Management of Common Comorbidities in Diabetes
1
Management of Common Comorbidities in Diabetes
Obesity
4
Prevalence of Obesity inType 2 Diabetes
0
20
40
60
80
100
5
63%
24%
13% Normal (BMI <25)
Overweight(BMI 25-29)
Obese(BMI ≥30)
BMI, body mass index, in kg/m2.Ali MK, et al. New Engl J Med. 2013;368:1613-1624.
NHANES 1999-2004(N=984)
T2D
M P
atie
nts
(%
)
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
6
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Goal: 5% to 10% weight loss
Energy intake
Ingestion of:
Proteins
Fats
Carbohydrates
Energy expenditure
Physical activity
Diet-induced thermogenesis
Basal metabolic rate
Body Weight
Increase Decrease
Energy Homeostasis
7
Badman MK, et al. Science. 2005;307(5717):1909-1914.
GI tract
Adipose tissue
Pancreatic islets
Hypothalamus
Hindbrain
CCK
Adiponectin
Insulin
Amylin
Leptin
OXM
Ghrelin
GLP-1
PYY3-36
GIP PP
ResistinVisfatin
Vagal afferents
Multihormonal Control of Body Weight: Fat-, Gut-, and Islet-Derived Signals
8
Small Amounts of Weight Gain or Loss Have Important Effects on CHD Risk
*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.
Framingham Offspring Study 16-year Follow-up*
Ch
ang
e in
Ris
k F
acto
r S
um
(%
)
**
**
****
9
Abdominal Obesity and Increased Risk of Cardiovascular Events
Dagenais GR, et al. Am Heart J. 2005;149:54-60.
Waist Circumference (cm)
Men Women
Tertile 1 <95 <87
Tertile 2 95-103 87-98
Tertile 3 >103 >98
The HOPE Study
*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
Pulmonary diseaseAbnormal functionObstructive sleep apneaHypoventilation syndrome
Nonalcoholic fatty liver diseaseSteatohepatitisCirrhosis
Coronary heart disease Diabetes Dyslipidemia Hypertension
Gynecologic abnormalitiesAbnormal mensesInfertilityPolycystic ovary syndrome (PCOS)
Osteoarthritis
Skin
Gall bladder disease
CancerBreast, uterus, cervix, colon, esophagus, kidney, pancreas, prostate
PhlebitisVenous stasis
Gout
Idiopathic intracranial hypertension
StrokeCataracts
Severe pancreatitis
Medical Complications of Obesity
11
• 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
• Weight gain– A 5-kg weight gain increases
CHD risk by 30%3
Health Effects of Weight Change in T2DM
12 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.
13
Intensive Intervention Reduces Significantly More Weight than Standard Approaches in T2DM
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.
Red
uct
ion
in
in
itia
l w
eig
ht
(%)
-2
-10
Years
0
-4
-6
-8
0 1 2 3 4
Retention at 4 years:ILI = 94.1%DSE = 93.1%
-1.1%
-4.7%
P<0.0001Diabetes support and educationIntensive lifestyle intervention
Look AHEAD Trial(N=5145)
Long-term Limitations of Weight Loss Benefits in T2DM
Look AHEAD Trial(N=5145)
*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.
Est
ima
ted
me
an A
1C
(%
)
Est
ima
ted
me
an w
eig
ht
(kg
)
Main effect: -4 (95% CI -5 to -3)P<0.001
Main effect:-0.22 (95% CI -0.28 to -0.16)P<0.001
15
Long-term Effects of Lifestyle Change on Cardiovascular Risk in T2DM
Look AHEAD Trial
T2DM, type 2 diabetes mellitus.
Look AHEAD Research Group. N Engl J Med. 2013;369:145-154.
HR 0.95 (95% CI, 0.80 to 1.09)P=0.51
Patients experiencingdeath from cardiovascular
causes, nonfatal myocardial infarction, nonfatal
stroke, or hospitalization for angina (%)
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
AACE Healthful Eating Recommendations
16
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Topic Recommendation
General eating habits
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
• 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
AACE Physical Activity Recommendations
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 ↑↑
18Inzucchi 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 ERin Advanced T2DM
-2
-1.5
-1
-0.5
0
-1.13
-1.61
*P=0.038 vs placebo.†Net 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.
