Glycemic Management in
Type 2 Diabetes
1
AACE Comprehensive Care
Plan
Disease management from
a multidisciplinary team
Antihyperglycemic
pharmacotherapy
Comprehensive
Care Plan
Comprehensive diabetes
self-education for the
patient
Therapeutic lifestyle
change
2
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Glycemic Management in
Type 2 Diabetes
Therapeutic Lifestyle Change
3
Components of Therapeutic
Lifestyle Change
•
•
•
•
•
•
Healthful eating
Sufficient physical activity
Sufficient sleep
Avoidance of tobacco products
Limited alcohol consumption
Stress reduction
4
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
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 fats

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
5
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
AACE Medical Nutritional
Therapy Recommendations
• Consistency in day-to-day carbohydrate intake
• Adjusting insulin doses to match carbohydrate
intake (eg, use of carbohydrate counting)
• Limitation of sucrose-containing or highglycemic index foods
• Adequate protein intake
• “Heart-healthy” diets
• Weight management
• Exercise
• Increased glucose monitoring
6
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
AACE Physical Activity
Recommendations
• ≥150 minutes per week
of moderate-intensity
exercise
– Flexibility and strength
training
– Aerobic exercise (eg, brisk
walking)
• Start slowly and build up
gradually
• 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
7
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Glycemic Management in
Type 2 Diabetes
Antihyperglycemic Therapy
8
Noninsulin Agents Available for
Treatment of Type 2 Diabetes
Class
Primary Mechanism of Action
Agent
Acarbose
Miglitol
Available as
Precose or generic
Glyset
-Glucosidase
inhibitors

Delay carbohydrate
absorption from intestine



Decrease glucagon secretion
Slow gastric emptying
Increase satiety
Pramlintide
Symlin
Biguanide


Decrease HGP
Increase glucose uptake in
muscle
Metformin
Glucophage or generic
Bile acid
sequestrant


Decrease HGP?
Increase incretin levels?
Colesevelam
WelChol

Increase glucose-dependent
insulin secretion
Decrease glucagon secretion
Alogliptin
Linagliptin
Saxagliptin
Sitagliptin
Nesina
Tradjenta
Onglyza
Januvia
Activates dopaminergic
receptors
Bromocriptine
Cycloset
Amylin analogue
DPP-4 inhibitors

Dopamine-2
agonist

9
HGP, hepatic glucose production.
Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
Noninsulin Agents Available for
Treatment of Type 2 Diabetes
Class
Primary Mechanism of Action
Glinides

Increase insulin secretion

Increase glucose-dependent
insulin secretion
Decrease glucagon secretion
Slow gastric emptying
Increase satiety
GLP-1 receptor
agonists
Sulfonylureas





Thiazolidinediones

Increase insulin secretion
Increase glucose uptake in
muscle and fat
Decrease HGP
Agent
Nateglinide
Repaglinide
Available as
Starlix or generic
Prandin
Exenatide
Byetta
Exenatide XR
Bydureon
Liraglutide
Victoza
Glimepiride
Glipizide
Amaryl or generic
Glucotrol or generic
Glyburide
Diaeta, Glynase,
Micronase, or generic
Pioglitazone
Actos
Rosiglitazone*
Avandia
*Use restricted due to increased risk of myocardial infarction (MI)
10
HGP, hepatic glucose production.
Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
Insulins Available for the Treatment
of Type 2 Diabetes
Class
Primary Mechanism of Action
Basal
Prandial
Premixed


Increase glucose uptake
Decrease HGP
Agent
Detemir
Glargine
Available as
Levemir
Lantus
Neutral protamine
Hagedorn (NPH)
Generic
Aspart
Glulisine
Lispro
Regular human
Biphasic aspart
Biphasic lispro
NovoLog
Apidra
Humalog
Humulin, generic
NovoLog Mix
Humalog Mix
11
Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
Pharmacokinetics of Insulin
Agent
Onset (h)
Peak (h)
Duration (h)
Considerations
NPH
2-4
4-10
10-16
Glargine
~1-4
No pronounced
peak*
Up to 24
hours†
Less nocturnal hypoglycemia
compared to NPH
~0.5-1
~2-3
Up to 8

