucose Control in Advanced T2D
Poorly Controlled Type 2 Diabetes
Change in Diabetes Medications†
Change in A1C
8.6
8.8
40
30
30
20
-0.5
Score
LS Mean A1C (%)
Baseline
Mean A1C (%)
0
Placebo
(n=55)
Phen/TPN
15/92 mg
(n=75)
-1
10
0
-1.13
-10
-1.5
-1.61
-2
-20
*
*P=0.038 vs placebo.
†Net score reflecting change in medication number and change in dose level of diabetes medications.
-16
Placebo
(n=55)
Phen/TPN
15/92 mg
(n=75)
T2D, type 2 diabetes.
Garvey WT, et al. Diabetes. 2009;58(suppl 2): Abstr. 361-OR.
26
Effect of Lorcaserin on Glycemia
in Type 2 Diabetes
BLOOM-DM Study
LS Mean A1C (%)
Baseline
Mean A1C (%)
0
Placebo
(n=248)
8.0
Change in Diabetes Medications
Lorcaserin Lorcaserin
10 mg BID 10 mg QD
(n=251)
(n=93)
8.1
8.1
-0.2
-0.4
-0.4
-0.6
-0.8
-1
-1.2
-0.9
*
-1
*
Patients Increasing Use of
Antidiabetic Agents (%)
Change in A1C
100
88.3
80
†
82.9
†
76.6
60
40
20
0
Placebo Lorcaserin Lorcaserin
(n=248) 10 mg BID 10 mg QD
(n=251)
(n=95)
*P<0.001 vs placebo.
†P=0.087 vs placebo.
BLOOM-DM, Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus.
O’Neil PM, et al. Obesity. 2012;20:1426-1436.
27
Effects of High- and Low-Dose
Liraglutide in Type 2 Diabetes
SCALE Diabetes Study
Change in A1C
-0.5
Liraglutide Liraglutide
1.8 mg
3 mg
(n=211)
(n=423)
7.9
-0.38
-1
-1.13
-1.5
*
-1.32
*
0
LS Mean Weight (%)
LS Mean A1C (%)
Baseline
Mean A1C (%)
0
Placebo
(n=212)
Change in Weight
Placebo
(n=212)
Liraglutide Liraglutide
1.8 mg
3 mg
(n=211)
(n=423)
-1
-2
-3
-2
-4
-5
-4.6
-6
*
-7
-5.9
*
*P<0.0001 vs placebo.
Davies M, et al. Diabetes. 2014;63(suppl 1):A26, Abstr. 97-OR.
28
Management of Common Comorbidities in Diabetes
DYSLIPIDEMIA
29
Prevalence of Hyperlipidemia in
Type 2 Diabetes
Normal
35%
35%
Eligible for
lipid-lowering
therapy but
untreated
LDL-C
≥100 mg/dL
or using
cholesterollowering
medication
65%
LDL-C, low density lipoprotein cholesterol.
CDC. National diabetes statistics report, 2014. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control
and Prevention, 2014.
30
Common Secondary Causes of
Dyslipidemia
Affected lipids
Conditions
•
•
•
↑ Total cholesterol
•
and LDL-C
•
↑ Triglycerides
and VLDL-C
•
Hypothyroidism
Nephrosis
Dysgammaglobulinemia (systemic lupus erythematosus, multiple myeloma)
Progestin or anabolic steroid treatment
Cholostatic diseases of the liver due to abnormal lipoproteins, as in primary biliary
cirrhosis
Protease inhibitors for treatment of HIV infection
•
•
•
•
•
•
•
•
•
Chronic renal failure
T2D
Obesity
Excessive alcohol intake
Hypothyroidism
Antihypertensive medications (thiazide diuretics and b-adrenergic blocking age
Corticosteroid therapy (or severe stress that increases endogenous corticosteroids)
Orally administered estrogens, oral contraceptives, pregnancy
Protease inhibitors for treatment of HIV infection
HIV, human immunodeficiency virus; LDL-C, low-density lipoprotein cholesterol; T2D, type 2 diabetes; VLDL-C, very low-density lipoprotein
cholesterol.
Jellinger P, et al. Endocr Practice. 2017;23(4):479-497; NHLBI. NIH Publication No. 02-5215. 2002; Rodbard HW, et al. Endocr Pract. 13(Suppl
1):1-68; Vodnala D, et al. Am J Cardiol. 2012;110(6):823-825.
31
Atherogenic Dyslipidemia
• Common in type 2 diabetes and the insulin
resistance syndrome
• Features
–
–
–
–
Elevated triglycerides
Decreased HDL-C
Small, dense LDL particles
Postprandial increase in triglyceride-rich
lipoproteins
HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein.
Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1-87.
32
Effect of Weight Loss on Lipids in T2D
Look AHEAD Trial
(N=5145)
LDL-C
HDL-C
49
110
105
Main effect: 1.6 (95% CI 0.3, 2.9)
P<0.05
100
*
95
*
Estimated mean
(mg/dL)
Estimated mean
(mg/dL)
115
*
90
48
*
*
47
*
*
*
46
45
Main effect: 1.2 (95% CI 0.6, 1.9)
P<0.05
44
43
85
0
1
2
3
4
5
6
7
8
9
10
Estimated mean
(mg/dL)
Years
0
1
2
3
150
*
140
*
5
6
7
8
9
10
Years
Triglycerides
160
4
Main effect (%): 99 (95% CI 96, 101)
P=0.261
ILI
DSE
130
120
0
1
*P<0.05 for between-group comparisons.
2
3
4
5
6
7
8
9
10
Years
Main effect is the average of post-baseline differences.
CI, confidence interval; DSE, diabetes support and education; ILI, intensive lifestyle intervention; T2D, type 2 diabetes.
Look AHEAD Research Group. N Engl J Med. 2013;369:145-154.
33
LDL-C and LDL Particle Number
in T2D
Patients With LDL-C <100 mg/dL
(N=2355)
th
th
th
th
5
LDL-C
Subjects (%)
30
50
80
percentile
130
160
mg/dL
37%
63%
(n=870) (n=1485)
20
10
0
LDL-P
20
Subjects (%)
20
70
7%
(n=162)
100
31%
(n=741)
38%
(n=891)
16%
(n=383)
62%
15
10
8%
(n=178)
62% at high risk
(LDL-P exceeds 1000)
despite optimum LDL-C
(<100 mg/dL)
24%
5
0
700
1000
1300
1600
nmol/L
LDL-C, low-density lipoprotein cholesterol; LDL-P, low-density lipoprotein particles.
Cromwell WC, Otvos JD Am J Cardiol. 2006;98:1599-1602.
34
LDL Particle Number Distribution
in T2D
5th
LDL-C
71-99 mg/dL
Subjects (%)
(n=1484)
20
1%
(n=19)
21%
(n=307)
63%
80th
percentile
11%
(n=163)
32%
10
5
20
Subjects (%)
(n=871)
43%
(n=631)
50th
15
0
LDL-C
≤70 mg/dL
24%
(n=364)
20th
70
16%
(n=147)
100
43%
(n=377)
15
130
160
30%
(n=260)
9%
(n=76)
mg/dL
2%
(n=15)
41%
10
11%
5
0
700
1000
1300
1600
nmol/L
LDL-C, low-density lipoprotein cholesterol.
Cromwell WC, Otvos JD Am J Cardiol. 2006;98:1599-1602.
35
36
CVD Risk Factors: AACE Targets
Risk Factor
Recommended Goal
Individualize, but generally:
Blood pressure,
mm Hg
Lipids
Systolic <130
Diastolic <80
High CV risk
Very high CV risk
Extreme CV risk
LDL-C, mg/dL
<100
<70
<55
Non-HDL-C,
mg/dL
<130
<100
<80
Triglycerides,
mg/dL
ApoB, mg/dL
Garber AL, et al. Endocr Pract. 2017;23:207-238.
<150
<90
<80
<70
37
Lipid Management in Diabetes
LDL-C at goal but nonHDL-C not at goal
(TG ≥200 mg/dL
and/or low HDL-C)
TG ≥500 mg/dL
• May use fibrate, niacin, or
high-dose omega-3 fatty
acid to achieve non-HDLC goal
• Use high-dose omega-3
fatty acid, fibrate, or niacin
to reduce TG and risk of
pancreatitis
Elevated LDL-C, non-HDLC, TG, TC/HDL-C ratio,
ApoB, LDL particles
• Statin = treatment of
choice
• Add bile acid sequestrant,
niacin, and/or cholesterol
absorption inhibitor if
target not met on
maximum-tolerated dose
of statin
• Use bile acid sequestrant,
niacin, or cholesterol
absorption inhibitor
instead of statin if
contraindicated or not
tolerated
ApoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; HDL-C, high density lipoprotein
cholesterol; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; TC = total cholesterol.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
38
Dyslipidemia Treatment Options
Class
MOA
Efficacy
LDL-C
HDL-C
Triglycerides
HMG CoA reductase inhibitors
(statins)
Competitively inhibit rate-limiting
step of cholesterol synthesis,
slowing production in liver
Cholesterol absorption inhibitors
Inhibit intestinal absorption of
cholesterol
PCSK9 inhibitors
Inhibit PCSK9 binding to LDL
receptors, increasing availability
of receptors for LDL clearance
Fibric acid derivatives
Stimulate lipoprotein lipase
activity
Main Limitations
•
 21-55%
 2-10%
 6-30%
•
•
•
Risk of myopathy, increased liver
transaminases
Contraindicated in liver disease
Liver enzyme monitoring required
Risk of new-onset diabetes
 10-18%
(monotherapy)
 34-61%
(add-on to
statins)
—
—
•
Risk of myopathy
 48-71%
(add-on to
statins)
—
—
•
Injection
•
GI symptoms, possible
cholelithiasis
Gemfibrozil may  LDL-C
Myopathy risk increased when
used with statins
 VLDL
Fenofibrate
may  LDL-C
20-25%
 6-18%
 20-35%
•
•
HDL-C, high-density lipoprotein cholesterol; HMG-CoA, hydroxymethylglutaryl-coenzyme A; LDL-C, low-density
lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; VLDL-C, very low density
lipoprotein cholesterol.
Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1-87.
Continued on next slide
39
Dyslipidemia Treatment Options
Class
MOA
Efficacy
LDL-C
HDL-C
Triglycerides
Niacin/nicotinic acid
Reduce hepatic synthesis of
LDL-C and VLDL-C
Bile acid sequestrants
Bind bile acids in the intestine
•
Skin flushing, pruritus, GI
symptoms, potential increases in
blood glucose and uric acid
•
•
GI symptoms
May  triglycerides
•
•
Liver enzyme monitoring required
Steatosis of liver and small
intestine
 21%
•
•
Liver enzyme monitoring required
Steatosis of liver and small
intestine
VLDL-C
 20-42%
•
•
•
Increase LDL-C levels
Monitor coagulation status
Increased frequency of
symptomatic AF
 10-25%
 10-35%
 20-30%
 15-25%
—
—
 Up to 40%
—
 45%
MTP inhibitor
Inhibit synthesis of chylomicrons
and VLDL
Anti-sense ApoB oligonucleotide
Degrade mRNA for apoB-100,
which is needed for synthesis of
LDL
Omega-3 fatty acids
Reduce hepatic synthesis of
VLDL-triglycerides and/or
enhancing triglyceride clearance
Main Limitations
 27-45%
ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein
cholesterol; MTP, microsomal transfer triglyceride; VLDL-C, very low density lipoprotein cholesterol.
Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1-87.
Continued from previous slide
40
Statin Starting Dosages and
Dosage Ranges
Agent
Usual
recommended
starting daily
dosage
Dosage range
Administration
Lovastatin
20 mg
10-80 mg
Oral
Pravastatin
40 mg
10-80 mg
Oral
Simvastatin
20-40 mg
5-80 mg*
Oral
40 mg
20-80 mg
Oral
10-20 mg
10-80 mg
Oral
10 mg
5-40 mg
Oral
2 mg
2-4 mg
Oral
Fluvastatin
Atorvastatin
Rosuvastatin
Pitavastatin
*Simvastatin 80 mg not approved for therapy unless individual has been on
treatment for more than 1 year without myopathy.
Crestor (rosuvastatin calcium); [PI]; 2016; Jellinger P, et al. Endocr Practice. 2017;23:479-497; Lescol (fluvastatin sodium) [PI]; 2012 Lipitor
(atorvastatin calcium) [PI]; 2015; Livalo (pitavastatin) [PI]; 2013; ; Mevacor (lovastatin) [PI]; 2014; Pravachol (pravastatin sodium) [PI]; 2016;
Zocor (simvastatin) [PI]; 2015.
41
Statins: Primary Metabolic
Effects and Main Considerations
Metabolic Effects
•
•
Primarily ↓ LDL-C 21%-55% by competitively inhibiting rate-limiting step of cholesterol synthesis in
the liver, leading to upregulation of hepatic LDL receptors
Effects on TG and HDL-C are less pronounced (↓ TG 6%-30% and ↑ HDL-C 2%-10%)
Main Considerations
•
•
•
•
•
•
•
•
Liver function test prior to therapy and as clinically indicated thereafter
Myalgias and muscle weakness in some individuals
Potential for drug-drug interaction between some statins and CYP450 3A4 inhibitors, cyclosporine,
warfarin, and protease inhibitors
Myopathy/rhabdomyolysis in rare cases; increased risk with coadministration of some drugs (see
product labeling)
Simvastatin dosages should not exceed 40 mg in most individuals; dosages of 80 mg are no longer
recommended except in those who have tolerated 80 mg for 12 months or more without muscle
toxicity
Do not exceed 20 mg simvastatin daily with amlodipine or ranolazine
Plasma elevations of rosuvastatin may be higher among Asian persons than other ethnic groups
New-onset diabetes is increased in individuals treated with statins; however, it is dose-related, occurs
primarily in individuals with MetS, appears to be less common with pravastatin and possibly
pitavastatin, and occurs overall to a lesser extent than the associated decrease in ASCVD
ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; LDL-C, low-density
lipoprotein cholesterol; MetS, metabolic syndrome; TG, triglycerides.
Bissonnette S, et al. Can J Cardiol. 2006;22:1035-1044; Denke M, et al. Diab Vasc Dis Res. 2006;3:93-102; Jellinger P, et al. Endocr
Practice. 2017;23:479-497; Preiss D, et al. JAMA. 2011;305: 2556-2564.
42
Comparison of Statin Effects on
Lipids After 6 Weeks of Treatment
Men and Women With LDL-C ≥160 and ≤250 mg/dL
(N=2,431)
Dosage range,
mg daily
TC
(mg/dL)
LDL-C
(mg/dL)
HDL-C
(mg/dL)
TG
(mg/dL)
Lovastatin
20-80
↓ 21 to ↓ 36
↓ 29 to ↓ 48
↑ 4.6 to ↑ 8.0
↓ 12 to ↓ 13
Pravastatin
10-40
↓15 to ↓ 22
↓ 20 to ↓30
↑ 3.2 to ↑ 5.6
↑ 8 to ↓ 13
Simvastatin
10-80*
↓ 20 to ↓ 33
↓ 28 to ↓ 46
↑ 5.2 to ↑ 6.8
↓ 12 to ↓ 18
Fluvastatin
20-40
↓ 13 to ↓ 19
↓ 17 to ↓ 23
↑ 0.9 to ↓ 3.0
↓ 5 to ↓ 13
Atorvastatin
10-80
↓ 27 to ↓ 39
↓ 37 to ↓ 51
↑ 2.1 to ↑ 5.7
↓ 20 to ↓ 28
Rosuvastatin
10-40
↓ 33 to ↓ 40
↓ 45 to ↓ 55
↑ 7.7 to ↑ 9.6
↓ 20 to ↓ 26
Statin
*Not to be used at dosages of 80 mg unless individual has been on treatment for more than
12 months.
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides.
AAP NCEP Pediatrics. 1992;89:525-584; Daniels SR, et al. EPIGCVHRRCAFR, 2012; Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr
Practice. 2017;23:479-497; Jones P, et al. Am J Cardiol. 1998;81:582-587; Jones PH, et al. Am J Cardiol. 2003; 92:152-160; ; LIPID Study Group. N
Engl J Med. 1998;339:1349-1357; Pfeffer MA, et al. J Am Coll Cardiol. 1999;33:125-130; Plehn JF, et al. Circulation. 1999;99:216-223.
43
PCSK9 Inhibitor Starting
Dosages and Dosage Ranges
Agent
Usual recommended
starting daily dosage
Dosage range
Administration
Alirocumab
75 mg every 2 weeks
75-150 mg every 2 weeks
SC
Evolocumab
140 mg every 2 weeks or
420 mg once monthly
Not applicable
SC
Metabolic Effects
•
↓LDL-C 48%-71%, ↓ non-HDL-C 49%-58%, ↓TC 36%-42%, ↓Apo B 42%-55% by inhibiting PCSK9
binding with LDLRs, increasing the number of LDLRs available to clear LDL, and lowering LDL-C
levels
Main Considerations
•
•
•
•
Require subcutaneous self-injection; refrigeration generally needed
Overall levels of adverse reactions and discontinuation very low
Adverse reactions with significantly different rates between drug and placebo were: local injection site
reactions and influenza
The most common adverse reactions with similar rates for drug vs. placebo were:
• Alirocumab: nasopharyngitis, influenza, urinary tract infections, diarrhea, bronchitis, and myalgia
• Evolocumab: nasopharyngitis, back pain, and upper respiratory tract infection
Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; LDLR,
low-density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; SC, subcutaneous injection; TC, total cholesterol.
Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23:479-497; Praluent (alirocumab) [PI] 2015; Repatha (evolocumab) [PI]; 2016.
44
Fibrate Starting Dosages and
Dosage Ranges
Usual
recommended
starting daily dose
Dosage range
Administration
Fenofibrate
48-145 mg
48-145 mg
Oral
Gemfibrozil
1200 mg
1200 mg
Oral
45-135 mg
45-135 mg
Oral
Agent
Fenofibric acid
Metabolic Effects
• Primarily ↓ TG 20%-35%, ↑ HDL-C 6%-18% by stimulating lipoprotein lipase activity
• Fenofibrate may ↓ TC and LDL-C 20%-25%
• Lower VLDL-C and LDL-C; reciprocal rise in LDL-C transforms the profile into a less
atherogenic form by shifting fewer LDL particles to larger size
• Fenofibrate ↓ fibrinogen level
HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein, LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG,
triglycerides; VLDL-C, very low-density lipoprotein cholesterol.
Aguilar-Salinas CA, et al. Metabolism. 2001;50:729-733; Athyros VG, et al. Coron Artery Dis. 1995;6:25-1256; Avellone G, et al. Blood Coagul
Fibrinolysis. 1995;6:543-548; Bröijersen A, et al. Arterioscler Thromb Vasc Biol. 1996;16:511-516; Bröijersén A, et al. Thromb Haemost.
1996;76:171-176; Davidson MH, et al. Am J Cardiol. 2007;99:3C-18C; Farnier M, et al. Eur Heart J. 2005;26:897-905; Guyton JR, et al. Arch Intern
Med. 2000;160:1177-1184; Hottelart C, et al. Nephron. 2002;92:536-541; Insua A, et al. Endocr Pract. 2002;8:96-101; Jellinger P, Handelsman Y,
Rosenblit P, et al. Endocr Practice. 2017;23:479-497; Kockx M, et al. Thromb Haemost. 1997;78:1167-1172; Lopid (gemfibrozil) [PI] 2010;
McKenney JM, et al. J Am Coll Cardiol. 2006;47:1584-1587; Syvänne M, et al. Atherosclerosis. 2004;172:267-272; Tricor (fenofibrate) [PI]; 2010;
Trilipix (fenofibric acid) [PI]; 2016; Westphal S, et al. Lancet. 2001; 358:39-40.
