Transcript Type 2 Diabetes Management Goals

Management of Common
Comorbidities in Diabetes
1
Management of Common
Comorbidities in Diabetes
Obesity
4
Prevalence of Obesity in
Type 2 Diabetes
NHANES 1999-2004
(N=984)
T2DM Patients (%)
13% Normal (BMI <25)
24%
63%
Overweight
(BMI 25-29)
Obese
(BMI ≥30)
5
BMI, body mass index, in kg/m 2.
Ali MK, et al. New Engl J Med. 2013;368:1613-1624.
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
6
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Energy Homeostasis
Body Weight
Increase
Energy intake
Decrease
Energy
expenditure
Ingestion of:
Physical activity
Proteins
7
Fats
Diet-induced
thermogenesis
Carbohydrates
Basal metabolic rate
Multihormonal Control of Body
Weight: Fat-, Gut-, and IsletDerived Signals
Vagal afferents
Hypothalamus
GI tract
Adipose tissue
Ghrelin
Hindbrain
CCK
Leptin
PYY3-36
Insulin
Amylin
GLP-1
Resistin
Visfatin
OXM
Adiponectin
GIP
PP
Pancreatic islets
8
Badman MK, et al. Science. 2005;307(5717):1909-1914.
Small Amounts of Weight Gain or Loss
Have Important Effects on CHD Risk
Change in Risk Factor Sum (%)
Framingham Offspring Study 16-year Follow-up*
9
**
**
**
**
*Patients with Low HDL-C, high cholesterol, high BMI, high systolic BP, high triglyceride, high glucose.
**P <0.002 vs baseline.
Wilson PW, et al. Arch Intern Med. 1999;159:1104-1109.
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
*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.
10
Dagenais GR, et al. Am Heart J. 2005;149:54-60.
Medical Complications of
Obesity
Pulmonary disease
Abnormal function
Obstructive sleep apnea
Hypoventilation syndrome
Nonalcoholic fatty liver
disease
Steatohepatitis
Cirrhosis
Gall bladder disease
Gynecologic abnormalities
Abnormal menses
Infertility
Polycystic ovary syndrome
(PCOS)
Osteoarthritis
Skin
11
Gout
Idiopathic intracranial
hypertension
Stroke
Cataracts
Coronary heart disease
Diabetes
Dyslipidemia
Hypertension
Severe pancreatitis
Cancer
Breast, uterus, cervix, colon,
esophagus, kidney, pancreas,
prostate
Phlebitis
Venous stasis
Health Effects of Weight
Change in T2DM
• Weight loss
– Every kg of weight loss is
associated with 3-4 months
of improved survival1
– In a prospective analysis of
5000 people with type 2
diabetes, 35% reported
intentional weight loss; this
subgroup experienced a
25% reduction in mortality
over 12 years2
12
• Weight gain
– A 5-kg weight gain increases
CHD risk by 30%3
1. Lean ME, et al. Diabet Med. 1990;7:228-233.
2. Williamson DF, et al. Diabetes Care. 2000;23:1499-1503.
3. Anderson JW, et al. J Am Coll Nutr. 2003;22:331-339.
Intensive Intervention Reduces Significantly More
Weight than Standard Approaches in T2DM
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
3
2
4
Years
13
Differences between groups were statistically significant (P˂0.0001) at all 4 years.
ILI, intensive lifestyle intervention; DSE, diabetes support and education.
Look AHEAD Research Group. Arch Intern Med. 2010;170:1566-1575.
Long-term Limitations of Weight
Loss Benefits in T2DM
Look AHEAD Trial
Main effect: -4 (95% CI -5 to -3)
P<0.001
Estimated mean A1C (%)
Estimated mean weight (kg)
(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; T2DM, type 2 diabetes mellitus.
Look AHEAD Research Group. N Engl J Med. 2013;369:145-154.
Long-term Effects of Lifestyle Change on
Cardiovascular Risk in T2DM
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
15
T2DM, type 2 diabetes mellitus.
Look AHEAD Research Group. N Engl J Med. 2013;369:145-154.
AACE Healthful Eating
Recommendations
Topic
General eating
habits
Recommendation

Regular meals and snacks; avoid fasting to lose weight

Plant-based diet (high in fiber, low calories, low glycemic index, high in phytochemicals/antioxidants)