Basal
Detemir
Greater risk of nocturnal
hypoglycemia compared to insulin
analogues
Prandial
Regular

Aspart
<0.5
~0.5-2.5
Glulisine
Lispro
12
~3-5


Must be injected 30-45 min
before a meal
Injection with or after a meal
could increase risk for
hypoglycemia
Can be injected 0-15 min before
a meal
Less risk of postprandial
hypoglycemia compared to
regular insulin
* Exhibits a peak at higher dosages.
† Dose-dependent.
Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print].
Combination Agents Available for the
Treatment of Type 2 Diabetes
Class
Metformin + DPP-4 inhibitor
Metformin + glinide
Metformin + sulfonylurea
Metformin + thiazolidinedione
Thiazolidinedione + DPP-4 inhibitor
Thiazolidinedione + sulfonylurea
Added Agent
Available as
Alogliptin
Kazano
Linagliptin
Jentadueto
Sitagliptin
Janumet
Repaglinide
Prandimet
Glipizide
Metaglip and generic
Glyburide
Glucovance and generic
Pioglitazone
ACTOplus Met
Rosiglitazone*
Avandamet
Pioglitazone +
alogliptin
Oseni
Pioglitazone
Duetact
Rosiglitazone*
Avandaryl
*Use restricted due to increased risk of myocardial infarction (MI)
13
First Principles of the
AACE/ACE T2DM Algorithm
•
•
•
•
Avoid hypoglycemia
Avoid weight gain
Consider all medication options
Recognize that acquisition cost is not
the total cost of a drug
• Stratify therapy selection by A1C
• Recognize that postprandial glucose is
an important target
14
Rodbard HW, et al. Endocr Pract. 2009;15:540-559
Secondary Principles of
AACE/ACE T2DM Algorithm
• Adherence is improved by
– Ease of use
– Minimal side effects
• Improved -cell performance over a
longer period is possible
• Multiple combinations are required
15
Rodbard HW, et al. Endocr Pract. 2009;15:540-559
Overview of AACE/ACE
T2DM Algorithm
• Stratify treatment based
on initial A1C level
• Initial monotherapy for
A1C 6.5% to 7.5%
• Initial dual therapy for
A1C 7.6% to 9.0%
• Initial triple therapy or
insulin for A1C >9.0%
• Monitor A1C carefully and
intensify therapy at 2- to 3month intervals if A1C goal
not achieved
– Monotherapy → dual
therapy
– Dual therapy → triple
therapy or insulin ± oral
agents
• Combine agents with
different mechanisms of
action
16
Rodbard HW, et al. Endocr Pract. 2009;15:540-559
Benefits are classified according to major effects on fasting glucose, postprandial glucose, and nonalcoholic fatty liver disease (NAFLD). Eight
broad categories of risks are summarized. The intensity of the background shading of the cells reflects relative importance of the benefit or risk.*
17
* The abbreviations used here correspond to those used on the algorithm (Fig. 1).
Available at www.aace.com/pub
** The term ‘glinide’ includes both repaglinide and nateglinide.
© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE
A1C 6.5 – 7.5%**
A1C 7.6 – 9.0%
A1C > 9.0%
Under Treatment
Drug Naive
Symptoms
Monotherapy
MET † DPP4 1
GLP-1
Dual Therapy 8
TZD 2
AGI 3
2 - 3 Mos.***
MET
+
GLP-1 or DPP4
1
TZD 2
+
Glinide or SU 5
TZD
2 - 3 Mos.
INSULIN
± Other
Agent(s) 6
GLP-1
or DPP4 1
MET
GLP-1
or DPP4 1
+ TZD 2
Colesevelam
MET
+
MET
***
+
GLP-1
or DPP4 1
+ SU 7
TZD 2
Triple Therapy
MET +
GLP-1 or
DPP4 1
18
2 - 3 Mos.
TZD 2
+
Glinide or SU 4,7
2 - 3 Mos.
INSULIN
± Other
Agent(s) 6
TZD
± SU 7
2
GLP-1
or DPP4 1
INSULIN
± Other
Agent(s) 6
± TZD 2
*
May not be appropriate for all patients
**
For patients with diabetes and A1C < 6.5%,
pharmacologic Rx may be considered
***
If A1C goal not achieved safely
† Preferred initial agent
AGI 3
2 - 3 Mos.
+
***
Triple Therapy 9
GLP-1 or DPP4 1