45
Fibrates: Main Considerations
•
•
•
•
•
•
•
•
•
Gemfibrozil may ↑ LDL-C 10%-15%
GI symptoms, possible cholelithiasis
May potentiate effects of orally administered anticoagulants
Gemfibrozil may ↑ fibrinogen level
Gemfibrozil and fenofibrate can ↑ homocysteine independent of
vitamin concentrations
May cause muscle disorders; myopathy/rhabdomyolysis when
used with statin
Fibrates are associated with increased serum creatinine levels,
which may not reflect renal dysfunction
Fenofibrate dose should be cut by two-thirds and gemofibrozil
by one-half when eGFR is 15-60, and fibrates should be
avoided when eGFR is <15
Can improve diabetic retinopathy
eGFR, estimated glomerular filtration rate; GI, gastrointestinal; LDL-C, low-density lipoprotein cholesterol.
Jellinger P, et al. Endocr Practice. 2017;23:479-497.
46
Bile Acid Sequestrant Starting
Dosages and Dosage Ranges
Agent
Cholestyramine
Usual
recommended
daily dosage
Dosage range
Administration
8-16 g
4-24 g
Oral
2g
2-16 g
Oral
3.8 g
3.8-4.5 g
Oral
Colestipol
Colesevelam
Metabolic Effects
•
•
Primarily ↓ LDL-C 15%-25% by binding bile
acids and preventing their reabsorption in the
ileum (causing hepatic cholesterol depletion
and LDL-receptor upregulation)
Colesevelam ↓ glucose and hemoglobin A1C
(~0.5%); FDA-approved to treat T2D
Main Considerations
• May ↑ serum TG
• Frequent constipation and/or bloating,
which can reduce adherence
• Many potential drug interactions
(decreased drug absorption), less so with
colesevelam (see product labeling)
• May reduce absorption of folic acid and
fat-soluble vitamins such as vitamins A, D,
and K
FDA, Food and Drug Administration; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; T2D, type 2 diabetes; TG,
triglyceride.
Colestid (colestipol hydrochloride) [PI]; 2014; Jellinger P, et al. Endocr Practice. 2017;23:479-497; Prevalite (cholestyramine for oral
suspension, USP) [PI]; 2015; WelChol (colesevelam hydrochloride) [PI]; 2014; Zieve FJ, et al. Ther. 2007;29:74-839:74-83.
47
Cholesterol Absorption Inhibitor Starting
Dosages and Dosage Ranges
Agent
Ezetimibe
Ezetimibe/
simvastatin
Usual
recommended
daily dosage
Dosage range
Administration
10 mg
10 mg
Oral
10/20 mg
10/10 to 10/80 mg
Oral
Metabolic Effects
•
•
•
•
Primarily ↓ LDL-C 10%-18% by inhibiting
intestinal absorption of cholesterol and
decreasing delivery to the liver, leading to
upregulation of hepatic LDL receptors
↓ Apo B 11%-16%
In combination with statins, additional ↓ LDL-C
25%, total ↓ LDL-C 34%-61%
In combination with fenofibrate, ↓ LDL-C 20%22% and ↓ apo B 25%-26% without reducing
↑ HDL-C
Main Considerations
• Myopathy/rhabdomyolysis (rare)
• When coadministered with
statins or fenofibrate, risks
associated with those drugs
remain (e.g., myopathy/
rhabdomyolysis, cholelithiasis)
Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
Bays HE, et al. Clin Ther. 2001;23:1209-1230; Bays HE, et al. Clin Ther. 2004;26:1758-1773; Bissonnette S, et al. Can J Cardiol.
2006;22:1035-1044; Brohet C, et al. Curr Med Res Opin. 2005;21:571-578; Denke M et al. Diab Vasc Dis Res. 2006;3:93-102; Dujovne CA,
et al. Am J Cardiol. 2002;90:109-21097; Farnier M, et al. Eur Heart J. 2005;26:897-905; Gagne C, et al. Am J Cardiol. 2002;90:1084-1091;
Jellinger P, et al. Endocr Practice. 2017;23:479-497; Knopp RH, et al. Int J Clin Pract. 2013. 57:363-368; McKenney JM, et al. J Am Coll
Cardiol. 2006;47:1584-1587; Zetia (ezetimibe) [PI] 2013.
48
Omega-3 Fatty Acid Starting
Dosages and Dosage Ranges
Agent
Omega-3-acid ethyl
esters (Lovaza)
Icosapent ethyl
(Vascepa)
•
•
Usual
recommended
daily dosage
Dosage range
Administration
4g
4g
Oral
4g
4g
Oral
Metabolic Effects
↓ TG 27%-45%, TC 7%-10%, VLDL-C 20%-42%, apo B 4%, and non-HDL-C 8%14% in individuals with severe hypertriglyceridemia most likely by reducing hepatic
VLDL-TG synthesis and/or secretion and enhancing TG clearance from circulating
VLDL particles. Other potential mechanisms of action include: increased -oxidation;
inhibition of acyl-CoA; 1,2-diacylglyceral acyltransferase; decreased hepatic
lipogenesis; and increased plasma lipoprotein activity
Icosapent ethyl ↓ LDL-C 5%, whereas, omega-3-acid ethyl esters ↑ LDL-C 45%
Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG,
triglycerides; VLDL, very low-density lipoprotein.
Jellinger P, et al. Endocr Practice. 2017;23:479-497; Lovaza (omega-3-acid ethyl esters) [PI]; 2015; Vascepa (icosapent ethyl) [PI]; 2016.
49
50
Omega-3 Fatty Acids: Main
Considerations
•
•
•
•
•
Assess TG levels prior to initiating and
periodically during therapy
Omega-3-acid ethyl esters can increase
LDL-C levels. Monitor LDL-C levels during
treatment
May prolong bleeding time. Monitor
coagulation status periodically in patients
receiving treatment with omega-3 fatty acids
and other drugs affecting coagulation
Monitor ALT and AST levels periodically
during treatment in patients with hepatic
impairment. Some patients may experience
increases in ALT levels only
Exercise caution when treating patients with
a known hypersensitivity to fish and/or
shellfish
AF, atrial fibrillation.
Jellinger P, et al. Endocr Practice. 2017;23:479-497.
•
•
•
•
The effect of omega-3 fatty acids on
cardiovascular morbidity and mortality and the
risk of pancreatitis has not been determined in
patients with severe hypertriglyceridemia
In patients with paroxysmal or persistent atrial
fibrillation, therapy with omega-3-acid ethyl
esters may be associated with increased
frequency of symptomatic AF or flutter,
especially within the first 2 to 3 months after
initiation
Most common adverse events include
arthralgia (2.3%), eructation (4%), dyspepsia
(3%), and taste perversion (4%). May also
experience constipation, gastrointestinal
disorders, vomiting, rash, or pruritus
Should be used with caution in nursing
mothers and only be used in pregnant women
if the benefits of treatment outweigh the
potential risk of fetal harm
Niacin Starting Dosages and
Dosage Ranges
Usual
recommended
daily dosage
Dosage range
Administration
Immediate release
250 mg
250-3000 mg
Oral
Extended release
500 mg
500-2000 mg
Oral
Agent
Metabolic Effects
•
•
•
↓ LDL-C 10%-25%, ↓ TG 20%-30%, ↑ HDL-C
10%-35% by decreasing hepatic synthesis of
LDL-C and VLDL-C
↓ Lipoprotein (a)
Transforms LDL-C to less atherogenic form by
increasing average particle size and also
decreases LDL particle concentration
Main Considerations
•
•
•
Potential for frequent skin flushing, pruritus,
abdominal discomfort, hepatoxicity (rare but
may be severe), nausea, peptic ulcer, atrial
fibrillation
Deleterious effect on serum glucose at higher
dosages
Increases uric acid levels; may lead to gout
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; VLDL-C, very low-density
lipoprotein cholesterol.
Guyton JR, et al. Arch Intern Med. 2000;160:1177-1184; Jellinger P, et al. Endocr Practice. 2017;23:479-497; Niaspan (niacin extendedrelease) [PI] 2015.
51
MTP Inhibitor Starting Dosage
and Dosage Range
Agent
Lomitapide
•
•
•
•
•
Recommended
starting dose
Dosage range
Administration
5 mg
5-60 mg
Oral
Metabolic Effects
↓ Up to LDL-C 40%, TC 36%, apo B 39%, TG 45%, and non-HDL-C 40% (depending on dose) in
individuals with HoFH by binding and inhibiting MTP, which inhibits synthesis of chylomicrons and
VLDL
Main Considerations
Can cause increases in transminases (ALT, AST); monitoring of ALT, AST, alkaline phosphatase,
and total bilirubin prior to initiation, and of ALT and AST during treatment, is required per FDA
REMS
Causes increases in hepatic fat (steatosis) with or without concomitant elevated transminases,
which may be a risk for progressive liver diseases
Also causes steatosis of the small intestine with resulting abdominal pain and steatorrhea unless a
very-low-fat diet is followed; may also cause fat-soluble vitamin deficiency unless vitamin
supplements are taken
Caution should be exercised when used with other drugs with potential hepatoxicity; because of
hepatoxicity risk, only available through REMS program
ALT, aspartate amino transferase; AST, amino alanine transferase; FDA, Food and Drug Administration; HDL-C, high-density lipoprotein cholesterol;
HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; MTP, microsomal transfer protein; REMS, Risk
Evaluation and Mitigation Strategy; TG, triglycerides; VLDL, very low-density lipoprotein.
Jellinger P, et al. Endocr Practice. 2017;23:479-497; Juxtapid (lomitapide) [PI]; 2012.