Understand Nutrition Facts Label information

Incorporate beliefs and culture into discussions

Informal physician-patient discussions

Use mild cooking techniques instead of high-heat cooking
Carbohydrate

Understand health effects of the 3 types of carbohydrates: sugars, starch, and fiber

Target 7-10 servings per day of healthful carbohydrates (fresh fruits and vegetables, pulses, whole
grains)

Lower-glycemic index foods may facilitate glycemic control:* multigrain bread, pumpernickel bread,
whole oats, legumes, apple, lentils, chickpeas, mango, yams, brown rice
Fat

Eat healthful fats: low-mercury/low-contaminant-containing nuts, avocado, certain plant oils, fish

Limit saturated fats (butter, fatty red meats, tropical plant oils, fast foods) and trans fat

Use no- or low-fat dairy products
Protein

Consume protein from foods low in saturated fats (fish, egg whites, beans)

Avoid or limit processed meats
Micronutrients

Routine supplementation not necessary except for patients at risk of insufficiency or deficiency

Chromium; vanadium; magnesium; vitamins A, C, and E; and CoQ10 not recommended for glycemic
control
*Insufficient evidence to support a formal recommendation to educate patients that sugars have both positive and negative
health effects
16
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
AACE Physical Activity
Recommendations
• Evaluate for
contraindications and/or
limitations to increased
physical activity before
patient begins or
intensifies exercise
program
• Develop exercise
recommendations
according to individual
goals and limitations
• ≥150 minutes per week of
moderate-intensity
exercise
– Flexibility and strength
training
– Aerobic exercise (eg, brisk
walking)
• Start slowly and build up
gradually
17
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Weight Gain/Loss Potential with
Antidiabetic Agents
Class
Agent(s)
Weight Effect
Amylin analogs
Pramlintide
↓
Biguanides
Metformin
↓
GLP-1 receptor agonists
Exenatide, exenatide XR, liraglutide
↓↓
SGLT-2 inhibitors
Canagliflozin
↓
-Glucosidase inhibitors
Acarbose, miglitol
↔
Bile acid sequestrants
Colesevelam
↔
DPP-4 inhibitors
Alogliptin, linagliptin, saxagliptin, sitagliptin
↔
Dopamine-2 agonists
Bromocriptine
↔
Glinides
Nateglinide, repaglinide
↑
Sulfonylureas
Glimepiride, glipizide, glyburide
↑
Insulins
Aspart, detemir, glargine, glulisine, lispro,
NPH, regular
↑↑
Thiazolidinediones
Pioglitazone, rosiglitazone
↑↑
18
Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. Garber AJ, et al. Endocr Pract. 2013;19:327-336.
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Stenlof K, et al. Diabetes Obes Metab 2013;15:372-382.
Effects of Phentermine/Topiramate ER
in Advanced T2DM
Poorly Controlled Type 2 Diabetes
Weight
Baseline
Mean A1C (%)
Change in diabetes
medications (score)
P<0.0001
†Net
8.6
8.8
LS Mean
A1C (%)
Phen/TPN
15/92 mg
(n=75)
Mean Weight (%)
Placebo
(n=55)
Glucose Control
P=0.038
Placebo
(n=55)
Phen/TPN
15/92 mg
(n=75)
*P=0.038 vs placebo.
score reflecting change in medication number and change in dose level of diabetes medications.
Garvey WT, et al. Diabetes. 2009;58(suppl 2): Abstr. 361-OR.
Effect of Lorcaserin in Type 2
Diabetes
BLOOM-DM Study
*
20
*
8.0
LS Mean
A1C (%)
LS Mean
A1C (%)
Lorcaserin Lorcaserin
Placebo 10 mg BID 10 mg QD
(n=248)
(n=251)
(n=95)
Glucose Control
Baseline
Mean A1C (%)
Patients
Increasing Use
of Antidiabetic
Agents (%)
Weight
8.1
8.1
*
*
†
†
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.
A1C from 93 patients in lorcaserin 10 mg QD group.
BLOOM-DM, Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus.
O’Neil PM, et al. Obesity. 2012;20:1426-1436.
‡Mean
Management of Common