+
GLP-1 or DPP4 1
or TZD 2
SU or Glinide 4,5
Dual Therapy
MET
No Symptoms
***
INSULIN
± Other
Agent(s) 6
***
AACE/ACE Algorithm for Glycemic
Control Committee
Cochairpersons:
Helena W. Rodbard, MD, FACP, MACE
Paul S. Jellinger, MD, MACE
Zachary T. Bloomgarden, MD, FACE
Jaime A. Davidson, MD, FACP, MACE
Daniel Einhorn, MD, FACP, FACE
Alan J. Garber, MD, PhD, FACE
James R. Gavin III, MD, PhD
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Edward S. Horton, MD, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, MACE
Etie S. Moghissi, MD, FACP, FACE
Stanley S. Schwartz, MD, FACE
1 DPP4 if  PPG and  FPG or GLP-1 if  PPG
2 TZD if metabolic syndrome and/or
nonalcoholic fatty liver disease (NAFLD)
3 AGI if  PPG
4 Glinide if  PPG or SU if  FPG
5 Low-dose secretagogue recommended
6 a) Discontinue insulin secretagogue
with multidose insulin
b) Can use pramlintide with prandial insulin
7 Decrease secretagogue by 50% when added
to GLP-1 or DPP-4
8 If A1C < 8.5%, combination Rx with agents
that cause hypoglycemia should be used
with caution
9 If A1C > 8.5%, in patients on Dual Therapy,
insulin should be considered
Available at www.aace.com/pub
© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE
LIFESTYLE
MODIFICATION
AACE/ACE DIABETES ALGORITHM
FOR GLYCEMIC CONTROL
A1C 6.5 – 7.5%**
Monotherapy
MET † DPP4 1
GLP-1
TZD 2 AGI
3
2 - 3 Mos.***
Dual Therapy
GLP-1 or DPP4 1
MET
TZD 2
+
Glinide or SU 5
TZD
+
MET
+
GLP-1 or DPP4 1
Colesevelam
***
If A1C goal not achieved safely
†
Preferred initial agent
1
DPP4 if  PPG and  FPG or GLP-1
if  PPG
2
TZD if metabolic syndrome and/or
nonalcoholic fatty liver disease
(NAFLD)
TZD 2
3
AGI if  PPG
4
Glinide if  PPG or SU if  FPG
Glinide or SU 4,7
5
Low-dose secretagogue
recommended
2 - 3 Mos.***
6
a) Discontinue insulin
secretagogue with multidose
insulin
b) Can use pramlintide with
prandial insulin
7
Decrease secretagogue by 50%
when added to GLP-1 or DPP-4
AGI
3
2 - 3 Mos.
***
Triple Therapy
MET +
GLP-1 or
DPP4 1
+
INSULIN
± Other
Agent(s)
6
19
Available at www.aace.com/pub
© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE
LIFESTYLE
MODIFICATION
A1C 7.6 – 9.0%
AACE/ACE DIABETES ALGORITHM
FOR GLYCEMIC CONTROL
Dual Therapy 8
MET
+
GLP-1 or DPP4 1
or TZD 2
SU or Glinide 4,5
2 - 3 Mos.***
Triple Therapy 9
GLP-1
or DPP4 1
MET
+
GLP-1
or DPP4 1
+ TZD 2
+ SU 7
***
If A1C goal not achieved safely
†
Preferred initial agent
1
DPP4 if  PPG and  FPG or GLP-1
if  PPG
2
TZD if metabolic syndrome and/or
nonalcoholic fatty liver disease
(NAFLD)
4
Glinide if  PPG or SU if  FPG
5
Low-dose secretagogue
recommended
6
a) Discontinue insulin
secretagogue with multidose
insulin
b) Can use pramlintide with
prandial insulin
7
Decrease secretagogue by 50%
when added to GLP-1 or DPP-4
8
If A1C < 8.5%, combination Rx with
agents that cause hypoglycemia
should be used with caution
9
If A1C > 8.5%, in patients on Dual
Therapy, insulin should be
considered
TZD 2
2 - 3 Mos.
INSULIN
± Other
Agent(s)
***
6
20
Available at www.aace.com/pub
© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE
LIFESTYLE
MODIFICATION
Drug Naive
Symptoms
INSULIN
± Other
Agent(s)
AACE/ACE DIABETES ALGORITHM
FOR GLYCEMIC CONTROL
A1C > 9.0%
Under Treatment
No Symptoms
GLP-1 or DPP4 1
MET
+
± SU 7
TZD 2
6
GLP-1 or DPP4 1
± TZD 2
INSULIN
± Other
Agent(s)
6
1
DPP4 if  PPG and  FPG or GLP-1
if  PPG
2
TZD if metabolic syndrome and/or
nonalcoholic fatty liver disease
(NAFLD)
6
a) Discontinue insulin
secretagogue with multidose
insulin
b) Can use pramlintide with