52
Anti-sense Apolipoprotein B
Oligonucleotide Starting Dosage
and Dosage Range
Agent
Mipomersen
•
•
•
•
Usual
recommended
dosage
Dosage range
Administration
200 mg once
weekly
200 mg once
weekly
SC
Metabolic Effects
↓ LDL-C 21%, TC 19%, apo B 24%, and non-HDL-C 22% in individuals with HoFH by degrading
mRNA for apo B-100, the principal apolipoprotein needed for hepatic synthesis of VLDL (and
subsequent intra-plasma production of IDL and LDL)
Main Considerations
Can cause increases in transminases (ALT, AST); monitoring of ALT, AST, alkaline phosphatase,
and total bilirubin before initiation, and of ALT and AST during treatment is recommended
Causes increases in hepatic fat (steatosis) with or without concomitant elevated transminases,
which may be a risk for progressive liver diseases
Caution should be exercised when used with other drugs with potential hepatoxicity; because of
hepatoxicity risk, only available through REMS program
ALT, aspartate amino transferase; apo, apolipoprotein; AST, amino alanine transferase; HDL-C, high-density lipoprotein cholesterol; HoFH,
homozygous familial hypercholesterolemia; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein
cholesterol; mRNA, messenger RNA; SQ, subcutaneous; VLDL, very low-density lipoprotein.
Jellinger P, et al. Endocr Practice. 2017;23:479-497; Kynamro (mipomersen sodium) Injection [PI]; 2016.
53
Benefits of Aggressive LDL-C
Lowering in Diabetes
Primary event rate (%)
Aggressive Lipid Lowering
Difference
P value in LDL-C
(mg/dL)
Treatment
Control
Better Worse
TNT
Diabetes, CHD
13.8
17.9
0.026
22*
ASCOT-LLA
Diabetes, HTN
9.2
11.9
0.036
35†
CARDS
Diabetes, no CVD
5.8
9.0
0.001
46†
HPS
All diabetes
9.4
12.6
<0.0001
39†
HPS
Diabetes, no CVD
9.3
13.5
0.0003
39†
0.4
*Atorvastatin 10 vs 80 mg/day.
†Statin vs placebo.
0.6
0.8
1.0
1.2
Relative risk
Shepherd J, et al. Diabetes Care. 2006;29:1220-1226. Sever PS, et al. Diabetes Care. 2005;28:1151-1157.
Colhoun HM, et al. Lancet. 2004;364:685-696. HPS Collaborative Group. Lancet. 2003;361:2005-2016.
1.4
54
Randomized Trials of Statins: A
Meta-Analysis of CV Events
Patients with Diabetes
(N=18,686; 14 RCTs)
Risk Reduction in Major Vascular Events per mmol/L Decrease in LDL-C
Cholesterol Treatment Trialists’ Collaborators. Lancet. 2008;371:117-125.
55
Treat Patients With the Greatest
Absolute Risk the Most Aggressively
Robinson JG, et al. Am J Cardiol. 2006;98:1405-1408.
56
Statin Benefits Across a Range
of Baseline Levels
Cholesterol Treatment Trialists’ Collaboration
LDL-C 90-130 mg/dL shows same benefit as LDL-C 50-90 mg/dL
Events (% per annum)
Statin
<2 mmol/L (<77 mg/dL)
RR (CI) per 1 mmol/L reduction in LDL-C
Control
910 (4.1%)
1,012 (4.6%)
0.78 (0.61-0.99)
≥2 to <2.5 mmol/L (77-96 mg/dL)
1,528 (3.6%)
1,729 (4.2%)
0.77 (0.67-0.89)
≥2.5 to <3.0 mmol/L (97-116 mg/dL)
1,866 (3.3%)
2,225 (4.0%)
0.77 (0.70-0.85) P=0.3
≥3.0 to <3.5 mmol/L (117-135 mg/dL)
2,007 (3.2%)
2,454 (4.0%)
0.76 (0.70-0.82)
≥3.5 mmol/L (>136 mg/dL)
4,508 (3.0%)
5,736 (3.9%)
0.80 (0.76-0.83)
10,973 (3.2%)
13,350 (4.0%)
0.78 (0.76-0.80)
Total
1 mmol/L = 38.6 mg/dL
LDL-C, low-density lipoprotein cholesterol.
Baigent C, et al. Lancet. 2010;376:1670-1681.
57
Effect on CHD and Diabetes
Primary Prevention
Cholesterol Treatment Trialists’ Collaboration
Events (% per annum)
Previous Vascular Disease
CHD
No CHD, vascular
Statin
RR (CI) per 1 mmol/L reduction in LDL-C
Control
8,395 (4.5%) 10,123 (5.6%)
0.79 (0.76-0.82)
674 (3.1%)
802 (3.7%)
0.81 (0.71-0.92)
1,904 (1.4%)
2,425 (1.8%)
0.75 (0.69-0.82)
Type 1 diabetes
145 (4.5%)
192 (6.0%)
0.77 (0.58-1.01)
Type 2 diabetes
2,494 (4.2%)
2,920 (5.1%)
0.80 (0.74-0.86)
No diabetes
8,272 (3.2%) 10,163 (4.0%)
0.78 (0.75-0.81)
None
P=0.3
Diabetes
P=0.8
1 mmol/L = 38.6 mg/dL.
CHD: coronary heart disease; CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; RR: relative risk.
Baigent C, et al. Lancet. 2010;376:1670-1681.
58
Residual Cardiovascular Risk
in Major Statin Trials
CHD events still occur in patients treated with statins
Secondary
CARE
40
Placebo
HPS
CARDS
Statin
30
20
15.9
12.3
13.2
10
0
N=
 LDL-C
9014
-25%
30
10.2
4159
-28%
11.8
8.7
20,536
-29%
5.5
3.6
2841
-40%
37.0
40
Patients with
Diabetes (%)
Total
Population (%)
LIPID
Primary
29.0
23.0
20
19.0
25.1
20.2
5.5
10
3.6
0
N=
782
586
5963
LIPID Study Group. N Engl J Med. 1998;339:1349-1357. Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.
HPS Collaborative Group. Lancet. 2002;360:7-22. Colhoun HM, et al. Lancet. 2004:364:685-696.
2841
59
IMPROVE-IT: Improved Reduction of
Outcomes, Vytorin Efficacy International Trial
Trial design: Patients with recent ACS were randomized 1:1 to either ezetimibe 10
mg + simvastatin 40 mg or simvastatin 40 mg and followed for a median of 6 years
Primary composite CV endpoint
Percent reduction
50%
Results
•
Primary endpoint (CV death/MI/UA/coronary
revasc/stroke/moderate/severe bleeding) for
ezetimibe/simvastatin vs. simvastatin: 32.7% vs.
34.7% (HR 0.94, 95% CI 0.89-0.99; P=0.016)
•
MI: 13.1% vs. 14.8%, P=0.002; stroke: 4.2% vs.
4.8%, P=0.05; CVD/MI/stroke: 20.4% vs. 22.2%,
P=0.003
•
Median LDL follow-up average: 53.7 vs. 69.5 mg/dL
(P=0.016)
32.7%
34.7%
25%
Conclusions
0%
Ezetimibe/simvastatin
(n = 9,067)
Simvastatin
(n = 9,077)
• In patients with high-risk ACS, ezetimibe 10
mg/simvastatin 40 mg was superior to simvastatin
40 mg alone in reducing adverse CV events
• This is the first study powered for clinical outcomes
to show a benefit with a non-statin agent
Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; CVD,
cardiovascular disease; LDL, low-density lipoprotein; LDL-C, low-density
lipoprotein cholesterol; MI, myocardial infarction.
Cannon CP, et al. N Engl J Med. 2015;372:2387-2397.
• Reaffirms the “lower is better” hypothesis
with LDL-C
60
IMPROVE-IT
Major Prespecified Subgroups
Simvastatin
EZE/Simvastatin
(BL LDL-C: 69.5 mg/dL) (BL LDL-C: 53.7 mg/dL)
P value for
interaction
Male
Female
34.9
34.0
33.2
31.0
0.267
Age <65 years
Age ≥65 years
30.8
39.9
29.9
36.4
0.098
No diabetes
Diabetes
30.8
45.5
30.2
40.0
0.023
Prior LLT
No prior LLT
43.4
30.0
40.7
28.6
0.272
LDL-C >95 mg/dL
LDL-C ≤95 mg/dL
31.2
38.4
29.6
36.0
0.670
0.7
0.8
0.9
1
1.1
Ezetimibe/simvastatin better Simvastatin better
EZE, ezetimibe; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy.
Cannon CP, et al. N Engl J Med. 2015;372:2387-2397.
61
Lipid Effects of Adding a Fenofibrate
to a Statin in Patients With T2D
Action to Control Cardiovascular Risk in Diabetes
(N=5518)
ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.
62
Effect of Fenofibrate Plus Statin on
CV Events in Patients With T2D
Action to Control Cardiovascular Risk in Diabetes
(N=5518)
ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.
63
Benefits of Fenofibrate Plus
Statin in Patients With T2D
Action to Control Cardiovascular Risk in Diabetes
(N=5518)
ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.
64
Fenofibrate Benefits Most Likely in
Patients with High TG and Low HDL-C
Major Fatal or Nonfatal CV Events (%)
Action to Control Cardiovascular Risk in Diabetes
(N=5518)
20
18
16
14
17.32%
RR
31%
(P=0.06)
The benefit associated with fenofibrate treatment
was confined to the high TG/low HDL-C subgroup
(<18% of ACCORD-LIPID trial population)
12.37%
12
12.37%
10.11%
10
8
6
4
2
0
High TG / low HDL-C
All others in cohort
(TG>204 mg/dL; HDL-C <34 mg/dL;
n=941)
(n=4,548)
CV, cerebrovascular; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; RR, risk reduction; TG, triglycerides.
Elam M, et al, Clin Lipidol. 2011;6:9-20. ACCORD Study Group. NEJM. 2010; 362:1563-1574.
