Download Type 2 Diabetes Management Goals

Management of Common
Comorbidities in Diabetes
1
Management of Common Comorbidities in Diabetes
OBESITY
2
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
8
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.
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
12
Peripheral and Central Regulation of
Energy Intake
Bray GA, et al. Lancet. 2016;387:1947-1956.
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
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. 2012;18(suppl 1):1-78.
31
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.
32
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.
33
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.
34
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
36
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.
37
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 Feb 3 [epub before print].
Continued on next slide
38
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 Feb 3 [epub before print].
Continued from previous slide
39
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
40
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.
41
Treat Patients With the Greatest
Absolute Risk the Most Aggressively
Robinson JG, et al. Am J Cardiol. 2006;98:1405-1408.
42
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
43
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.
44
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.
45
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.
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.
47
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.
48
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. 2012;18(suppl 1):1-78.
49
Management of Common Comorbidities in Diabetes
HYPERTENSION
50
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.
52
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.
53
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
54
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
55
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)
56
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.
57
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.
58
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.
59
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
60
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.
61
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.
62
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.
63
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.
64
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.
65
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.
66
Management of Common Comorbidities in Diabetes
CHRONIC KIDNEY DISEASE
67
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.
68
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.
69
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.
70
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.
71
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.
72
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.
73
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.
74
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.
75
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
76
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.
77
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.
78
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.
79
Management of Common Comorbidities in Diabetes
CARDIOVASCULAR DISEASE
80
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.
81
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)
82
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 Feb 3 [epub ahead of print].
83
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 Feb 3 [epub ahead of print].
84
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.
85
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.
86
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.
87
Management of Common Comorbidities in Diabetes
DEPRESSION
88
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
89
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.
90
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.
91
Management of Common Comorbidities in Diabetes
SLEEP APNEA
92
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
 Male sex
 Age
 Smoking
Treatment
Options
 Family history
 Alcohol or
sedatives
 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 .
93
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.
94
Management of Common Comorbidities in Diabetes
CANCER
95
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
96
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.
97
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.
98
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.
99