prandial insulin
7
Decrease secretagogue by 50%
when added to GLP-1 or DPP-4
21
Available at www.aace.com/pub
© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE
Basal Insulin Therapy in T2DM:
AACE/ACE Recommendations
• Initiate insulin treatment by adding a long-acting
basal formulation to existing noninsulin agents
Basal insulin analogues (detemir, degludec,* or glargine) are strongly
preferred over human NPH insulin
Relatively
peakless
time-action
curves
•
•
•
Greater dayto-day
consistency
Lower risk of
hypoglycemia
Start with 10 U or 0.1-0.2 U/kg per day at bedtime
Slowly titrate by 1-3 U every 2-3 days until FPG reaches the desired target
(<100 mg/dL for most patients)
Decrease dosage if FPG declines below a threshold specified for individual
patient
22
*Under FDA review as of October 2012.
Rodbard HW, et al. Endocr Pract. 2009;15:540-559.
Prandial Insulin Therapy in T2DM:
AACE/ACE Recommendations
• Add prandial insulin when A1C levels remain high despite
optimal control of FPG with basal insulin ± noninsulin agents
• Basal-bolus insulin therapy is flexible and is recommended for
intensive insulin therapy
• Premixed insulin analogues
– Consider for patients with adherence problems
– Lack dosage flexibility and may increase risk of hypoglycemia
Rapid-acting insulin analogues are preferred over regular human insulin
Faster onset
of action
Faster offset
of action
Lower risk of
hypoglycemia
23
Rodbard HW, et al. Endocr Pract. 2009;15:540-559.
Early Insulin Use in Type 2 Diabetes
Offers No Benefits Over Standard
Approaches
Outcome Reduction With an Initial Glargine Intervention
CV risk factors + prediabetes or T2DM (N=12,537)
24
ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328.
AACE/ACE T2DM Algorithm: Special
Considerations and Caveats
• Metformin is the preferred
initial agent for most patients
• DPP-4 inhibitors are preferred
if both PPG and FPG are
elevated
• GLP-1 agonists are preferred if
the principal problem is
elevated PPG
• TZDs can be used to treat
patients with metabolic
syndrome and/or nonalcoholic
fatty liver disease (NAFLD)
• AGIs are useful for treatment of
elevated PPG
• Glinides can be useful for
treatment of elevated PPG
• SUs may be useful if major
problem is elevated FPG
• Colesevelam may be useful for
patients near A1C goal but
needing additional LDL-C
control
25
Rodbard HW, et al. Endocr Pract. 2009;15:540-559.
AACE/ACE T2DM Algorithm: Special
Considerations and Caveats
• A1C goal ≤6.5% may not be
• If A1C is <8.5%, combination
appropriate for all patients
therapy with agents that cause
hypoglycemia should be used
• For patients with diabetes and
with caution
A1C <6.5%, pharmacologic
– Decrease dose of secretagogue
therapy may still be considered
by 50% when added to GLP-1
• If A1C goal is not achieved,
or DPP-4
intensify therapy (if it can be
• If A1C ≥8.5% in patients on dual
done safely)
therapy, consider use of insulin
– Discontinue insulin
secretagogue with multi-dose
insulin
– Consider use of pramlintide with
prandial insulin
26
Rodbard HW, et al. Endocr Pract. 2009;15:540-559.
ADA/EASD T2DM Treatment Algorithm
27
Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
ADA/EASD T2DM Treatment Algorithm:
Sequential Insulin Strategies
28
Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
Common Principles in AACE/ACE and
ADA/EASD T2DM Treatment Algorithms
• Individualize glycemic goals based on patient
characteristics
• Promptly intensify antihyperglycemic therapy to maintain