Comorbidities in Diabetes
Dyslipidemia
21
Prevalence of Hyperlipidemia
in T2DM
Retrospective Medical
Database Study, T2DM
NHANES
T2DM Patients With
Hyperlipidemia*
(N=125,464)
1%, No need
for treatment
63%
Receiving
statin
35%
Eligible for
lipid-lowering
therapy but
untreated
22
*LDL-C ≥100 mg/dL, TC≥200 mg/dL, or TG≥150 mg/dL (treatment not assessed).
Fu AZ, et al. Curr Med Res Opin. 2011;27:1035-1040.
Suh DC, et al. J Diabetes Complications. 2010;24:382-391.
Atherogenic Dyslipidemia
• Common in T2DM and the insulin
resistance syndrome
• Features
– Elevated triglycerides
– Decreased HDL-C
– Small, dense LDL particles
– Postprandial increase in triglyceride-rich
lipoproteins
23
HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein.
Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78.
Effect of Weight Loss in T2DM on Lipids
Look AHEAD Trial
(N=5145)
LDL-C
HDL-C
110
105
Main effect: 1.6 (95% CI 0.3, 2.9)
P<0.05
100
*
95
*
Estimated mean
(mg/dL)
49
*
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
Years
Estimated mean
(mg/dL)
Estimated mean
(mg/dL)
115
0
1
2
3
4
150
*
140
*
6
7
8
9
10
Years
Triglycerides
160
5
Main effect (%): 99 (95% CI 96, 101)
P=0.261
ILI
DSE
130
120
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; T2DM, type 2 diabetes mellitus.
Look AHEAD Research Group. N Engl J Med. 2013;369:145-154.
LDL-C and LDL Particle Number in T2DM
Patients With LDL-C <100 mg/dL
(N=2355)
5th
Subjects (%)
LDL-C
20th
Subjects (%)
80th
percentile
130
160
mg/dL
37%
63%
(n=870) (n=1485)
70
LDL-P
50th
7%
(n=162)
100
31%
(n=741)
38%
(n=891)
16%
(n=383)
62%
8%
(n=178)
62% at high risk
(LDL-P exceeds
1000) despite
optimum LDL-C
(<100 mg/dL)
24%
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.
LDL Particle Number
Distribution in T2DM
(n=1484)
1%
(n=19)
24%
(n=364)
Subjects (%)
(n=871)
43%
(n=631)
50th
21%
(n=307)
63%
80th
percentile
11%
(n=163)
32%
70
LDL-C
≤70 mg/dL
20th
Subjects (%)
LDL-C
71-99 mg/dL
5th
16%
(n=147)
100
43%
(n=377)
130
160
30%
(n=260)
9%
(n=76)
mg/dL
2%
(n=15)
41%
11%
700
1000
1300
1600
nmol/L
LDL-C, low-density lipoprotein cholesterol.
Cromwell WC, Otvos JD Am J Cardiol. 2006;98:1599-1602.
Dyslipidemia Treatment
Options
Efficacy
Class
MOA
HMG CoA reductase inhibitors
(statins)
Competitively inhibit rate-limiting
step of cholesterol synthesis,
slowing production in liver
Fibric acid derivatives
Stimulate lipoprotein lipase
activity
LDL-C
HDL-C
Triglycerides
Main Limitations
•
 21-55%
 VLDL
Fenofibrate
may  LDL-C
20-25% (612% in FIELD)
 2-10%
 6-30%
•
•
•
•
 6-18%
 20-35%
•
•
Risk of myopathy, increased liver
transaminases
Contraindicated in liver disease
Liver enzyme monitoring required
Risk of new-onset diabetes
GI symptoms, possible
cholelithiasis
Gemfibrozil may  LDL-C
Myopathy risk increased when used
with statins
•
Skin flushing, pruritus, GI
symptoms, potential increases in
blood glucose and uric acid
—
•
•
GI symptoms
May  triglycerides
—
•
Risk of myopathy
Niacin/nicotinic acid
Reduce hepatic synthesis of
LDL-C and VLDL-C
 10-25%
 10-35%
 20-30%
Bile acid sequestrants
Bind bile acids in the intestine
 15-25%
—
Cholesterol absorption
inhibitors
Inhibit intestinal absorption of
cholesterol
 10-18%
(as
monotherapy)
—
27
HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein.
Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78. FIELD Study Investigators. Lancet. 2005;366:1849-1861.
Benefits of Aggressive LDL-C
Lowering in Diabetes
Aggressive lipid- Aggressive lipidlowering better lowering worse
Primary event rate (%)
Treatment
TNT
Diabetes, CHD
ASCOT-LLA
Diabetes, HTN
CARDS
Diabetes, no CVD
HPS
All diabetes
Control
P
Difference in
LDL-C
(mg/dL)
