Type 2 Diabetes Glucose Management Goals
1
2
AACE Comprehensive Diabetes Care: Glucose Goals Parameter Treatment Goal for Nonpregnant Adults
A1C (%) Individualize based on age, comorbidities, and duration of disease*
• ≤6.5 for most• Closer to normal for healthy• Less stringent for “less healthy”
FPG (mg/dL) <110
2- hour PPG (mg/dL) <140
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
*Considerations include
• Residual life expectancy• Duration of T2DM• Presence or absence of
microvascular and macrovascular complications
• CVD risk factors• Comorbid conditions• Risk for severe hypoglycemia• Patient’s psychological, social,
and economic status
3
Well-Recognized Risks for Hypoglycemia in T2DM
• Use of insulin secretagogues and insulin therapy in any of the following settings:– Missed or irregular meals– Advanced age– Longer duration of diabetes– Impaired awareness of hypoglycemia– Exercise– Taking greater than the prescribed medication dose – Excessive alcohol intake– Preexisting impairment, or sudden worsening, of renal or hepatic
function• Less well-recognized risks: female sex, African-American
race, less education (ACCORD)
Amiel SA, et al. Diabet Med. 2008;25:245-254.ADA. Diabetes Care. 2005;28:1245-1249.
4
Limitations of Management Goals: Potential Consequences of Hypoglycemia
• Neurogenic symptoms– Tremor, palpitations, anxiety, sweating, hunger (weight gain),
paresthesias
• Neuroglycopenia morbidity– Cognitive impairment, psychomotor abnormalities, abnormal behavior,
seizure, coma, mortality (brain death)
• Rebound hyperglycemia, brittle diabetes• Barrier to glycemic control and adherence to treatment
secondary to fear of hypoglycemia• Greater risk of dementia• Prolonged QT interval with increased risk of dysrhythmias,
sudden death• Harm to property or to others (eg, if driving)
Cryer PE. J Clin Invest. 2007;117:868-870.Cryer PE. Diabetes Care. 2003;26:1902-1912.
5
Mortality Risk
Mortality Benefit
Glucose Control and Mortality:ACCORD Posthoc Analysis
66%
<0.0001
Risk increase with each 1% increase in A1C
P Value
14%
0.17
1
0
-1
6 7 8 9
Adjusted Log (Hazard Ratio) by Treatment Strategy
Relative to Standard at A1C of 6%
Lo
g (
Haz
ard
Rat
io)
Average A1C (%)
Standard
Intensive
Riddle MC, et al. Diabetes Care. 2010;33:983-990.
6
Algorithm for Individualizing Glycemic Targets
Ismail-Beigi F, Moghissi E, et al. Ann Intern Med. 2011;154:554-559.
Highly motivated, adherent, knowledgeable, excellent self-care capacities, and comprehensive support systems
Less motivated, nonadherent, limited insight, poor self-care capacities, and
weak support systems
Psychosocioeconomic considerations
Hypoglycemia riskLow Moderate High
Patient age, years40 45 50 55 60 65 70 75
Disease duration, years5 10 15 20
Other comorbid conditionsNone Few or mild Multiple or severe
Established vascular complicationsNone Cardiovascular disease
Early microvascular Advanced microvascular
Most intensive Less intensive Least intensive6.0% 7.0% 8.0%
ADA-Recommended Approach to Management of Hyperglycemia
Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
More Stringent Less Stringent
Patient attitude and expected treatment efforts Highly motivated, adherent,
excellent self-care capacitiesLess motivated, nonadherent,
poor self-care capacities
Risks potentially associated with hypoglycemia, other adverse events Low High
Disease durationNewly diagnosed Long-standing
Life expectancyLong Short
Resources, support systemReadily available Limited
Important comorbiditiesAbsent SevereFew/mild
Established vascular complicationsAbsent SevereFew/mild
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8
Hyperglycemia and Microvascular Complications
9
Hyperglycemia-Induced Tissue Damage: General Features
Diabetic tissue damage
Genetic determinants of individual susceptibility
Repeated acute changes in cellular
metabolism
Cumulative long-term changes in stable macromolecules
Independent accelerating factors
(eg, hypertension, dyslipidemia)
Hyperglycemia
Brownlee M. Diabetes. 2005;54:1615-1625.
