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Type 2 Diabetes Update
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• Donald Eagerton M.D., F.A.C.P., F.A.C.E.
• September 2019
Disclosures
• I have served as an investigator for or speaker
for the following: NovoNordisk, Ely Lilly,
Boehringer Engleheim, Aventis, Abbott,
Merck, Sanofi Aventis, BMS,
• I was a site investigator for the LEADER,
DEVOTE, SUSTAIN, LIXI, PIONEER, and
EMPA-REG trials
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The Burden of Diabetes
3
Prevalence of Diabetes and
Prediabetes in the United States
4
1. CDC. National diabetes fact sheet, 2008. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2008.pdf.
2. CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf.
3. CDC. National diabetes statistics report, 2014. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf
Prediabetes
37% of US population
Diabetes
9.1% of US population
57
79 86
17.9
18.821.0
5.7
7.8.1
0.
30.
60.
90.
120.
150.
2007 2011 2014
Pers
on
s (
mil
lio
ns
)
Undiagnosed DM
Diagnosed DM
Prediabetes
1 2 3
3
4
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3
6.6 12. 21.37.9
55.571.2
86.6
0.
22.5
45.
67.5
90.
112.5
1990 2000 2010 2020 2030 2040 2050
Nu
mb
er
(mil
lio
ns
)
Diagnosed
Projected Prevalence of Diabetes in
the United States: 1990 to 2050
5
1. National Diabetes Surveillance System. http://www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm. 2. CDC. National diabetes fact
sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. 3. Boyle JP, et al. Popul Health Metr. 2010 Oct 22;8:29.
Year
1 1 2 3 3 3 3
T2D Prevalence Parallels
Prevalence of Obesity
6
0.
15.
30.
45.
60.
75.
1980 1994 2000 2008 2010 2012
BMI, body mass index (in kg/m2); CDC, Centers for Disease Control and Prevention; NHANES, National Health and Nutrition Examination
Survey (x-axis lists last year of each survey); T2D, type 2 diabetes.
*NHANES 1994 data.
Flegal KM, et al. Int J Obes Relat Metab Disord. 1998;22:39-47. Flegal KM, et al. JAMA. 2002 ;288:1723-1727. Flegal KM, et al. JAMA.
2010;303:235-241. Flegal KM, et al. JAMA. 2012;307:491-497. Ogden CL, et al. JAMA. 2014;311:806-814. Harris MI, et al. Diabetes Care.
1998;21:518-524. CDC. Diabetes data & trends. Available at: http://www.cdc.gov/diabetes/statistics/prev/national/figraceethsex.htm and
http://www.cdc.gov/diabetes/statistics/prev/national/fighispanicthsex.htm.
0.
2.5
5.
7.5
10.
12.5
1980 1994* 2000 2008 2010 2011
White men
White women
Black men
Black women
ObeseNHANES Data,
U.S. Adults ≥20 Years
Diagnosed DiabetesCDC Data,
U.S. Population
Po
pu
lati
on
(%
)
5
6
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4
Increase in Diabetes Parallels the
Increase in Obesity in the United States
7*BMI ≥30 kg/m2.
CDC. National diabetes statistics report, 2014. Atlanta, GA: US Department of Health and Human Services, Centers for Disease
Control and Prevention, 2014. Mokdad AH, et al. JAMA. 1999;282:1519-1522; Mokdad AH, et al. Diabetes Care. 2000;23:1278-1283;
Ogden CL, et al. JAMA. 2014;311:806-814.
Obesity* Diabetes
17.9
35.1
0.
9.
18.
27.
36.
45.
1998 2012
Po
pu
lati
on
(%
)
96% increase
6.5
9.3
0.
3.
6.
9.
12.