65
Effect of Fenofibrate on Progression of
Coronary Atherosclerosis in Patients With
Type 2 Diabetes
Diabetes Atherosclerosis Intervention Study
Fenofibrate
Quantitative Coronary
Angiography
Placebo
4
Baseline
Endpoint
2.59
-29%
2.42
+1%
HDL-C (mmol/L)
Baseline
1.01
1.05
Endpoint
+7%
+2%
Change in Stenosis (%)
Triglycerides (mmol/L)
3.7
3.5
3
*
2.5
2.1
2
1.5
1
0.5
0
Placebo
(n=207)
Fenofibrate
(n=211)
*P=0.02 vs placebo
Diabetes Atherosclerosis Intervention Study. Lancet. 2001;357:905-910.
66
FIELD: Fenofibrate Intervention
in Event Lowering in Diabetes
Multinational, randomized controlled trial (N=9,795) of patients with T2D currently
taking statin therapy assigned to add-on treatment with fenofibrate or placebo
Outcome
Fenofibrate
% (n)
Placebo
% (n)
HR
95% CI
P value
Coronary events
5% (256)
6% (288)
0.89
0.75-1.05
0.16
CHD mortality
2% (110)
2% (93)
1.19
0.90-1.57
0.22
Nonfatal MI
3% (158)
4% (207)
0.76
0.62-0.94
0.01
CHD, coronary heart disease; MI, myocardial infarction; T2D, type 2 diabetes.
Keech A, et al. Lancet. 2005;366:1849-1861.
67
Fenofibrate and CV Events
FIELD
(N=9795 Patients With T2D)
Baseline cholesterol (mg/dL): TC 194; TG 154; HDL-C 42; LDL-C 119; Non-HDL-C 152
Placebo
Fenofibrate 200 mg
11% Reduction, P=0.035
16
Event Rate (%)*
14
12
10
8
6
13.9
11%
Reduction
P=0.16
5.9
5.2
12.5
24%
Reduction
P=0.01
4.2
4
3.2
2
19%
Increase
P=0.22
Nonfatal MI
* Not corrected for large placebo-group statin drop-in rate.
7.4
5.9
1.9 2.2
0
CHD Events**
(Primary Endpoint)
21%
Reduction
P=0.003
CHD Death
Total CVD Events†
(Secondary
Endpoint)
Coronary
Revascularization
** Nonfatal MI and CHD death.
† CHD
events, stroke, CVD death, revascularizations.
CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein
cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; T2D, type 2 diabetes; TC, total cholesterol; TG, triglycerides.
Keech A, et al. Lancet. 2005;366:1849-1861.
68
Greatest Benefit of Fenofibrate Seen in Patients
With Elevated TG and Low HDL-C
FIELD
Placebo
RR
11%
5-Year Total CV
Event Rate (%)
20
15
13.9
12.5
RR
14%
Fenofibrate
17.2
RR
23%
17.8
RR
27%
15.1
13.5
13
13.4
Low HDL-C**
TG >200 mg/dL
Low HDL-C + TG >200
mg/dL
0.86
0.75-0.99
<0.01
0.77
0.63-0.94
<0.01
0.73
0.58-0.91
<0.05
10
5
0
Any MetS Criteria
Hazard ratio
95% CI
P value
0.89
0.80-0.99
<0.01
*Not corrected for large placebo group statin drop-in rate
**HDL-C <40 mg/dL (men) and <50 mg/dL (women).
CI, confidence interval; CV, cerebrovascular; FIELD, Secondary Endpoints from the Fenofibrate Intervention and Event Lowering in Diabetes
trial; HDL-C, high-density lipoprotein cholesterol; MetS, metabolic syndrome; RR, risk reduction; TG, triglycerides.
Scott R, et al. Diabetes Care 2009;32:493-498
69
Coronary Drug Project:
15-Year Follow-up
Placebo (n = 2008)
Niacin (n = 827)
60
11% Reduction
P =0.0004
Event Rate (%)
55
50
45
12% Reduction
P <0.05
40
35
30
Total Mortality
CHD Mortality
Canner PL, et al. J Am Coll Cardiol. 1986;8:1245-1255. Canner PL, et al. J Am Coll Cardiol. 2005;95:254-257.
70
Dyslipidemia Summary
• Patients with diabetes and insulin resistance
syndrome have atherogenic dyslipidemia and
an increased risk for CVD
• Although statin therapy is effective in lowering
LDL-C, residual CVD risk remains after statin
therapy
• To reduce residual CVD risk, lipid
abnormalities beyond LDL-C (non–HDL-C,
triglycerides, HDL-C) should be intensively
treated
CVD, cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1-87.
71
Management of Common Comorbidities in Diabetes
HYPERTENSION
72
73
Meta-Regression Analysis of Major
CV Events and BP Reduction
2.0
Relative risk
1.0
0.5
Reduction in risk per 5 mm Hg reduction in SBP
Age <65: 11.9% (5.3% to 18.0%)
Age >65: 9.1% (3.6% to 14.3%)
P for heterogeneity of slopes = 0.38
0.25
-15
-12
-9
-6
-3
0
3
6
Difference in reduction in systolic BP (mm Hg)
BPLTTC. BMJ. 2008;336:1121-1123.
74
BP Reduction and Effect on CV
Mortality at 4 Years
Hypertension Optimal Treatment Trial
The lower the target BP in patients with diabetes,
the lower the rates of CV events and CV deaths
30
25
20
CV Deaths
P=0.005
24.4
18.6
15
51%
11.9
10
P=0.50
9.9 10 9.3
5
0
Events per
1000 Patient-years
Events per
1000 Patient-years
Major CV Events
15
DBP ≤ 90
DBP ≤85
DBP ≤ 80
P=0.016
11.1 11.2
10
67%
5
3.7
P=0.49
3.7 3.8 4.1
0
T2DM
n=1501
All Patients
n=18,790
T2DM
n=1501
All Patients
n=18,790
DBP, diastolic blood pressure, in mmHg.
Hansson L, et al. Lancet. 1998;351:1755-1762.
75
Blood Pressure and Diabetic
Complications in T2D
10
10
P<0.0001
1
13% Decrease
per 10 mmHg reduction in SBP
0.5
110
120
130
140
150
Updated Mean A1C
Adler Al, et al. BMJ. 2000;321:412-419.
160
170
Myocardial Infarction
Hazard Ratio
Microvascular Complications
Hazard Ratio
United Kingdom Prospective Diabetes Study
P<0.0001
1
12% Decrease
per 10 mmHg reduction in SBP
0.5
110
120
130
140
150
160
170
Updated Mean A1C
76
BP Reductions and Risk of Microvascular
and Macrovascular Complications in T2D
United Kingdom Prospective Diabetes Study
(N=1148)
Benefits of 144/82 vs. 154/87 mm Hg
Risk Reduction (%)
0
Any
diabetesMyocardial related
infarction endpoint
Diabetesrelated
death
Stroke
Heart
failure
Renal
failure
Vision
deteriorRetinopathy ation
-10
-20
-30
-21
P=0.13
-24
P=0.005
-40
-50
-60
UKPDS Group. BMJ. 1998;317:703-713.
-32
P=0.019
-42
P=0.29
-44
P=0.013
-56
P=0.004
-34
P=0.004
-47
P=0.004
77
Long-Term Follow-up After Tight
Control of Blood Pressure in T2D
UKPDS Post-monitoring Study
Good BP control must be continued if benefits are to be maintained
Any Diabetes-Related Endpoint
•
•
BP became similar within 2 years of
trial termination (mainly due to
increased BP in tight control group)
Relative risk reductions achieved
with tight BP control during the trial
were not sustained for:
–
–
–
–
•
Holman RR, et al. N Engl J Med. 2008;359;1565-1576.
Any diabetes-related end point
Diabetes-related death
Microvascular disease
Stroke
Peripheral vascular disease risk
reduction became significant during
the follow-up (P = 0.02)
78
Intensive Blood Pressure Control
in Type 2 Diabetes
Action to Control Cardiovascular Risk in Diabetes
(N=4733)
ACCORD Study Group. N Engl J Med. 2010;362:1575-1585.
79
Effect of Intensive Blood-Pressure Control
on CV Outcomes and Death in T2D
Action to Control Cardiovascular Risk in Diabetes
(N=4733)
ACCORD Study Group. N Engl J Med. 2010;362:1575-1585.
80
Effect of Weight Loss on Blood
Pressure in Type 2 Diabetes
Look AHEAD Trial
(N=5145)
ILI
DSE
Systolic Blood Pressure
Diastolic Blood Pressure
128
*
126
* *
*
*
*
*
124
Main effect: -1.9 (95% CI -2.6, -1.1)
P<0.05
122
120
0
1
2
3
4
5
6
7
8
9
Estimated mean
(mm Hg)
Estimated mean
(mm Hg)
130
71
70
69
68
67
66
65
64
10
Years
Main effect: -0.1 (95% CI -0.5, 0.3)
P=0.72
*
*
*
0
1
2
3
4
5
6
7
8
9
10
Years
*P<0.05 for between-group comparisons.
Main effect is the average of post-baseline differences.
CI, confidence interval; DSE, diabetes support and education; ILI, intensive lifestyle intervention.
Look AHEAD Research Group. N Engl J Med. 2013;369:145-154.
81
Multiple Antihypertensive Agents
Are Usually Required to Achieve
BP Control
RENAAL (BP <140/90)
3
IRMA-2 (BP <135/85)
3.1
IDNT (BP <135/85)
3
UKPDS (DBP <85)
2.7
ABCD (DBP <75)
2.8
HOT (DBP <80)
3.3
0
0.5
1
1.5
2
2.5
3
Number of Agents Required to Achieve Goal BP
ABCD, Appropriate Blood pressure Control in Diabetes trial; DBP, diastolic blood pressure, in mm Hg; HOT,
Hypertension Optimal Treatment trial; IDNT, Irbesartan in Diabetic Nephropathy trial; IRMA-2, Irbesartan
Microalbuminuria Type 2 Diabetes in Hypertensive Patients trial; RENAAL, Reduction of Endpoints in NIDDM with the
Angiotensin II Antagonist Losartan study; UKPDS, United Kingdom Prospective Diabetes Study.