LS
Mea
nA
1C (
%)
Poorly Controlled Type 2 Diabetes
BaselineMean A1C (%) 8.6 8.8
Placebo(n=55)
Phen/TPN 15/92 mg
(n=75)
Series1-20
0
20
40 30
-16
Placebo(n=55)
Phen/TPN 15/92 mg
(n=75)
Glucose Control
Ch
ang
e i
n d
iab
etes
m
edic
atio
ns
(sco
re)
Weight
-10-9-8-7-6-5-4-3-2-10
-2.7
-9.4
Mea
n
Wei
gh
t (%
)
P=0.038
P<0.0001
20
Effect of Lorcaserin in Type 2 Diabetes
BLOOM-DM Study
-1.2-1
-0.8-0.6-0.4-0.2
0
-0.4
-0.9-1
LS
Mea
nA
1C (
%)
BaselineMean A1C (%) 8.0 8.1 8.1
Series10
40
8088.3 82.9 76.6
Pat
ien
ts
Incr
easi
ng
Use
o
f A
nti
dia
bet
ic
Ag
ents
(%
)
†
Placebo(n=248)
Lorcaserin 10 mg BID
(n=251)
Lorcaserin 10 mg QD
(n=95)‡
*P<0.001 vs placebo. †P=0.087 vs placebo.‡Mean 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.
†
* *
Glucose ControlWeight
-6
-5
-4
-3
-2
-1
0
-1.5
-4.5-5
LS
Mea
nA
1C (
%)
Placebo(n=248)
Lorcaserin 10 mg BID
(n=251)
Lorcaserin 10 mg QD
(n=95)
**
Management of Common Comorbidities in Diabetes
Dyslipidemia
21
Prevalence of Hyperlipidemia in T2DM
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.
1%, No need for treatment
63%Receiving statin
35%Eligible for lipid-lowering therapy but untreated
Retrospective Medical Database Study, T2DM
(N=125,464)
NHANEST2DM Patients With
Hyperlipidemia*
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
23HDL-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 LipidsLook AHEAD Trial
(N=5145)
*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.
ILIDSE
Es
tim
ate
d m
ea
n
(mg
/dL
)
10
100
90
85
95
105
0 21
110
115
3 54 6 87 9
LDL-C
Main effect: 1.6 (95% CI 0.3, 2.9)P<0.05
**
*
Years10
46
44
43
45
47
0 21
48
49
3 54 6 87 9
HDL-C
Main effect: 1.2 (95% CI 0.6, 1.9)P<0.05E
sti
ma
ted
me
an
(m
g/d
L) * * * * *
Years
120
130
140
150
160
100 21 3 54 6 87 9
Triglycerides
Main effect (%): 99 (95% CI 96, 101)P=0.261
Es
tim
ate
d m
ea
n
(mg
/dL
) **
Years
Dyslipidemia Treatment Options
ClassMOA
Efficacy
Main LimitationsLDL-C HDL-C Triglycerides
HMG CoA reductase inhibitors (statins)Competitively inhibit rate-limiting step of cholesterol synthesis, slowing production in liver
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
Fibric acid derivativesStimulate lipoprotein lipase activity
VLDLFenofibrate
may LDL-C 20-25% (6-
12% in FIELD)
6-18% 20-35%
• GI symptoms, possible cholelithiasis
• Gemfibrozil may LDL-C• Myopathy risk increased when
used with statins
Niacin/nicotinic acidReduce hepatic synthesis ofLDL-C and VLDL-C
10-25% 10-35% 20-30%• Skin flushing, pruritus, GI
symptoms, potential increases in blood glucose and uric acid
Bile acid sequestrantsBind bile acids in the intestine
15-25% — —• GI symptoms• May triglycerides
Cholesterol absorption inhibitorsInhibit intestinal absorption of cholesterol
10-18%(as
monotherapy)— — • Risk of myopathy
25HDL-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
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.