blood glucose at individual targets
– Combination therapy necessary for most patients
– Base choice of agent(s) on individual patient medical history,
behaviors and risk factors, ethno-cultural background, and
environment
• Insulin eventually necessary for many patients
• SMBG vital for day-to-day management of blood sugar
– All patients using insulin
– Many patients not using insulin
29
Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
Rodbard HW, et al. Endocr Pract. 2009;15:540-559.
Pipeline Classes and Agents
(2012)
Class
Phase of Development
Dual peroxisome proliferator activated
receptor - (PPAR-) agonist
Phase 3
Short-acting GLP-1 receptor agonist
Long-acting GLP-1 receptor agonists
Phase 3
Insulin
Phase 3
Description
Lixisenatide
Improve insulin sensitivity in the periphery as well as lipid profiles
Approved agents may reduce both cardiovascular risks and potential for
diabetes complications
Human-derived molecule with effects similar to exenatide
Albiglutide
Taspoglutide
Effects probably similar to currently available GLP-1 receptor agonists
Longer duration of action will permit longer intervals between injections
Aleglitazar
Degludec
DegludecPlus
Ultra-long-acting basal insulin (half-life ~25 hours) with low within-subject
variability and potential for reduced incidence of hypoglycemia
Premixed insulin containing degludec plus aspart, providing both fasting
and postprandial glucose control
Generically available anti-inflammatory medication currently approved for
treatment of arthritis; inhibits activity of NF-B, an inflammatory factor
Salicylates
Phase 3
Salsalate
Sodium-dependent glucose
cotransporter 2 (SGLT-2) inhibitors
Phase 3
Canagliflozin
Dapagliflozin
Empagliflozin
Tofogliflozin
Act in the kidney
Reduce hyperglycemia by inhibiting glucose reabsorption into the
bloodstream from the renal filtrate, increasing urinary excretion of glucose
INCB13739
RG4929
Inhibit 11HSD-1 mediated conversion of low-activity cortisone to cortisol,
which is primarily produced in the liver and adipose tissue
May lessen stress-induced obesity, improve insulin sensitivity, enhance
insulin-secretory responsiveness, and improve glucose tolerance in
patients with metabolic syndrome and/or type 2 diabetes
11-Hydroxysteroid dehydrogenase
type 1 (11HSD-1) inhibitors
Phase 2
30
Agents
Bakris GL, et al. Kidney Int. 2009;75:1272-1277; Calado J, et al. Kidney Int Suppl. 2011:S7-S13;
Garber AJ. Expert Opin Investig Drugs. 2012;21:45-57; Goldfine AB, et al. Ann Intern Med. 2010;152:346-357;
King A. J Fam Pract. 2012;61:S28-S31; Tahrani AA, et al. Lancet. 2011;378:182-197;
Tahrani AA, et al. Lancet. 2012;379:1465-1467.
Glycemic Management in
Type 2 Diabetes
Technology for Type 2 Diabetes
Management
31
SMBG in Type 2 Diabetes:
AACE/ACE Recommendations
Noninsulin Users
• Introduce at diagnosis
• Personalize frequency of
testing
• Use SMBG results to inform
decisions about whether to
target FPG or PPG for any
individual patient
Testing positively affects glycemia in
T2DM when the results are used to:
• Modify behavior
• Modify pharmacologic treatment
Insulin Users
• All patients using insulin should
test glucose
– ≥2 times daily
– Before any injection of insulin
• More frequent SMBG (after
meals or in the middle of the
night) may be required
– Frequent hypoglycemia
– Not at A1C target
32
SMBG, self-monitoring of blood glucose.
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
SMBG in Noninsulin Using
Patients With T2DM
Adjusted Mean A1C (%)
9.0