0.026
22*
0.036
35†
0.001
46†
<0.0001
39†
0.0003
39†
0.75
13.8
17.9
0.77
9.2
11.9
0.63
5.8
9.0
0.73
9.4
12.6
0.67
Diabetes, no CVD
9.3
13.5
0.5
*Atorvastatin 10 vs 80 mg/day
†Statin vs placebo
0.7
0.9 1
1.7
Relative risk
28
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.
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
29
Cholesterol Treatment Trialists’ Collaborators. Lancet. 2008;371:117-125.
Treat Patients With the Greatest
Absolute Risk the Most Aggressively
30
Robinson JG, et al. Am J Cardiol. 2006;98:1405-1408.
Residual Cardiovascular Risk
in Major Statin Trials
CHD events still occur in patients treated with statins
Secondary
Primary
CARE
HPS
CARDS
9014
-25%
4159
-28%
20,536
-29%
2841
-40%
782
586
5963
2841
Total
Population
(%)
LIPID
Patients with
Diabetes
(%)
N=
 LDL-C
N=
31
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.
Lipid Effects of Adding a Fenofibrate
to a Statin in Patients With T2DM
Action to Control Cardiovascular Risk in Diabetes
(N=5518)
32
ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.
Effects of Adding a Fenofibrate to a Statin
on CV Events in Patients With T2DM
Action to Control Cardiovascular Risk in Diabetes
(N=5518)
33
ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.
Adding a Fenofibrate to a Statin in
Patients With T2DM: Subgroup Analyses
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
Placebo
Triglycerides (mmol/L)
Baseline
2.59
2.42
Endpoint
-29%
+1%
Baseline
1.01
1.05
Endpoint
+7%
+2%
HDL-C (mmol/L)
Change in Stenosis (%)
Fenofibrate
*
(n=207)
(n=211)
35
*P=0.02 vs placebo
Diabetes Atherosclerosis Intervention Study. Lancet. 2001;357:905-910.
Coronary Drug Project:
15-Year Follow-up
Event Rate (%)
11% Reduction
P =0.0004
12% Reduction
P <0.05
36
Canner PL, et al. J Am Coll Cardiol. 1986;8:1245-1255. Canner PL, et al. J Am Coll Cardiol. 2005;95:254-257.
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
37
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.
Management of Common
Comorbidities in Diabetes
Hypertension
38
Meta-Regression Analysis of Major
CV Events and BP Reduction
Relative Risk
2.0
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
Difference in reduction in systolic BP (mm Hg)
3
6
39
BPLTTC. BMJ. 2008;336:1121-1123.
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
CV Deaths
P=0.005
51%
P=0.50
n=1501
n=18,790
Events per
1000 Patient-years
Events per
1000 Patient-years
Major CV Events
DBP ≤ 90
DBP ≤85
DBP ≤ 80
P=0.016
67%
n=1501
P=0.49
n=18,790
40
DBP, diastolic blood pressure, in mmHg.
Hansson L, et al. Lancet. 1998;351:1755-1762.
Blood Pressure and Diabetic
Complications
10
10
P<0.0001
1
13% Decrease
per 10 mmHg reduction in SBP
0.5
110 120 130 140 150 160 170
Updated Mean A1C
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
41
Adler Al, et al. BMJ. 2000;321:412-419.
BP Reductions and Risk of Micro- and
Macrovascular Complications in T2DM
United Kingdom Prospective Diabetes Study
Benefits of 144/82 vs. 154/87 mm Hg (N=1148)
Risk Reduction (%)
Any
diabetesMyocardial related
infarction endpoint
P=0.13
Diabetesrelated
death
Stroke
Heart
failure
P=0.005
P=0.019
P=0.004
P=0.29
P=0.013
42
Vision
Renal
deteriorfailure Retinopathy ation
P=0.004
P=0.004
UKPDS Group. BMJ. 1998;317:703-713.
Effect of Intensive Blood-Pressure Control
on CV Outcomes and Death in T2DM
Action to Control Cardiovascular Risk in Diabetes
(N=4733)
43
ACCORD Study Group. N Engl J Med. 2010;362:1575-1585.
Long-Term Follow-up After Tight
Control of Blood Pressure in T2DM
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:
–
–
–
–
•
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)
44
Holman RR, et al. N Engl J Med. 2008;359;1565-1576.