Difference in LDL-C
(mg/dL)
Aggressive lipid-lowering better
Aggressive lipid-lowering worse
0.026
0.036
0.001
<0.0001
0.0003
Primary event rate (%)
17.9
11.9
9.0
12.6
13.5
Control
13.8
9.2
5.8
9.4
9.3
Treatment
0.63
0.67
0.73
P
TNT Diabetes, CHD
ASCOT-LLA Diabetes, HTN
CARDS Diabetes, no CVD
HPS All diabetes
Diabetes, no CVD
*Atorvastatin 10 vs 80 mg/day†Statin vs placebo Relative riskRelative risk
0.7 0.9 10.5 1.7
0.77
22*
35†
46†
39†
39†
0.75
26
Patients with Diabetes(N=18,686; 14 RCTs)
Cholesterol Treatment Trialists’ Collaborators. Lancet. 2008;371:117-125.
Randomized Trials of Statins: A Meta-Analysis of CV Events
27
Risk Reduction in Major Vascular Events per mmol/L Decrease in LDL-C
Treat Patients With the Greatest Absolute Risk the Most Aggressively
Robinson JG, et al. Am J Cardiol. 2006;98:1405-1408.
28
Residual Cardiovascular Risk in Major Statin Trials
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.
Secondary Primary
CHD events still occur in patients treated with statins
N = 9014 4159 20,536 2841 LDL-C -25% -28% -29% -40%
29
Tota
lP
op
ula
tio
n(%
)
Pat
ien
ts w
ith
D
iab
etes
(%)
N = 782 586 5963 2841
LIPID CARE HPS CARDS
Lipid Effects of Adding a Fenofibrate to a Statin in Patients With T2DM
ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.
30
Action to Control Cardiovascular Risk in Diabetes(N=5518)
Effects of Adding a Fenofibrate to a Statin on CV Events in Patients With T2DM
ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.
31
Action to Control Cardiovascular Risk in Diabetes(N=5518)
Adding a Fenofibrate to a Statin in Patients With T2DM: Subgroup Analyses
ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.
Action to Control Cardiovascular Risk in Diabetes(N=5518)
*P=0.02 vs placeboDiabetes Atherosclerosis Intervention Study. Lancet. 2001;357:905-910.
Diabetes Atherosclerosis Intervention Study
Effect of Fenofibrate on Progression of Coronary Atherosclerosis in Patients With
Type 2 Diabetes
*
Cha
nge
in S
teno
sis
(%)
(n=207) (n=211)
33
Fenofibrate Placebo
Triglycerides (mmol/L)
Baseline 2.59 2.42
Endpoint -29% +1%
HDL-C (mmol/L)
Baseline 1.01 1.05
Endpoint +7% +2%
Coronary Drug Project:15-Year Follow-up
Canner PL, et al. J Am Coll Cardiol. 1986;8:1245-1255. Canner PL, et al. J Am Coll Cardiol. 2005;95:254-257.
Eve
nt
Rat
e (%
)
12% ReductionP <0.05
11% ReductionP =0.0004
34
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
35CVD, 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
36
BPLTTC. BMJ. 2008;336:1121-1123.
Meta-Regression Analysis of Major CV Events and BP Reduction
-15 -12 - 9 -6 -3 0 36
Rel
ativ
e R
isk
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
Difference in reduction in systolic BP (mm Hg)
2.0
1.0
0.5
0.25
37
DBP, diastolic blood pressure, in mmHg.Hansson L, et al. Lancet. 1998;351:1755-1762.
BP Reduction and Effect on CV Mortality at 4 Years
Hypertension Optimal Treatment Trial
Eve
nts
per
1000
Pat
ien
t-ye
ars
n=18,790n=1501
67%
38
The lower the target BP in patients with diabetes,the lower the rates of CV events and CV deaths
P=0.016
P=0.49
CV Deaths
Eve
nts
per
1000
Pat
ien
t-ye
ars
n=18,790n=1501
51%
P=0.005
P=0.50
Major CV Events
DBP ≤ 90
DBP ≤85
DBP ≤ 80
Adler Al, et al. BMJ. 2000;321:412-419.