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Microvascular Complications of Diabetes
Nephropathy Retinopathy Neuropathy
11
Microvascular Complications Increase With Increasing A1C
0
2
4
6
8
10
12
14
16
18
20
6 7 8 9 10 11 12
Rel
ativ
e R
isk
Retinopathy
Nephropathy
Neuropathy
Microalbuminuria
A1C (%)
Diabetes Control and Complications Trial
Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254.
12
Reducing A1C Reduces Microvascular Risk
United Kingdom Prospective Diabetes Study
Stratton IM, et al. BMJ. 2000;321:405-412.
37% Decrease per 1% reduction in A1C
Updated Mean A1C
Mic
rova
scu
lar
Co
mp
licat
ion
sH
azar
d R
atio
0.5
1
10
0 5 6 7 8 9 10
P<0.0001
Reducing A1C Reduces Nephropathy Risk in T2DM
13
UKPDS ADVANCE ACCORD
A1C reduction (%)* 0.9 0.8 1.3
Nephropathy risk reduction (%)* 30 21 21
Newonsetmicro-
albuminuria(P=0.033)
New orworsening
nephropathy(P=0.006)
Newmicroalbuminuria
(P=0.0005)
*Intensive vs standard glucose control.1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.
2. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.3. Ismail-Beigi F, et al. Lancet. 2010;376:419-430.
14
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.
Stage 1; 10.4%
Stage 2; 13.4%
Stage 3; 14.1%
Stage 4; 1.1%
No kidney disease;
60.4%
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
15
Genetically susceptible individuals
Hyperglycemia
Hypertension
Angiotensin II
Hyperfiltration
Enlarged kidneys
Breakdown of glomerular
filtration barrier
Micro-albuminuria
Macro-albuminuria
Decreasing GFR
Capillary occlusion
Protein reabsorption and accumulation in
renal epithelial cells
Release of vasoactive and inflammatory
cytokines
Tubule and podocyte damage
Tubular atrophy and fibrosis,
podocyte destruction
Development ofDiabetic Nephropathy
Radbill B, et al. Mayo Clin Proc. 2008;83:1373-1381.Remuzzi G, Bertani T. N Engl J Med. 1998;339:1448-1456.
Renal failure
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CV Risk Increases With Comorbid Diabetes and CKD
AMI, acute myocardial infarction; ASVD, atherosclerotic vascular disease; CHF, congestive heart failure; CVA/TIA, cerebrovascular accident/transient ischemic attack; PVD, peripheral 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.
CHF AMI CVA/TIA PVD ASVD* Death0
10
20
30
40
50
60
No diabetes/no CKD Diabetes/no CKD Diabetes/CKD
Inc
ide
nc
e p
er
10
0 P
ati
en
t-Y
ea
rs
x 2.8
x 2.3
x 1.7x 2.1
x 2.0
x 2.5
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Appropriate Staging and Management of DKD
DKD, diabetic 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;39(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
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KDIGO CKD Classification by Relative Risk
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
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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
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Dietary Guidelines for DKD
CKD Stage
Macronutrient 1-2 1-4 3-4
Sodium <2.3
Total fat, % calories* <30
Saturated fat, % calories <10
Cholesterol, mg/day <200
Carbohydrate, % calories 50-60
Protein, g/kg/day (% calories) 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.
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22
Reducing A1C Reduces Retinopathy Progression in T2DM
*Intensive vs standard glucose control.UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.
Ismail-Beigi F, et al. Lancet. 2010;376:419-430.Chew EY, et al. N Engl J Med. 2010;363:233-244.
UKPDS ACCORD
A1C reduction (%) 0.9 1.3
Retinopathy risk reduction (%)* 29 17 33
Retinopathy onset
(P=0.003)
Retinopathy progression(P=0.017)
Retinopathy progression(P=0.003)
Vision-threaten-ing*; 4.4%
NPDR; 24.1%
None; 71.5%
Prevalence of Diabetic Retinopathy
*Severe NPDR, PDR, or clinically significant macular edema.NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; T2DM, type 2 diabetes mellitus.
CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Zhang X, et al. JAMA. 2010;304:649-656.
NHANES 2005-2008Adults Age ≥40 Years (N=1006)
Diabetic Retinopathy Is the Leading Cause of Adult Blindness in the United States
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Diabetic Retinopathy Management
Lesion Type Management Recommendation
Background or nonproliferative retinopathy
• Optimal glucose and blood pressure control
Macular edema • Optimal glucose and blood pressure control• Ranibizumab injection therapy• Focused laser photocoagulation guided by fluorescein
angiography
Preproliferative retinopathy • Optimal glucose and blood pressure control• Panretinal scatter laser photocoagulation
Proliferative retinopathy • Optimal glucose and blood pressure control• Panretinal scatter laser photocoagulation• Vitrectomy for patients with persistent vitreous
hemorrhage or significant vitreous scarring and debris
• Goal: detect clinically significant retinopathy before vision is threatened• Annual dilated eye examination by experienced ophthalmologist,
starting at diagnosis for all T2DM patients
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
25
Reducing A1C Reduces Neuropathy Risk in T2DM
*Intensive vs standard glucose control.Ismail-Beigi F, et al. Lancet. 2010;376:419-430.
ACCORD
A1C reduction (%) 1.3
Neuropathy risk reduction (%)* 12
Loss of sensation to light touch(P=0.045)
26
• Neuropathy is a heterogenous disorder
• 70% to 100% of T2DM patients may have at least mild damage to– Proximal nerves
– Distal nerves
– Somatic nerves
– Autonomic nerves
• Neuropathy may be– Acute and self-limiting
– Chronic and indolent
Prevalence of Diabetic Neuropathy
CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf.
Gregg EW, et al. Diabetes Res Clin Pract. 2007;77:485-488.Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
None; 81.5%
DPN; 18.5%
NHANES 1999-2004Adults With Diabetes, Age ≥40 Years3
(N=559)
Diabetic Peripheral Neuropathy Is the LeadingCause of Nontraumatic Amputations in the United States
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Diabetic Neuropathies: Key Characteristics and Management Recommendations
Type Condition(s) Clinical Features Treatment
Focal Mononeuritis Single nerve involvement
Entrapment
Carpal tunnel syndrome Proximal lumbosacral Thoracic Cervical radiculoplexus
neuropathies involving the proximal limb girdle
Inflammatory demyelinating conditions
Immunotherapy
• Optimize glucose, lipid, and blood pressure control for all T2DM patients
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
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Diabetic Neuropathies: Key Characteristics and Management Recommendations
Type Condition(s) Clinical Features Treatment
Distal neuropathy
Large-fiber sensorimotor polyneuropathy
Symmetric, glove and stocking distribution with Loss of sensation Poor coordination Ataxia
Low-impact activities that improve muscular strength and coordination and challenge the vestibular system Pilates Yoga Tai Chi
Small-fiber neuropathy
Symmetric, glove and stocking distribution with Loss of sensation Pain Autonomic features
Protect insensate feet from ulceration Padded socks Daily inspection by patient Moisturizing lotionsTreat neuropathic pain Amitriptyline Gabapentin Pregabalin Duloxetine Topical lidocaine
• Optimize glucose, lipid, and blood pressure control for all T2DM patients
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
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Diabetic Neuropathies: Key Characteristics and Management Recommendations
Type Condition(s) Clinical Features Treatment
Autonomic Cardiac Symptoms Tachycardia Exercise intolerance Orthostatic hypotension, weakness,
fatigue, syncopeAssociated with significant mortality and possibly also Silent myocardial ischemia Coronary artery disease Stroke Diabetic nephropathy progression Perioperative morbidity
Intensive control of CV risk factors For tachycardia, exercise intolerance Supervised exercise ACE inhibitors -adrenergic blockersFor hypotension, weakness, etc Mechanical measures Clonidine Midodrine Octreotide Erythropoietin