Active control group (n=227)
Structured testing group (n=256)
8.8
8.6
8.4
8.2
8.0
-0.3%
7.8
(P=0.04)
7.6
7.4
7.2
Baseline M1
M3
M6
M9
M12
ACG
8.9%
(0.08)
8.7%
(0.1)
8.2%
(0.1)
7.9%
(0.1)
8.0%
(0.1)
8.0%
(0.1)
STG
8.9%
(0.07)
8.5%
(0.09)
7.9%
(0.09)
7.9%
(0.09)
7.6%
(0.09)
7.7%
(0.09)
33
ACG, active cotnrol group; STG, structured testing group.
Polonsky WH, et al. Diabetes Care. 2011;34:262-267.
CSII in Type 2 Diabetes:
Patient Candidates
• Absolutely insulin-deficient
• Take 4 or more insulin
injections a day
• Assess blood glucose levels 4
or more times daily
• Motivated to achieve tighter
glucose control
• Mastery of carbohydrate
counting, insulin correction, and
adjustment formulas
• Ability to troubleshoot problems
related to pump operation and
plasma glucose levels
• Stable life situation
• Frequent contact with members
of their healthcare team, in
particular their pumpsupervising physician
34
CSII, continuous subcutaneous insulin infusion.
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Glycemic Management in
Type 2 Diabetes
Surgical Intervention
35
Surgical Intervention in
Type 2 Diabetes
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Baseline
P<0.001
P<0.001
3
6
9
12
 FPG (mg/dL)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Baseline
Sleeve gastrectomy
Roux-en-Y gastric bypass
20
0
-20
-40
-60
-80
-100
-120
-140
-160
Baseline
P=0.02
P<0.001
3
6
9
12
0
P<0.001
P<0.001
3
6
Months
9
12
 BMI (kg/m2)
Average no. diabetes
medications
 A1C (%)
Intensive medical therapy
-2
-4
-6
P<0.001
-8
-10
-12
Baseline
P<0.001
3
6
9
12
Months
36
Schauer PR, et al. N Engl J Med. 2012;366:1567-1576.
Glycemic Management in
Type 2 Diabetes
Safety Concerns: Hypoglycemia
37
Type 2 Diabetes Pathophysiology:
Origins of Hypoglycemia
Defect
β-cells
Increased insulin availability due to use of secretagogues or exogenous
insulin
Liver
Suppressed hepatic glucose production due to impaired counterregulatory response
Skeletal muscle
Increased glucose uptake due to exercise
α-cells
Suppressed glucagon due to impaired counter-regulatory response
Brain
Hypoglycemia unawareness
38
Cryer PE. Am J Physiol. 1993; 264(2 Pt 1):E149-E155.
Hypoglycemia: Risk Factors
Patient Characteristics
Behavioral and Treatment
Factors
• Older age
• Female gender
• African American
ethnicity
• Longer duration of
diabetes
• Neuropathy
• Renal impairment
• Previous hypoglycemia
• Missed meals
• Elevated A1C
• Insulin or sulfonylurea
therapy
39
Miller ME, et al. BMJ. 2010 Jan 8;340:b5444. doi: 10.1136/bmj.b5444.
Symptoms and Signs with
Progressive Hypoglycemia
Blood Glucose (mg/dL)
100
90
80
70
60
50
40
30
20
10
Decreased insulin secretion
Increased glucagon, epinephrine,
ACTH, cortisol, and growth hormone
Palpitation, sweating
Decreased cognition, hunger
Aberrant behavior
Seizures, coma
Neuronal cell death
0
Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print].
Hypoglycemia: Clinical
Consequences
Acute
• Symptoms (sweating,
irritability, confusion)
• Accidents
• Falls
Long-term
• Recurrent hypoglycemia
and hypoglycemia
unawareness
• Refractory diabetes
• Dementia (elderly)
• CV events
– Cardiac autonomic
neuropathy
– Cardiac ischemia
– Fatal arrhythmia
– Angina
41
Cryer PE, et al. Diabetes Care. 2003;26:1902-1912.
ADA. Diabetes Care. 2013;36(suppl 1):S11-S66.
Zammit NN, et al. Diabetes Care. 2005;28:2948-2961.
Treatment of Hypoglycemia:
AACE/ACE Recommendations
Blood
Glucose
Level
~50-60
<50
Classification
Typical Signs and
Symptoms
Treatment
Mild hypoglycemia