Blood Pressure and Diabetic Complications
12% Decrease per 10 mmHg reduction in SBP
Updated Mean A1C
Myo
card
ial I
nfa
rcti
on
Haz
ard
Rat
io
0.5
1
10
110 120 130 150 160 170140
P<0.0001
13% Decrease per 10 mmHg reduction in SBP
Updated Mean A1C
Mic
rova
scu
lar
Co
mp
licat
ion
sH
azar
d R
atio
0.5
1
10
110 120 130 150 160 170140
P<0.0001
United Kingdom Prospective Diabetes Study
39
BP Reductions and Risk of Micro- and Macrovascular Complications in T2DM
UKPDS Group. BMJ. 1998;317:703-713.
United Kingdom Prospective Diabetes StudyBenefits of 144/82 vs. 154/87 mm Hg (N=1148)
Ris
k R
edu
ctio
n (
%)
Myocardial infarction
Any diabetes-related
endpoint
Diabetes-related death Stroke
Heart failure
Renal failure Retinopathy
Vision deterior-
ation
P=0.013
P=0.004
P=0.004
P=0.004
P=0.13P=0.005
P=0.019
P=0.29
40
Effect of Intensive Blood-Pressure Control on CV Outcomes and Death in T2DM
ACCORD Study Group. N Engl J Med. 2010;362:1575-1585.
Action to Control Cardiovascular Risk in Diabetes(N=4733)
41
Good BP control must be continued if benefits are to be maintained
Holman RR, et al. N Engl J Med. 2008;359;1565-1576.
• 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)
Long-Term Follow-up After Tight Control of Blood Pressure in T2DM
UKPDS Post-monitoring Study
Any Diabetes-related Endpoint
42
Intensive Blood Pressure Control in T2DM
ACCORD Study Group. N Engl J Med. 2010;362:1575-1585.
43
Action to Control Cardiovascular Risk in Diabetes(N=4733)
44
Effect of Weight Loss on Blood Pressure in T2DM
Look AHEAD Trial(N=5145)
*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.
Diastolic Blood Pressure
ILIDSE
Systolic Blood Pressure
Es
tim
ate
d m
ea
n(m
m H
g)
10
126
122
120
124
128
0 21
130
3 54 6 87 9
Main effect: -1.9 (95% CI -2.6, -1.1)P<0.05
*** ** *
*
Years
**
*
Main effect: -0.1 (95% CI -0.5, 0.3)P=0.72
Es
tim
ate
d m
ea
n(m
m H
g)
10
68
66
65
67
69
0 21
7071
3 54 6 87 964
Years
Multiple Antihypertensive Agents Are Usually Required to Achieve BP Control
45
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 Indication
Recommended Drugs
Clinical Trial BasisDiuretic BB ACEI ARB CCBAldoANT
Heart failure • • • • •
ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES, CHARM
Post-myocardial infarction
• • •ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS
High coronary disease risk
• • • •ALLHAT, HOPE, ANBP2, LIFE, CONVINCE, EUROPA, INVEST
Diabetes • • • • •NKF-ADA Guideline, UKPDS, ALLHAT
Chronic kidneydisease
• •NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK
Recurrent stroke prevention
• • PROGRESS
Compelling Indications for Individual Drug Classes
Aldo ANT = aldosterone antagonist.
Chobanian AV, et al. Hypertension. 2003;42:1206-1252.
46
The Renin Angiotensin System: ACE Inhibition
Unger T, et al. Am J Cardiol. 2007;100:25J-31J.
AT2AT1
Angiotensin I
Angiotensin II
B2 NO, PGI2
Vasodilation, etc
NOVasodilation
Tissue protection
Vasoconstriction
Proliferation
Aldosterone
Sympathetic NS
NaCl retention
Inflammation
Apoptosis
ACEI
Antiproliferation
Differentiation
Regeneration
Anti-inflammation
Apoptosis?