Bakris G, et al. Am J Kidney Dis. 2000;36:646-661.
3.5
82
Compelling Indications
for Individual Drug Classes
Recommended Drugs
Compelling
Indication
Diuretic
Heart failure
•
Post-myocardial
infarction
BB
•
ACEI
•
•
•
ARB
•
High coronary
disease risk
•
•
•
Diabetes
•
•
•
•
•
•
Chronic kidney
disease
Recurrent stroke
prevention
•
•
CCB
Aldo
ANT
Clinical Trial Basis
•
ACC/AHA Heart Failure Guideline,
MERIT-HF, COPERNICUS, CIBIS,
SOLVD, AIRE, TRACE, ValHEFT,
RALES, CHARM
•
ACC/AHA Post-MI Guideline,
BHAT, SAVE, Capricorn,
EPHESUS
•
ALLHAT, HOPE, ANBP2, LIFE,
CONVINCE, EUROPA, INVEST
•
NKF-ADA Guideline, UKPDS,
ALLHAT
NKF Guideline, Captopril Trial,
RENAAL, IDNT, REIN, AASK
PROGRESS
Aldo ANT = aldosterone antagonist.
Chobanian AV, et al. Hypertension. 2003;42:1206-1252.
83
The Renin Angiotensin System:
ACE Inhibition
ACEI
Angiotensin I
ACE-independent
formation of ANG II
ACE
Bradykinin
Angiotensin II
AT1
AT2
Vasoconstriction
Proliferation
Antiproliferation
Differentiation
Aldosterone
Sympathetic NS
Regeneration
Anti-inflammation
NaCl retention
Inflammation
Apoptosis?
B2
NO, PGI2
Vasodilation, etc
NO
Vasodilation
Tissue protection
Apoptosis
ACE, angiotensin converting enzyme; ACEI, angiotensin converting enzyme inhibitor; ANG II, angiotensin II; AT 1, angiotensin II type 1;
AT2, angiotensin II type 2; B2, bradykinin 2; NO, nitric oxide; PGI2, prostacyclin.
Unger T, et al. Am J Cardiol. 2007;100:25J-31J.
84
The Renin Angiotensin System:
AT1 Blockade
Angiotensin I
ARB
ACE
Angiotensin II
AT1
AT2
Vasoconstriction
Proliferation
Antiproliferation
Differentiation
Aldosterone
Sympathetic NS
Regeneration
Anti-inflammation
NaCl retention
Inflammation
Apoptosis?
B2
NO, PGI2
Vasodilation, etc
NO
Vasodilation
Tissue protection
Apoptosis
ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; AT 1, angiotensin II type 1; AT2, angiotensin II type 2;
B2, bradykinin 2; NO, nitric oxide; PGI2, prostacyclin.
Unger T, et al. Am J Cardiol. 2007;100:25J-31J.
85
MI Risk With ACEIs and ARBs
Events
ARBs
ACEIs
Odds Ratio
ARB vs ACEI
ELITE
1997
ELITE II
OPTIMAAL
DETAIL
VALIANT (val)
ONTARGET (tel)
Fixed effect model
(I2=0.0%, p=0.884)
Random effect model
ARB + ACEI vs ACEI
2000
2002
2004
2003
2008
VALIANT (val + cap)
2003
ONTARGET (tel+ram)
Fixed effect model
(I2=0.0%, p=0.148)
Random effect model
Overall Effect
2008
Fixed effect model
(I2=0.0%, p=0.759)
4/352
31/1578
384/2744
9/120
796/4909
440/8542
0.79 (0.17,3.54)
4/370
28/1574
379/2733
6/130
798/4909
413/8576
1.11 (0.66,1.85)
1.01 (0.87,1.18)
1.68 (0.58,4.86)
1.00 (0.90,1.11)
1.07 (0.94,1.23)
1663/18,245 1628/18,292
1.03 (0.95, 1.10)
1.03 (0.95,1.10)
756/4885
438/8502
0.94 (0.85,1.05)
798/4909
413/8576
1.07 (0.94,1.23)
1194/13,387 1211/13,485
0.99 (0.91,1.08)
1.00 (0.88,1.13)
2857/31,632 2839/31,777
Random effect model
Heterogeneity between groups p=0.555
1.01 (0.96,1.07)
1.01 (0.96,1.07)
0.5
Favors
1st
1.0 Favors
Odds Ratio
listed
2nd
listed
2.0
ACE, angiotensin converting enzyme; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MI, myocardial
infarction.
Volpe M, et al. J Hypertension. 2009;27:941-946.
86
Not All Combinations Are Equal in
High Risk Patients
The ACCOMPLISH Trial
Blood Pressure Reductions
Time to Primary Endpoint*
Benazepril plus hydrochlorothiazide
Relative risk reduction: 20%
Hazard ratio: 0.80
(95% CI , 0.72 to 0.90;
P <0.001)
Benazepril plus amlodipine
By 1 year, 32.3% of patients in both treatment groups required
a third antihypertensive agent to maintain target BP
*Composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after
sudden, cardiac arrest, and coronary revascularization.
ACCOMPLISH, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension.
Jamerson K et al. N Engl J Med. 2008;359:2417-2428.
87
Hypertension Summary
• In T2D, blood pressure lowering has the greatest and most
immediate effect on morbidity and morality
• The recommended BP target for patients with diabetes is
~130/80 mmHg
• Multiple agents are usually required to achieve target BP
• BP treatment must be continued for benefits to be maintained
• An ACE inhibitor or ARB should be included in the BP-control
regimens of patients with diabetes because of beneficial effects
on the renin-angiotensin system
ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; T2D, type 2 diabetes.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
88
Management of Common Comorbidities in Diabetes
CHRONIC KIDNEY DISEASE
89
Prevalence of CKD in Diagnosed
Diabetes
Diabetic kidney disease is the leading cause of kidney failure in the United States
CKD may be both a pre-existing comorbidity and a secondary complication of diabetes
NKF
Description
Stage
GFR
1
Kidney damage* with
normal or  GFR
≥90
2
Kidney damage* with
mild  GFR
60-89
3
Moderate  GFR
30-59
4
Severe  GFR
15-29
5
Kidney failure or
ESRD
<15 or
dialysis
*Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.
CKD, chronic kidney disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate (mL/min/1.73 m 2); NKF, National Kidney
Foundation.
CDC. National diabetes statistics report, 2014. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and
Prevention, 2014. Plantinga LC, et al. Clin J Am Soc Nephrol. 2010;5:673-682.
90
Reducing A1C Reduces
Nephropathy Risk in Type 2 Diabetes
UKPDS
ADVANCE
ACCORD
A1C reduction (%)*
0.9
0.8
1.3
Nephropathy risk
reduction (%)*
30
21
21
New
onset
microalbuminuria
(P=0.033)
New or
worsening
nephropathy
(P=0.006)
New
microalbuminuria
(P=0.0005)
*Intensive vs standard glucose control.
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. ADVANCE Collaborative Group.
N Engl J Med. 2008;358:2560-2572. Ismail-Beigi F, et al. Lancet. 2010;376:419-430.
91
Cardiovascular Outcomes Worsen
With CKD Progression
Valsartan in Acute Myocardial Infarction Trial
(N=14,527*)
†
eGFR (mL/min/1.73 m2)
Estimated Event Rate (%)
60
50
†
†
40
75
60-74
45-59
<45
†
30
20
†
10
†
0
Composite
End Point
Death From
CV Causes
Reinfarction
CHF
Stroke
Resuscitation
*23% of patients had diabetes.
†P<0.001 vs GFR ≥75 by Cox model.
CHF, congestive heart failure; CV, cardiovascular.
Anavekar NS, et al. N Engl J Med. 2004;351:1285-1295.
92
CV Risk Increases With
Comorbid Diabetes and CKD
Incidence per 100 Patient-Years
No diabetes/no CKD
Diabetes/no CKD
Diabetes/CKD
60
x 2.8
x 2.0
50
40
30
x 2.1
x 1.7
x 2.5
20
x 2.3
10
0
CHF
AMI
CVA/TIA
PVD
ASVD*
Death
CHF, congestive heart failure; AMI, acute myocardial infarction; CVA/TIA, cerebrovascular accident/transient
ischemic attack; PVD, peripheral vascular disease; ASVD, atherosclerotic vascular disease.
*ASVD was defined as the first occurrence of AMI, CVA/TIA, or PVD.
Foley RN, et al. J Am Soc Nephrol. 2005;16:489-495.
93
Risk of Cardiovascular Mortality
with Decreasing eGFR and
Increasing Albuminuria
14
Relative Risk
12
10
8
6
4
2
≥300
30-299
10-29 ACR (mg/g)
0
>105
90-105
75-90
60-75
45-60
eGFR (mL/min/1.73
<10
30-45
15-30
m2)
ACR = albumin-creatinine ratio; eGFR = estimated glomerular filtration rate.
NKF. Kidney Int Suppl. 2013;3:1-150.
94
Assessment of Diabetic
Nephropathy
• Annual assessments
– Serum creatinine to determine eGFR
– Urine AER
• Begin annual screening
– 5 years after diagnosis of T1D if diagnosed before
age 30 years
– At diagnosis of T2D or T1D in patients diagnosed
after age 30 years
AER, albumin excretion rate; eGFR, estimated glomerular filtration rate; T1D, type 1 diabetes; T2D, type 2 diabetes.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
95
KDIGO CKD Classification by
Relative Risk
Albuminuria stages (mg/g)
A3
Optimal and high
normal
High
Very high and
nephrotic
10-29
30-299
300-1999
≥2000
Very low
Very low
Low
Moderate
Very high
Very low
Very low
Low
Moderate
Very high
Mild to
45-59
moderate
Low
Low
Moderate
High
Very high
Moderate
30-44
to severe
Moderate
Moderate
High
High
Very high
High
High
High
High
Very high
Very high
Very high
Very high
Very high
Very high
High and
optimal
G2
Mild
G5
A2
<10
G1
GFR
stages
(mL/min G3a
per 1.73
m2 body
surface G3b
area)
G4
A1
>105
90-104
75-89
60-74
Severe
15-29
Kidney
failure
<15
Levey AS, et al. Kidney Int. 2011;80:17-28.