Intensive Blood Pressure
Control
in
T2DM
Action to Control Cardiovascular Risk in Diabetes
(N=4733)
45
ACCORD Study Group. N Engl J Med. 2010;362:1575-1585.
Effect of Weight Loss on Blood
Pressure in T2DM
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
Years
6
7
8
9
10
Estimated mean
(mm Hg)
Estimated mean
(mm Hg)
130
71
70
69
68
67
66
65
64
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.
46
CI, confidence interval; DSE, diabetes support and education; ILI, intensive lifestyle intervention;
T2DM, type 2 diabetes mellitus.
Look AHEAD Research Group. N Engl J Med. 2013;369:145-154.
Multiple Antihypertensive Agents Are
Usually Required to Achieve BP Control
47
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.
Compelling Indications
for Individual Drug Classes
Recommended Drugs
Compelling
Indication
Heart failure
Diuretic
•
Post-myocardial
infarction
•
ACEI
•
•
•
ARB
•
•
•
Diabetes
•
•
•
•
•
•
Recurrent stroke
prevention
•
•
CCB
•
High coronary
disease risk
Chronic kidney
disease
48
BB
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.
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
49
Unger T, et al. Am J Cardiol. 2007;100:25J-31J.
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
50
Unger T, et al. Am J Cardiol. 2007;100:25J-31J.
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
listed
1.0 favors
2nd
listed
2.0
Odds Ratio
51
Volpe M, et al. J Hypertension. 2009;27:941-946.
Hypertension Summary
• In T2DM, 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 mm Hg
• 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 BPcontrol regimens of patients with diabetes because of
beneficial effects on the renin-angiotensin system
52
Torre JJ, et al. Endocr Pract. 2006;12:193-222.
Management of Common
Comorbidities in Diabetes
Chronic Kidney Disease
53
Reducing A1C Reduces
Nephropathy Risk in T2DM
54
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.
Prevalence of CKD in
Diagnosed Diabetes
Diabetic Kidney Disease Is the Leading Cause of Kidney Failure in the United States
NKF
Description
Stage
55
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.
ESRD, end-stage renal disease; GFR, glomerular filtration rate (mL/min/1.73 m 2); NKF, National Kidney Foundation.
CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf.
Plantinga LC, et al. Clin J Am Soc Nephrol. 2010;5:673-682.
Cardiovascular Outcomes Worsen
With CKD Progression
Valsartan in Acute Myocardial Infarction Trial
(N=14,527*)
eGFR (mL/min/1.73 m2)
†
75
60-74
45-59
<45
†
†
†
†
†
56
*23% of patients had diabetes.
vs GFR ≥75 by Cox model.
CHF, congestive heart failure; CV, cardiovascular.
Anavekar NS, et al. N Engl J Med. 2004;351:1285-1295.
†P<0.001
CV Risk Increases With
Comorbid Diabetes and CKD
x 2.8
x 2.0
x 2.1
x 1.7
x 2.5
x 2.3
57
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.
Appropriate Staging and
Management of CKD
GFR
Stage Description
Action*
Diagnose and treat CKD, slow
progression of CKD, treat comorbid
conditions, reduce CVD risk factors
1
Kidney damage† with
normal or  GFR
≥90
2
Kidney damage† with
mild  GFR
60-89
Estimate progression
3
Moderate  GFR
30-59
Evaluate and treat complications
4
Severe  GFR
15-29
Prepare for kidney replacement
therapy
5
Kidney failure
ESRD
58
(mL/min/1.73 m2)
<15 or dialysis
Kidney replacement, if uremia
present
Renal replacement therapy
CKD, chronic kidney disease.
*Includes actions from preceding stages.
†Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.
National Kidney Foundation. Am J Kidney Dis. 2002;49(suppl 1):S1-S266.
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
59
Levey AS, et al. Kidney Int. 2011;80:17-28.