ACE-independentformation of ANG II
BradykininACE
47
The Renin Angiotensin System: AT1 Blockade
Unger T, et al. Am J Cardiol. 2007;100:25J-31J.
ARB
AT2AT1
Angiotensin I
Angiotensin II
B2 NO, PGI2
Vasodilation, etc
NOVasodilation
Tissue protection
Vasoconstriction
Proliferation
Aldosterone
Sympathetic NS
NaCl retention
Inflammation
Apoptosis
Antiproliferation
Differentiation
Regeneration
Anti-inflammation
Apoptosis?
ACE
48
EventsARBs ACEIs Odds Ratio
ARB vs ACEI
ELITE 1997 4/352 4/370 0.79 (0.17,3.54)
ELITE II 2000 31/1578 28/1574 1.11 (0.66,1.85)OPTIMAAL 2002 384/2744 379/2733 1.01 (0.87,1.18)DETAIL 2004 9/120 6/130 1.68 (0.58,4.86)VALIANT (val) 2003 796/4909 798/4909 1.00 (0.90,1.11)ONTARGET (tel) 2008 440/8542 413/8576 1.07 (0.94,1.23)
Fixed effect model (I2=0.0%, p=0.884) 1663/18,245 1628/18,292 1.03 (0.95, 1.10)
Random effect model 1.03 (0.95,1.10)ARB + ACEI vs ACEI
VALIANT (val + cap) 2003 756/4885 798/4909 0.94 (0.85,1.05)
ONTARGET (tel+ram) 2008 438/8502 413/8576 1.07 (0.94,1.23)
Fixed effect model (I2=0.0%, p=0.148) 1194/13,387 1211/13,485 0.99 (0.91,1.08)
Random effect model 1.00 (0.88,1.13)
Overall Effect
Fixed effect model (I2=0.0%, p=0.759)
2857/31,632 2839/31,777 1.01 (0.96,1.07)
Random effect model 1.01 (0.96,1.07)
Heterogeneity between groups p=0.555
Volpe M, et al. J Hypertension. 2009;27:941-946.
0.5 1.0 2.0
Odds Ratiofavors 1st listed favors 2nd listed
MI Risk With ACEIs and ARBs
49
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 BP-control regimens of patients with diabetes because of beneficial effects on the renin-angiotensin system
50
Torre JJ, et al. Endocr Pract. 2006;12:193-222.
Management of Common Comorbidities in Diabetes
Chronic Kidney Disease
51
Reducing A1C Reduces Nephropathy Risk in T2DM
52
UKPDS ADVANCE ACCORD
A1C reduction (%)* 0.9 0.8 1.3
Nephropathy risk reduction (%)* 30 21 21
Newonset
microalbuminuria(P=0.033)
New orworsening
nephropathy(P=0.006)
Newmicroalbuminuria
(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
*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 m2); 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.
NKF Stage
Description GFR
1Kidney damage* with normal or GFR
≥90
2Kidney damage* with mild GFR
60-89
3 Moderate GFR 30-59
4 Severe GFR 15-29
5Kidney failure or ESRD
<15 or dialysis
Diabetic Kidney Disease Is the Leading Cause of Kidney Failure in the United States
53
Cardiovascular Outcomes Worsen With CKD Progression
*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.
75
60-74
45-59
<45
eGFR (mL/min/1.73 m2)
54
Valsartan in Acute Myocardial Infarction Trial(N=14,527*)
†
†
†
†
†
†
CV Risk Increases With Comorbid Diabetes and CKD
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.
x 2.8
x 2.3
x 1.7x 2.1
x 2.0
x 2.5
55
Appropriate Staging and Management of CKD
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.