96
Staging and Monitoring
of CKD in Diabetes
Persistent albuminuria categories
Description and range
GFR categories (mL/min/1.73 m2)
Description and range
Previous
NKF CKD
stage
Guide to frequency of monitoring
(number of times per year) by GFR
and albuminuria category
A1
A2
A3
Normal to mildly
increased
Moderately
increased
Severely
increased
<30 mg/g
<3 mg/mmol
30-300 mg/g
3-30 mg/mmol
>300 mg/g
>30 mg/mmol
1
G1
Normal or high
≥90
1 if CKD
1
2
2
G2
Mildly decreased
60-89
1 if CKD
1
2
G3a
Mild to moderately
decreased
45-59
1
2
3
G3b
Moderately to
severely decreased
30-44
2
3
3
4
G4
Severely decreased
15-29
3
3
4+
5
G5
Kidney failure
<15
4+
4+
4+
3
CKD = chronic kidney disease; GFR = glomerular filtration rate; NKF = National Kidney Foundation.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
97
DKD Risk Factor Management
Risk Factor
Goal
Hyperglycemia
Individualized A1C goals Avoid biguanide in moderate to severe CKD
≤6.5% for most (AACE) Consider need for dose reductions and/or risk of
hypoglycemia and other renal-related AEs with other
<7.0% (NKF)
antidiabetic agents
Hypertension
BP ~130/80 mmHg
Proteinuria
Dyslipidemia
Management Recommendation
Use ACE inhibitor or ARB in combination with other
antihypertensive agents as needed
Use ACE inhibitor or ARB as directed
LDL-C <100 mg/dL,
<70 mg/dL an option for
high risk
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.
Statin therapy recommended
Fibrate dose reduction may be required
98
Management of Diabetic
Nephropathy
• Optimal control of blood pressure, glucose, and lipids
• Smoking cessation
• RAAS blockade
– ACE inhibitor, ARB, or renin inhibitor
– Do not combine RAAS blocking agents
– Monitor serum potassium
• Nephrologist referral
– Atypical presentation
– Rapid decline in eGFR or albuminuria progression
– Stage 4 CKD
ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; CKD, chronic kidney disease; eGFR, estimated
glomerular filtration rate; RAAS, renin angiotensin aldosterone system.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
99
Use of Antihyperglycemic Agents
in Kidney Disease
Class: Agent(s)
Kidney Disease Recommendation
Amylin analog: pramlintide
Not recommended for CKD stage ≥4
Biguanide: metformin
Contraindicated if SCr >1.5 (men) or 1.4 (women) mg/dL
Bile acid sequestrant: colesevelam
No dosage adjustment
Dopamine-2 agonist: bromocriptine
Use with caution
DPP-4 inhibitors: alogliptin, linagliptin, saxagliptin,
sitagliptin
Reduce dosage for alogliptin, saxagliptin and sitagliptin if CrCl
<50 mg/dL
Glinides: nateglinide, repaglinide
Start at lowest effective dose if GFR <30 mL/min/1.73 m2
GLP-1 receptor agonists: albiglutide, dulaglutide,
exenatide, exenatide XR, liraglutide
Exenatide and liraglutide not recommended with GFR <30
mL/min/
-Glucosidase inhibitors: acarbose, miglitol
Avoid if GFR <25 (miglitol) or <30 (acarbose) mL/min/1.73 m2
Insulin: aspart, detemir, glargine, glulisine, inhaled, lispro,
NPH, regular
Adjust dose based on patient response
SGLT inhibitors: canagliflozin, dapagliflozin, empagliflozin
Ineffective if GFR <30 mL/min/1.73 m2
Sulfonylureas: glimepiride, glipizide, glyburide
No dose adjustment for glipizide; start glimepiride
conservatively; avoid glyburide and all other SUs
Thiazolidinediones: pioglitazone, rosiglitazone
No dosage adjustment
Garber AJ, et al. Endocr Pract. 2017;23:207-238. ADA. Diabetes Care. 2017;40:S64-S74. Handelsman YH, et al. Endocr Pract. 2015;21(suppl
1):1-87. National Kidney Foundation. Am J Kidney Dis. 2012;60:850-886.
100
Dietary Guidelines for DKD
CKD Stage
Macronutrient
1-2
1-4
Sodium
<2.3
Total fat, % calories*
<30
Saturated fat, % calories
<10
Cholesterol, mg/day
<200
Carbohydrate, % calories
50-60
Protein, g/kg/day (% calories)
3-4
0.8 (~10)
0.6-0.8 (~8-10)
Phosphorus
1.7
0.8-1.0
Potassium
>4
2.4
*Adjust so total calories from protein, fat, and carbohydrate are 100%.
Emphasize such whole-food sources as fresh vegetables, whole grains, nuts, legumes, low-fat or
nonfat dairy products, canola oil, olive oil, cold-water fish, and poultry.
Tailor dietary counseling to cultural food preferences.
National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.
101
Management of Common Comorbidities in Diabetes
CARDIOVASCULAR DISEASE
102
Prevalence of CV Risk Factors in
Diabetes
Overweight / Obese
Hyperlipidemia
BMI <25
kg/m2
12.9%
BMI 25-<30
kg/m2
25.9%
Normal
BMI ≥30
kg/m2
35%
Hypertension
61.2%
65%
Normal
29%
LDL-C
≥100 mg/dL
or using
cholesterollowering
medication
BP ≥140/90
mmHg
or taking
antihypertensive
medication
71%
BMI, body mass index.
Selvin S, et al. Ann Intern Med. 2014;160:517-525. CDC. National diabetes statistics report, 2014. Atlanta, GA: US
Department of Health and Human Services, Centers for Disease Control and Prevention, 2014.
103
Coincidence of CV Comorbidities
in Type 2 Diabetes
NHANES 1999-2004
(N=984)
Hypertension
(BP ≥140/90 mm Hg or
taking antihypertensive
medication)
16.9%
17.7%
12.2%
20.6%
Hyperlipidemia
Obesity
(BMI ≥30 kg/m2)
5.0%
Suh DC, et al. J Diabetes Complications. 2010;24:382-391.
5.9%
7.4%
(LDL-C ≥100 mg/dL,
TC ≥200 mg/dL, or
TG ≥150 mg/dL)
104
Cardiovascular Disease Risk
Factors
Major
Additional
Nontraditional
•
Advancing age
•
•
Increased lipoprotein (a)
•
High total serum
cholesterol level
Obesity or abdominal
obesity
•
Elevated clotting factors
•
Family history of
hyperlipidemia
•
Inflammation markers
(hsCRP; Lp-PLA2)
•
Elevated homocysteine
levels
•
High non–HDL-C
•
High LDL-C
•
Small, dense LDL-C
•
Low HDL-C
•
Increased Apo B
•
Diabetes mellitus
•
•
Apo E4 isoform
•
Hypertension
Increased LDL particle
concentration
•
Elevated uric acid
•
Cigarette smoking
•
Fasting/postprandial
hypertriglyceridemia
•
•
Family history of ASCVD
Increased triglyceride-rich
remnants
•
PCOS
•
Dyslipidemic triad*
*Hypertriglyceridemia; low HDL-C; and small, dense LDL-C.
Apo, apolipoprotein; ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; hs-CRP,
high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; Lp-PLA2, lipoprotein-associated phospholipase
A2; PCOS, polycystic ovary syndrome.
Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1-87.
105
7-Year Incidence of MI (%)
Diabetes Is a Cardiovascular
Disease Risk Equivalent
P<0.001
50
45
40
30
P<0.001
18.8
20.2
Prior MI
No prior MI
20
10
3.5
0
No prior MI
Nondiabetic
(n=1373)
Prior MI
Diabetic
(n=1059)
MI, myocardial infarction.
Grundy SM, et al. Circulation. 2004;110:227-239.
Haffner SM, et al. N Engl J Med. 1998;339:229-234.
106
Baseline Proteinuria Increases
Cardiovascular Risk
Systematic Review
(RCTs: N=29; Patients with DM: N=116,790;
~518,611 patient-years of follow-up)
~6-fold higher
Events/1,000 patient-years
40
No Proteinuria
39.9
Mixed Trials
All Proteinuria
30
~15-fold higher
18.7
18.6
20
~13-fold higher
~12-fold higher
11.6 12.9
10
12.4
9.3
7.5
6.3
1.2
0
All-Cause Death
CVD Death
0
0
MI
Stroke
CVD, cardiovascular disease; MI, myocardial infarction.
Preiss D, et al. Am Heart J. 2011;161:210-219.
107
Risk of All-Cause and CV Mortality
According to eGFR and Albuminuria
CV, cerebrovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio.
Chronic Kidney Disease Prognosis Consortium. Lancet. 2010;375:2073-2081 .
108
AACE ASCVD Risk Categories
Low risk:
Extreme risk:
•
•
Progressive ASCVD, including unstable
angina that persists after achieving an LDL-C
less than 70 mg/dL, or established clinical
ASCVD with diabetes, stage 3 or 4 CKD,
and/or HeFH, or in those with a history of
premature ASCVD (<55 years of age for
males or <65 years of age for females)
•
This category was added in this CPG based
on clinical trial evidence and supported by
meta-analyses that further lowering of LDL-C
produces better outcomes in individuals with
ACS. IMPROVE-IT demonstrated lower rates
of cardiovascular events in those with ACS
when LDL-C levels were lowered to 53 mg/dL
combining ezetimibe with statins.