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
Statin therapy recommended
Fibrate dose reduction may be required
60
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.
Dietary Guidelines for DKD
CKD Stage
Macronutrient
1-2
1-4
Sodium, g/d
<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.
61
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.
Use of Noninsulin Antidiabetic Therapies
in Patients With Kidney Disease
62
Class
Agent(s)
Kidney Disease Recommendation
Amylin analog
Pramlintide
No dosage adjustment
Thiazolidinediones
Pioglitazone, rosiglitazone
No dosage adjustment
Bile acid sequestrant
Colesevelam
No dosage adjustment
DPP-4 inhibitors
Linagliptin, saxagliptin, sitagliptin
Dopamine-2 agonist
Bromocriptine
Glinides
Nateglinide, repaglinide
Insulin
Aspart, detemir, glargine, glulisine, lispro, NPH,
regular
Sulfonylureas
Glimepiride, glipizide, glyburide
GLP-1 receptor agonists
Exenatide, exenatide XR, liraglutide
-Glucosidase inhibitors
Acarbose, miglitol
Biguanide
Metformin
Reduce dosage for saxagliptin and
sitagliptin if CrCl <50 mg/dL
Use with caution
Use lowest effective dose of nateglinide
for stage ≥3 CKD
Dosage reduction needed in
stage 4-5 CKD
Glimepiride preferred, use lowest
effective dose; avoid other SUs
Use with caution in stage 3 CKD;
avoid in stage 4-5 CKD
Not recommended if SCr >2 mg/dL;
avoid in dialysis
Contraindicated if SCr >1.5 in men or
1.4 in women
Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.
Management of Common
Comorbidities in Diabetes
Cardiovascular Disease
63
Coincidence of CV
Comorbidities in T2DM
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%
5.9%
7.4%
(LDL-C ≥100 mg/dL,
TC ≥200 mg/dL, or
TG ≥150 mg/dL)
64
Suh DC, et al. J Diabetes Complications. 2010;24:382-391.
Cardiovascular Disease Risk
Factors
Major
Additional
Nontraditional
•
Advancing age
•
•
Elevated clotting factors
•
Features of dyslipidemia
•
Inflammation markers
(hsCRP; Lp-PLA2)
•
High total serum
cholesterol level
•
High non–HDL-C
•
High LDL-C
•
Low HDL-C
Obesity or abdominal
obesity
•
PCOS
•
Family history of
hyperlipidemia
•
Hyperhomocysteinemia
•
Elevated uric acid
Features of dyslipidemia
•
Features of dyslipidemia
•
•
Small, dense LDL-C
•
Apo E4 isoform
•
Elevated lipoprotein (a)
•
Diabetes mellitus
•
Increased Apo B
•
Hypertension
•
•
Cigarette smoking
Increased LDL particle
number
•
Family history of CAD
•
Fasting/postprandial
hypertriglyceridemia
•
Dyslipidemic triad*
*Hypertriglyceridemia; low HDL-C; and small, dense LDL-C.
65
Apo, apolipoprotein; CAD, coronary artery 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. 2012;18(suppl 1):1-78.
Coronary Artery Disease Risk
Categories
66
Risk Category
Risk Determinant
Very high
Established or recent hospitalization for coronary, carotid, and
peripheral vascular disease
– or –
Diabetes plus 1 or more additional risk factor(s)
High
≥2 risk factors and 10-year risk* >20%
– or –
CHD risk equivalent
• Diabetes ± other risk factors
• Noncoronary atherosclerotic disease
• Peripheral arterial disease
• Abdominal aortic aneurysm
• Carotid artery disease
Moderately high
≥2 risk factors and 10-year risk 10% to 20%
Moderate
≥2 risk factors and 10-year risk <10%
Low
≤1 risk factor
*Framingham Risk Score
CHD, coronary heart disease.
Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78.
7-Year Incidence of MI (%)
Diabetes Is a Cardiovascular
Disease Risk Equivalent
P<0.001
P<0.001
No prior MI
Prior MI
Nondiabetic
(n=1373)
67
No prior MI
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.
CVD Risk Factors:
AACE Targets
Risk Factor
Recommended Goal
Anticoagulant therapy
Use aspirin for primary and secondary prevention of