Stage Description GFR(mL/min/1.73 m2)
Action*
1Kidney damage† with normal or GFR ≥90
Diagnose and treat CKD, slow progression of CKD, treat comorbid conditions, reduce CVD risk factors
2Kidney 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 <15 or dialysis
Kidney replacement, if uremia present
ESRD Renal replacement therapy
56
KDIGO CKD Classification by Relative Risk
57
Albuminuria stages (mg/g)
A1 A2 A3
Optimal and high
normalHigh
Very high and nephrotic
<10 10-29 30-299 300-1999 ≥2000
GFR stages(mL/min per 1.73 m2 body surface area)
G1High and optimal
≥105Very low Very low Low Moderate Very high
90-104
G2 Mild75-89
Very low Very low Low Moderate Very high60-74
G3aMild to moderate
45-59 Low Low Moderate High Very high
G3bModerate to severe
30-44 Moderate Moderate High High Very high
G4 Severe 15-29 High High High High Very high
G5Kidney failure
<15 Very high Very high Very high Very high Very high
Levey AS, et al. Kidney Int. 2011;80:17-28.
DKD Risk Factor Management
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.
Risk Factor Goal Management Recommendation
Hyperglycemia
Individualized A1C goals
≤6.5% for most (AACE)
<7.0% (NKF)
Avoid biguanide in moderate to severe CKD
Consider need for dose reductions and/or risk of hypoglycemia and other renal-related AEs with other antidiabetic agents
Hypertension BP <130/80 mmHgUse ACE inhibitor or ARB in combination with other antihypertensive agents as needed
Proteinuria Use ACE inhibitor or ARB as directed
DyslipidemiaLDL-C <100 mg/dL,<70 mg/dL an option for high risk
Statin therapy recommended
Fibrate dose reduction may be required
58
Dietary Guidelines for DKD
CKD Stage
Macronutrient 1-2 1-4 3-4
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) 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.
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.
59
Use of Noninsulin Antidiabetic Therapies in Patients With Kidney Disease
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.
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, sitagliptinReduce dosage for saxagliptin and
sitagliptin if CrCl <50 mg/dL
Dopamine-2 agonist Bromocriptine Use with caution
Glinides Nateglinide, repaglinideUse lowest effective dose of nateglinide
for stage ≥3 CKD
InsulinAspart, detemir, glargine, glulisine, lispro, NPH, regular
Dosage reduction needed instage 4-5 CKD
Sulfonylureas Glimepiride, glipizide, glyburideGlimepiride preferred, use lowest effective dose; avoid other SUs
GLP-1 receptor agonists Exenatide, exenatide XR, liraglutideUse with caution in stage 3 CKD;
avoid in stage 4-5 CKD
-Glucosidase inhibitors Acarbose, miglitolNot recommended if SCr >2 mg/dL;
avoid in dialysis
Biguanide MetforminContraindicated if SCr >1.5 in men or
1.4 in women
60
Management of Common Comorbidities in Diabetes
Cardiovascular Disease
61
Coincidence of CV Comorbidities in T2DM
62
NHANES 1999-2004(N=984)
5.0%
16.9%
7.4%
Hyperlipidemia(LDL-C ≥100 mg/dL,TC ≥200 mg/dL, orTG ≥150 mg/dL)
Obesity(BMI ≥30 kg/m2)
Hypertension(BP ≥140/90 mm Hg or taking antihypertensive medication)
5.9%
20.6%
17.7% 12.2%
Suh DC, et al. J Diabetes Complications. 2010;24:382-391.
Cardiovascular Disease Risk Factors
Major Additional Nontraditional
• Advancing age
• Features of dyslipidemia
• High total serum cholesterol level
• High non–HDL-C
• High LDL-C
• Low HDL-C
• Diabetes mellitus
• Hypertension
• Cigarette smoking
• Family history of CAD
• Obesity or abdominal obesity
• PCOS
• Family history of hyperlipidemia
• Features of dyslipidemia
• Small, dense LDL-C
• Increased Apo B
• Increased LDL particle number
• Fasting/postprandial hypertriglyceridemia
• Dyslipidemic triad*
• Elevated clotting factors
• Inflammation markers (hsCRP; Lp-PLA2)
• Hyperhomocysteinemia
• Elevated uric acid
• Features of dyslipidemia
• Apo E4 isoform
• Elevated lipoprotein (a)
*Hypertriglyceridemia; low HDL-C; and small, dense LDL-C.