Moderate
hypoglycemia

Severe
hypoglycemia


Neurogenic:
palpitations, tremor,
hunger, sweating,
anxiety, paresthesia
Neuroglycopenic:
behavioral changes,
emotional lability,
difficulty thinking,
confusion
Severe confusion,
unconsciousness,
seizure, coma, death
Requires help from
another individual




Consume glucose-containing
foods (fruit juice, soft drink,
crackers, milk, glucose tablets);
avoid foods also containing fat
Repeat glucose intake if SMBG
result remains low after 15 minutes
Consume meal or snack after
SMBG has returned to normal to
avoid recurrence
Glucagon injection, delivered by
family member or other close
associate
Victim should be taken to hospital
for evaluation and treatment after
any severe episode
42
Cryer PE, et al. Diabetes Care. 2003;26:1902-1912.
Elements of Hypoglycemia
Prevention

Set appropriate
glycemic targets for
individual patients



More stringent goals: young, newly diagnosed, no comorbidities, no micro- or
macrovascular disease, strong and effective self-care skills
Less stringent goals: older, limited life expectancy, history of hypoglycemia, longer
disease duration, established comorbidities, established vascular disease, limited selfcare skills




Signs and symptoms of hypoglycemia
Dietary education for improved glycemic control and appreciation of triggers for
hypoglycemia
Avoiding missed or delayed meals
Appropriate self-treatment
Understanding of hypoglycemia unawareness
Importance of reporting hypoglycemia
Use self-monitoring
of blood glucose




Patient education: technique and action
Observation of patient’s procedure and reaction
Patient access to providers for purposes of reporting results and for providing guidance
Provider reaction to results increases effectiveness of SMBG
Hold a high index
of suspicion for
hypoglycemia



Understand patients may not report “typical” symptoms
When hypoglycemia is suspected, adjust therapy
Consider use of continuous glucose monitoring to detect unrecognized hypoglycemia
Choose appropriate
therapy