CVD events
Weight
Lipids
Total cholesterol, mg/dL
LDL-C, mg/dL
Non-HDL-C, mg/dL
ApoB, mg/dL
HDL-C, mg/dL
Triglycerides, mg/dL
Blood pressure
Systolic, mm Hg
Diastolic, mm Hg
Reduce by 5% to 10%; avoid weight gain
<200
<70 very high risk; <100 all other risk categories
30 above LDL-C goal
<80 very high risk; <90 high risk
≥40 in both men and women
<150
<130
<80
68
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78.
Management of Common
Comorbidities in Diabetes
Depression
69
Prevalence of Comorbid
Depression and Diabetes
Diverse, Community Sample
Meta-analysis
2.1
% Population
% Population
1.9
P=0.5
OR
Major
Depressive
Disorder
Likely
Depression
Diagnostic
Interview
Self-report
Scale
70
Fisher L, et al. Diabetes Care. 2007;30:542-548; Anderson RJ, et al. Diabetes Care. 2001;24:1069-1078
Depression and Adherence to
Diabetes Self-management
Mean Adherent Days/Week
2.3-Fold increased risk of missing 1 or more prescribed
medications over previous week with major depression
(HANDS score ≥9)
(HANDS score <9)
P<0.001
P<0.001
P=0.001
P=0.006
P<0.001
General
diet
Carbohydrates
Exercise
P=0.348
P=0.241
Glucose
monitoring
Fruits
and
vegetables
High fat
foods
Foot care
71
HANDS, Harvard Department of Psychiatry/National Depression Screening Day Scale.
Gonzales JS, et al. Diabetes Care. 2007;30:2222-2227.
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
72
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
ADA. Diabetes Care. 2012;34(suppl 1):S11-S61.
Management of Common
Comorbidities in Diabetes
Sleep Apnea
73
Sleep Apnea
Obstructive
• Caused by relaxation of
muscles supporting palate
• Risk factors
–
–
–
–
–
–
–
–
–
Obesity
Hypertension
Male gender
Neck circumference >44 cm
Narrowed airway
Age
Family history
Alcohol, sedative use
Smoking
Central
• Caused by neural signaling
failure between brain and
muscles surrounding lungs
• Risk factors
–
–
–
–
CHF
Atrial fibrillation
Cerebrovascular disease
Brain tumor
74
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.
Obstructive Sleep Apnea and
Insulin Resistance
Sleep apnea
Sleep fragmentation
Sleep debt
EDS fatigue
Depression of
ventilation
Diaphragm mobility
Soft tissue edema
Stress hormones
Interleukin-6
Inflammatory
cytokines
Visceral fat
Insulin resistance
75
Vgontzas AN, et al. J Intern Med. 2003;254:32-44 .
Prevalence of Sleep Apnea
in T2DM
Sleep AHEAD Study
Obese Patients With T2DM
(N=305)
76
OSA, obstructive sleep apnea.
Foster GD, et al. Diabetes Care. 2009;32:1017-1019.
Treatment for Sleep Apnea
•
•
•
•
Obstructive Sleep Apnea
Continuous positive airway
pressure (CPAP)
Adjustable airway pressure
devices
Oral appliances
Surgery
– Uvulopalatopharyngoplasty
(UPPP)
– Maxillomandibular
advancement
– Tracheostomy
Central and Mixed Sleep Apnea
• Optimize therapy for associated
conditions
• Supplemental oxygen
• CPAP
• Bilevel positive airway pressure
(BiPAP)
• Adaptive servo-ventilation (ASV)
77
Aurora RN, et al. Sleep. 2012;35:17-40.
Epstein LJ, et al. J Clin Sleep Med. 2009;5:263-276.
Management of Common
Comorbidities in Diabetes
Cancer
78
Diabetes and Cancer Risk
• Diabetes (especially T2DM)
may:
– ↑ Cancer risk
•
•
•
•
•
•
Liver
Pancreas
Endometrium
Colon and rectum
Breast
Bladder
– ↓ Cancer risk: prostate
• Hyperinsulinemia,
hyperglycemia, and
inflammation may directly
increase cancer risk
• Shared risk factors
–
–
–
–
Aging
Obesity
Diet
Physical inactivity
79
Giovannucci E, et al. Diabetes Care. 2010;33:1674-1685.
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
80
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.
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
81
Giovannucci E, et al. Diabetes Care. 2010;33:1674-1685.