63Apo, 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
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 Score64
CHD, coronary heart disease.Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78.
Diabetes Is a Cardiovascular Disease Risk Equivalent
7-Y
ear
Inci
den
ce o
f M
I (%
)
Diabetic(n=1059)
Prior MINo prior MIPrior MINo prior MI
Nondiabetic(n=1373)
MI, myocardial infarction.Grundy SM, et al. Circulation. 2004;110:227-239.
Haffner SM, et al. N Engl J Med. 1998;339:229-234.
65
P<0.001
P<0.001
CVD Risk Factors:AACE Targets
Risk Factor Recommended Goal
Anticoagulant therapy Use aspirin for primary and secondary prevention of CVD events
Weight Reduce by 5% to 10%; avoid weight gain
Lipids
Total cholesterol, mg/dL <200
LDL-C, mg/dL <70 very high risk; <100 all other risk categories
Non-HDL-C, mg/dL 30 above LDL-C goal
ApoB, mg/dL <80 very high risk; <90 high risk
HDL-C, mg/dL ≥40 in both men and women
Triglycerides, mg/dL <150
Blood pressure
Systolic, mm Hg <130
Diastolic, mm Hg <80
66Handelsman 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
67
Prevalence of Comorbid Depression and Diabetes
68
Major Depressive
Disorder
Likely Depression
% P
op
ula
tio
n
Diagnostic Interview
Self-report Scale
1.9 OR 2.1
P=0.5
% P
op
ula
tio
n
Diverse, Community Sample Meta-analysis
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
Generaldiet
Foot care
P<0.001
Carbo-hydrates
Exercise Glucose monitoring
Fruitsand
vegetables
High fat foods
P<0.001
P<0.001
P=0.001P=0.006
P=0.241
P=0.348
Mea
n A
dh
eren
t D
ays/
Wee
k
HANDS, Harvard Department of Psychiatry/National Depression Screening Day Scale.Gonzales JS, et al. Diabetes Care. 2007;30:2222-2227.
2.3-Fold increased risk of missing 1 or more prescribed medications over previous week with major depression
(HANDS score <9) (HANDS score ≥9)
69
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 Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. ADA. Diabetes Care. 2012;34(suppl 1):S11-S61.
70
Management of Common Comorbidities in Diabetes
Sleep Apnea
71
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
Sleep Apnea
72 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
73
Vgontzas AN, et al. J Intern Med. 2003;254:32-44 .
Visceral fatInsulin resistance
Inflammatory cytokines
EDS fatigueSleep apnea
Sleep fragmentationSleep debt
Stress hormonesInterleukin-6
Depression of ventilation
Diaphragm mobility
Soft tissue edema
Prevalence of Sleep Apneain T2DM
74OSA, obstructive sleep apnea.
Foster GD, et al. Diabetes Care. 2009;32:1017-1019.
Sleep AHEAD StudyObese Patients With T2DM
(N=305)
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)
Treatment for Sleep Apnea
75Aurora 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
76
• 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
Diabetes and Cancer Risk
77
Giovannucci E, et al. Diabetes Care. 2010;33:1674-1685.
Insulin and Cancer Risk
78Gerstein 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.
Study Hazard Ratio (95% CI)
Outcome Reduction With an Initial Glargine Intervention (ORIGIN)N=12,537; prospective RCTMedian follow-up: 6.2 years
Any cancer: 1.00 (0.88-1.13); P=0.97Death from cancer: 0.94 (0.77-1.15); P=0.52
Northern European Database StudyN=447,821; observationalMean follow-up:
Glargine users: 3.1 yearsOther 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 CollaborationN=115,000; observationalMedian follow-up:
Glargine users: 1.2 yearsNPH 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 StudyN=52,453; observationalMean follow-up:
Glargine users: 1.2 yearsNPH users: 1.1 years
No increased risk for breast cancer
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
79
Giovannucci E, et al. Diabetes Care. 2010;33:1674-1685.