• Optimize glucose, lipid, and blood pressure control for all T2DM patients
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
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Diabetic Neuropathies: Key Characteristics and Management Recommendations
Type Condition(s) Clinical Features Treatment
Autonomic Gastrointestinal Gastroparesis, erratic glucose control Frequent small mealsProkinetic agents Metoclopramide Domperidone Erythromycin
Abdominal pain, early satiety, nausea, vomiting, bloating, belching
AntibioticsAntiemeticsBulking agents
Tricyclic antidepressantsPyloric BotoxGastric pacing
Constipation High-fiber dietBulking agentsOsmotic laxativesLubricating agents
Diarrhea (often nocturnal, alternating with constipation)
Soluble dietary fiberGluten and lactose restrictionAnticholinergic agents
CholestyramineAntibioticsSomatostatinPancreatic enzyme supplements
• Optimize glucose, lipid, and blood pressure control for all T2DM patients
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
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Diabetic Neuropathies: Key Characteristics and Management Recommendations
Type Condition(s) Clinical Features Treatment
Autonomic Sexual dysfunction Erectile dysfunction Sex therapyPsychological counseling5′-phosphodiesterase inhibitorsProstaglandin E1 injectionsDevicesProstheses
Vaginal dryness Vaginal lubricants
Bladder dysfunction Frequency, urgency, nocturia, urinary retention, incontinence
BethanecholIntermittent catheterization
Sudomotor dysfunction
AnhidrosisHeat intoleranceDry skinHyperhidrosis
Emollients and skin lubricantsScopolamineGlycopyrrolateBotulinum toxinVasodilators
• Optimize glucose, lipid, and blood pressure control for all T2DM patients
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
32
Hyperglycemia and Macrovascular Complications
33
Series10
10
20
30
40
50
3.5
18.8 20.2
45
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.
P<0.001
P<0.001
Lower A1C Is Associated With Lower Risk of Myocardial Infarction
Stratton IM et al. BMJ. 2000;321:405-412.
United Kingdom Prospective Diabetes Study
14% Decrease per 1% reduction in A1C
Updated Mean A1C
0.5
1
10
0 5 6 7 8 9 10
P<0.0001
Myo
card
ial I
nfa
rcti
on
Haz
ard
Rat
io
34
35
0.12
0.10
0.08
0.06
0.02
Randomizedtreatment
Intensive Glycemic Control Reduces Long-term Macrovascular Risk in Younger Patients With Shorter Duration of Disease
Randomizedtreatment
0.04
0.00
0 5 10 15 20
No. at RiskConventional 714 688 618 92Intensive 705 683 629 113
Years
DCCTT1DM, 5-6 years duration (N=1441)
42% risk reductionP=0.02
Conventional
Intensive
CV
Ou
tco
me
C
um
ula
tive
in
cid
en
ce
UKPDST2DM, newly diagnosed (N=4209)
15% risk reductionP=0.01
1138 1013 857 578 221 202729 2488 2097 1459 577 66
1.0
0.8
0.6
0.4
0.2
0.0
0 5 10 20 25Years
Conventional
Intensive
Pro
po
rtio
n
Wit
h M
I15
CV, cardiovascular; DCCT, Diabetes Control and Complications Trial; MI, myocardial infarction;UKPDS, United Kingdom Prospective Diabetes Study. Nathan DM, et al. N Engl J Med. 2005;353:2643-2653.Holman RR, et al. N Engl J Med. 2008;359:1577-1589.
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ACCORD ADVANCE VADT
T2DM duration (years) 10 8 12
A1C reduction (%)* 0.9 0.8 1.3
Macrovascular risk (%)* 10 6 12
P=0.16Mortality
increased in intensively
treated patients (P=0.04)
P=0.32 P=0.14
Intensive Glycemic Control Does Not Reduce Macrovascular Risk in Older
Patients With Longer Duration of Disease
*Intensive vs standard glucose control.ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.Duckworth W, et al. N Engl J Med. 2009;360:129-139.
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Macrovascular Risk Reduction in T2DM
• Individualized glucose control• Hypertension control• Dyslipidemia control• Smoking cessation• Aspirin therapy• Diagnosis and management of:
– Autonomic cardiac neuropathy– Kidney disease
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.