Use agents with a low risk of hypoglycemia
Be aware of additive effects of combination therapies on hypoglycemia risk
Recognize that long-term costs of hypoglycemia may offset the cost of using older, less
physiologic medications
Educate patients
43
Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print].
Hypoglycemia Risk With
Antihyperglycemic Agents Added
to Metformin
Initial Treatment
Additional Treatment
DPP-4 inhibitors
Less
Hypoglycemia
GLP-1 receptor agonists
TZDs
Metformin
More
Hypoglycemia
Sulfonylureas
Insulin (basal, basal-plus, premixed)
Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print].
Frequency of Severe Hypoglycemia
With Antihyperglycemic Agents
Percentage of Patients Treated in 1 Year
6%
Mixtures, Rapid-acting, Basal-bolus
5%
Insulin
4%
Basal
3%
2%
1%
0
Sulfonylureas
Meglinitides
DPP-4 inhibitors, GLP-1 receptor agonists,
Metformin, TZDs
Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print].
Relative Rates of Severe
Hypoglycemia with Insulin
Increasing rates
of hypoglycemia
Most
frequent
Prandial
and
premixed
Human insulin
Analogue insulins
Premixed (70/30, 75/25)
More
frequent
Basal +
Basal plus 2-3 prandial
Basal plus one prandial
Basal
only
NPH
Basal analogues (glargine, detemir)
Pipeline basal analogues
(degludec, pegylated lispro)
Less
frequent
Moghissi E, et al. Endocr Pract. 2013;Feb 20:1-33. [Epub ahead of print].
Glycemic Management in
Type 2 Diabetes
Safety Concerns: Weight
47
Antidiabetic Agents and Weight
Weight Gain
Weight Neutral or Weight Loss
Glinides
Insulin
Sulfonylureas
Thiazolidinediones
-Glucosidase inhibitors
Bromocriptine
Colesevelam
DPP-4 inhibitors
GLP-1 receptor agonists
Metformin
Pramlintide
• Risk of additional weight gain must be balanced against
the benefits of the agent
– Sulfonylureas may negate weight loss benefits of GLP-1
receptor agonists or metformin
– Insulin should not be withheld because of the risk of weight
gain
48
Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
Rodbard HW, et al. Endocr Pract. 2009;15:540-559.
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Glycemic Management in
Type 2 Diabetes
Safety Concerns: Cancer Risk
49
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
50
ORIGIN Trial Investigators. 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.
Glycemic Management in
Type 2 Diabetes
Special Populations and
Situations
51
Management Considerations
for Elderly Patients with
Diabetes
Increased risk of and
from falling
• Impaired vision
• Reduced strength and
stamina
• Sensitivity to
medication side effects
• Frailty
• Susceptibility to
hypoglycemia
Hypoglycemia
unawareness and
recurrent
hypoglycemia
• Impaired counterregulatory mechanisms
Other complicating
factors
• Diminished kidney
function
• Urinary incontinence
• Status of social support
and/or caregiver
• Drug-drug interactions
Consider risks before prescribing:
• Sulfonylureas and glinides (hypoglycemia risk)
• Thiazolidinediones (fracture risk)
• Metformin (risk of lactic acidosis with decreased kidney function)
Impaired capacity,
understanding, and/or
motivation for proper
self-care
• Cognitive decline and
dementia
• Depression
• Impaired vision
Consider when establishing
treatment goals
• Patient overall health and well-being
• Self-care capacities
• Social/family support
52
Bourdel Marchasson I, et al. J Nutr Health Aging. 2009;13:685-691. Handelsman Y, et al. Endocr Pract. 2011;17(suppl
2):1-53. Schwartz AV, et al. Diabetes Care. 2008;31:391-396. Zammitt NN, Frier BM. Diabetes Care. 2005;28:2948-2961.
Risk Considerations for
Religious/Cultural Fasting
Main Risks of Fasting
•
•
•
•
Risk Category
Low
Moderate
High
Very high
53
Hypoglycemia
Hyperglycemia
Diabetic ketoacidosis
Dehydration and thrombosis
Features

Glycemia well-controlled with antihyperglycemic agent that does not cause
hypoglycemia (eg, metformin, thiazolidinedione, DPP-4 inhibitor, GLP-1 receptor
agonist)

Otherwise healthy

Glycemia well-controlled with glinides

Moderate hyperglycemia (A1C 7.5-9.0%), renal insufficiency, cardiovascular
complications, and/or other comorbid conditions

Living alone, especially if taking sulfonylureas, insulin, or drugs that affect mentation

Elderly, especially with poor health

History of recurrent hypoglycemia, hypoglycemia unawareness, or episode of severe
hypoglycemia within 3 months prior to Ramadan

Poor glycemic control

Ketoacidosis or hyperosmotic hyperglycemic coma within 3 months prior to Ramadan

Acute illness or chronic dialysis

Intense physical labor

Pregnancy
Al-Arouj M, et al. Diabetes Care. 2005;28:2305-2311.
Glycemic Management During
Religious/Cultural Fasting
• Frequent glucose monitoring—break fast immediately if patient
has:
– Hypoglycemia
• SMBG <70 mg/dL while taking insulin or sulfonylureas
• SMBG <60 mg/dL while on other therapies
– Hyperglycemia: >300 mg/dL
• Healthful eating before and after each fasting period
– Complex carbohydrates prior to fast
– Avoid ingesting high-carbohydrate, high-fat foods when breaking
fast
• Avoid excessive physical activity but maintain normal exercise
routines
• Avoid fasting while ill
54
Al-Arouj M, et al. Diabetes Care. 2005;28:2305-2311.