No risk factors
Moderate risk:
•
2 or fewer risk factors and a calculated 10year risk of less than 10%
High risk:
•
An ASCVD equivalent including diabetes or
stage 3 or 4 CKD with no other risk factors, or
individuals with 2 or more risk factors and a
10-year risk of 10%-20%
Very high risk:
•
Established or recent hospitalization for ACS;
coronary, carotid or peripheral vascular
disease; diabetes or stage 3 or 4 CKD with 1
or more risk factors; a calculated 10-year risk
greater than 20%; or HeFH
ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CPG, clinical practice
guideline; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; IMPROVE-IT, Improved Reduction of
Outcomes: Vytorin Efficacy International Trial.
Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1-87. Cannon, CP, et al. N Engl J Med. 2015;372(25):2387-239.
109
AACE ASCVD Risk Categories
Risk
Category
Risk factors*/10-year risk†
Extreme risk
•
Treatment goals (mg/dL)
LDL-C
Non-HDL-C
Apo B
Progressive ASCVD including unstable angina
in patients after achieving LDL-C <70 mg/dL
Established clinical CVD in patients with
diabetes, stage 3 or 4 CKD, or HeHF
History of premature ASCVD (age <55 male,
<65 female)
<55
<80
<70
Established or recent hospitalization for ACS
or coronary, carotid, or peripheral vascular
disease, or 10-year risk >20%
Diabetes or stage 3 or 4 CKD plus ≥1
additional risk factor(s)
HeHF
<70
<100
<80
≥2 risk factors and 10-year risk 10-20%
Diabetes or stage 3 or 4 CKD with no other
risk factors
<100
<130
<90
Moderate risk ≤2 risk factors and 10-year risk <10%
<100
<130
<90
Low risk
<130
<160
NR
•
•
Very high risk •
•
•
High risk
•
•
0 risk factors
*High LDL-C, PCOS, cigarette smoking, hypertension, low HDL-C, family history of CAD, stage 3 or 4 CKD, coronary calcification, and age ≥45 years
in men and ≥55 years in women.
†Framingham risk score.
ASCVD, atherosclerotic cardiovascular disease; CAD, coronary artery disease; CKD, chronic kidney disease; HDL-C, high density lipoprotein
cholesterol; HeHF, heterozygous familial hypercholesterolemia; LDL-C low density lipoprotein cholesterol; NR, not recommended; PCOS, polycystic
ovary syndrome.
Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1-87.
110
Comprehensive Management of
Cardiovascular Risk
• Manage CV risk factors
– Weight loss
– Smoking cessation
– Optimal glucose, blood pressure, and lipid control
• Use low-dose aspirin for secondary prevention of CV
events in patients with existing CVD
– May consider low-dose aspirin for primary prevention of CV
events in patients with 10-year CV risk >10%
• Measure coronary artery calcification or use coronary
imaging to determine whether glucose, lipid, or blood
pressure control efforts should be intensified
CV, cardiovascular; CVD, cardiovascular disease.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
111
Statin Use in Patients with
Diabetes
• Majority of patients with T2D
• Use a statin regardless of LDLhave a high cardiovascular risk
C level in patients with diabetes
who meet the following criteria:
• People with T1D are at
– >40 years of age
elevated cardiovascular risk
– ≥1 major ASCVD risk factor
• LDL-C target: <70 mg/dL—for
• Hypertension
the majority of patients with
• Family history of CVD
diabetes who are determined
• Low HDL-C
to have a high risk
• Smoking
ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density
lipoprotein cholesterol.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
112
Management of Common Comorbidities in Diabetes
DEPRESSION
113
Prevalence of Comorbid
Depression and Diabetes
Community Sample
(N=506)
Meta-analysis
No diabetes
40
40
1.9
P=0.5
OR
2.1
30
22%
20
9.9%
Patients (%)
Patients (%)
30
10
Diabetes
26.1
20
14.4
9.0
10
5.0
0
Major
Depressive
Disorder
0
Likely
Depression
Diagnostic
Interview
Self-report
Scale
OR, odds ratio.
Fisher L, et al. Diabetes Care. 2007;30:542-548; Anderson RJ, et al. Diabetes Care. 2001;24:1069-1078
114
Depression and Adherence to
Diabetes Self-management
(HANDS score <9)
Unlikely major depression
Mean Adherent Days/Week
7
(HANDS score ≥9)
Probable major depression
6
5
P<0.001
4
P=0.001
P<0.001
P=0.006
P<0.001
3
P=0.348
P=0.241
2
1
0
General
diet
Carbohydrates
Exercise
Glucose
monitoring
Fruits
and
vegetables
High fat
foods
Foot care
2.3-Fold increased risk of missing 1 or more prescribed
medications over previous week with major depression
HANDS, Harvard Department of Psychiatry/National Depression Screening Day Scale.
Gonzales JS, et al. Diabetes Care. 2007;30:2222-2227.
115
Mental Health Referral for
Patients With Diabetes
•
•
Establish emotional well-being as a part of diabetes management
Include psychological assessment and treatment in routine care
– Do not wait for deterioration in psychological status
– Utilize patient-provider relationship as a foundation for psychological
management
•
Indications for referral
–
–
–
–
–
•
Gross noncompliance with medical regimen
Depression with the possibility of self-harm
Debilitating anxiety (alone or with depression)
Eating disorder
Cognitive functioning that significantly impairs judgment
Always refer to mental health specialist familiar with diabetes
management
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
116
Management of Common Comorbidities in Diabetes
SLEEP APNEA
117
Obstructive Sleep Apnea
Mechanisms
 Feedback loop involving interplay
between excess visceral adipose
tissue, insulin resistance, and
inflammatory cytokines
 Excess fat reduces diaphragm
mobility and promotes soft tissue
edema, which in turn lead to
depression of ventilation
 Ventilation depression causes sleep
apnea and poor sleep, which
contributes to daytime sleepiness and
fatigue
 Poor sleep promotes stress hormone
and interleukin 6 production, which
exacerbates insulin resistance
Risk Factors
 Obesity
 Neck
circumference
>44 cm
 Narrowed airway
 Hypertension
 Smoking




Male sex
Age
Family history
Alcohol or
sedatives
Treatment Options
 Continuous positive airway pressure
(CPAP)
 Adjustable airway pressure devices
 Oral appliances
 Surgery
 Uvulopalatopharyngoplasty
(UPPP)
 Maxillomandibular advancement
 Tracheostomy
Epstein LJ, et al. J Clin Sleep Med. 2009;5:263-276. NHLBI Working Group on Sleep Apnea. Am Fam Physician.
1996;53:247-253. Vgontzas AN, et al. J Intern Med. 2003;254:32-44 .
118
Prevalence of Sleep Apnea
in Type 2 Diabetes
Sleep AHEAD Study
Obese Patients With T2D
(N=305)
No OSA
13.4%
Severe OSA
22.6%
Moderate OSA
30.5%
Mild OSA
33.4%
OSA, obstructive sleep apnea.
Foster GD, et al. Diabetes Care. 2009;32:1017-1019.
119
Management of Common Comorbidities in Diabetes
CANCER
120
Diabetes and Cancer Risk
• Diabetes (especially T2D)
may:
– ↑ Cancer risk
•
•
•
•
•
•
Liver
Pancreas
Endometrium
Colon and rectum
Breast
Bladder
– ↓ Cancer risk: prostate
Giovannucci E, et al. Diabetes Care. 2010;33:1674-1685.
• Hyperinsulinemia,
hyperglycemia, and
inflammation may directly
increase cancer risk
• Shared risk factors
–
–
–
–
Aging
Obesity
Diet
Physical inactivity
121
Insulin and Cancer Risk
Study
Hazard Ratio (95% CI)
Outcome Reduction With an Initial
Glargine Intervention (ORIGIN)
N=12,537; prospective RCT
Median follow-up: 6.2 years
Any cancer: 1.00 (0.88-1.13); P=0.97
Death from cancer: 0.94 (0.77-1.15); P=0.52
Northern European Database Study
N=447,821; observational
Mean follow-up:
Glargine users: 3.1 years
Other insulin users: 3.5 years
Breast cancer (women): 1.12 (0.99-1.27)
Prostate cancer (men): 1.11 (1.00-1.24)
Colorectal cancer (men and women): 0.86 (0.76-0.98)
Kaiser-Permanente Collaboration
N=115,000; observational
Median follow-up:
Glargine users: 1.2 years
NPH users: 1.4 years
Breast cancer (women): 1.0 (0.9-1.3)
Prostate cancer (men): 0.7 (0.6-0.9)
Colorectal cancer (men and women): 1.00 (0.8-1.2)
All cancers (men and women): 0.9 (0.9-1.0)
MedAssurant Database Study
N=52,453; observational
Mean follow-up:
Glargine users: 1.2 years
NPH users: 1.1 years
No increased risk for breast cancer
Gerstein HC, et al. N Engl J Med. 2012;367:319-328. Kirkman MS, et al. Presented at the American Diabetes
Association 72nd Scientific Sessions. June 11, 2012. Session CT-SY13. Philadelphia, PA.
122
Diabetes and Cancer Risk
Management
• Conduct cancer screenings as recommended for age
and sex
• Encourage healthful diet, physical activity, and weight
management
• Evidence is inconclusive on effects of specific drugs
on cancer risk due to limited data and confounding
factors
• Cancer risk should not be a major factor in the choice
of antidiabetic agent unless the patient has a very
high risk of cancer occurrence or recurrence
Giovannucci E, et al. Diabetes Care. 2010;33:1674-1685.
123
Diabetes and Cancer: Summary
•
Screen obese individuals with diabetes more frequently and rigorously
for certain cancers
– Endometrial, breast, hepatic, bladder, pancreatic, colorectal cancers
•
Increased BMI (≥25 kg/m2) also increases risk of some cancers
– Strong associations: endometrial, gall bladder, esophageal , renal, thyroid,
ovarian, breast, and colorectal cancer
– Weaker associations: leukemia, malignant and multiple melanoma,
pancreatic cancer, non-Hodgkin lymphoma
•
To date, no definitive relationship has been established between
specific hyperglycemic agents and increased risk of cancer or cancerrelated mortality
– Consider avoiding medications considered disadvantageous to specific
cancers in individuals at risk for or with a history of that cancer
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
124