1998 2014
43% increase
Po
pu
lati
on
(%
)
• 7th leading cause of death
in US
• Leading cause of
blindness
• Most frequent cause of
kidney failure
• ~60% of nontraumatic
lower limb amputations
occur in people with
diabetes
• Diabetes also
– Doubles the risk of
periodontal disease
– Doubles the risk of
developing depression
• Depression increases T2D
risk by 60%
– Increases patients’
susceptibility to acute illness
(eg, pneumonia and
influenza)
• Worsens the prognosis of
patients with acute illnesses
Diabetes Morbidity and Mortality
8
CDC. National diabetes statistics report, 2014. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf.
CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf.
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Diabetes and Morbidity and Mortality
9
1.5
1.7
1.8
1.5
0. 0.5 0.9 1.4 1.8 2.3
All-cause death
CVD death
Myocardial infarction
Stroke
Risk increase
(relative to individuals without diabetes)
CDC. National diabetes statistics report, 2014. http://www.cdc.gov/diabetes/pubs/statsreport14/national-
diabetes-report-web.pdf
Costs of Diabetes
10
$176
$23$44
$244
$69
$9
0.
75.
150.
225.
300.
Diagnosed Undiagnosed Prediabetes Total*
US
Do
llars
(b
illio
ns)
Indirect
Direct
*Includes $1.3 billion in costs from gestational diabetes.
Dall TM, et al. Diabetes Care. 2014;37:3172-3179.
2012 Burden Estimate
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Development of Type 2 Diabetes Depends on Interplay
Between Insulin Resistance and β-Cell Dysfunction
11
Insulin resistance
Insulin resistance
Abnormalβ-Cell
Function
Relative insulin deficiency
Gerich JE. Mayo Clin Proc. 2003;78:447-456.
Type 2 diabetes
Normalβ-Cell
Function
Compensatory hyperinsulinemia
No diabetes
Genes &
environment
Genes &
environment
• Age ≥45 years
• Family history of T2D or
cardiovascular disease
• Overweight or obese
• Sedentary lifestyle
• Non-Caucasian ancestry
• Previously identified IGT, IFG,
and/or metabolic syndrome
• PCOS, acanthosis nigricans, or
NAFLD
• Hypertension (BP >140/90 mmHg)
• Dyslipidemia (HDL-C <35 mg/dL
and/or triglycerides >250 mg/dL)
• History of gestational diabetes
• Delivery of baby weighing
>4 kg (>9 lb)
• Antipsychotic therapy for
schizophrenia or severe bipolar
disease
• Chronic glucocorticoid exposure
• Sleep disorders
– Obstructive sleep apnea
– Chronic sleep deprivation
– Night shift work
Risk Factors for Prediabetes and
Type 2 Diabetes
12
BP, blood pressure; HCL-C, high density lipoprotein cholesterol; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; NAFLD,
nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome; T2D, type 2 diabetes.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
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Natural History of Type 2 Diabetes
13Figure courtesy of CADRE.
Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25;
Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med. 2002;347:1342-1349;
UKPDS Group. Diabetes. 1995;44:1249-1258
Fasting glucose
Type 2 diabetes
Years from
diagnosis0 5–10 –5 10 15
Prediabetes
Onset Diagnosis
Postprandial glucose
Macrovascular complications
Microvascular complications
Insulin resistance
Insulin secretion
b-Cell function
Dashed line = extrapolation based on Homeostasis Model Assessment (HOMA) data.
Data points from obese UKPDS population, determined by HOMA model.
Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25.
b-cell Loss Over Time
14
UKPDS
Type 2 Diabetes
b-C
ell
Fu
nc
tio
n (
%)
Years from Diagnosis
25 –
100 –
75 –
0 –
50 –
l
-12
l
-10
l
-6l
-2
l
0
l
2
l
6
l
10
l
14
PostprandialHyperglycemia
Impaired Glucose
Tolerance
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Tissues Involved in T2D
Pathophysiology
16
Organ System Normal Metabolic Function Defect in T2D
Major Role
Pancreatic beta cells Secrete insulin Decreased insulin secretion
Muscle Metabolizes glucose for energy Inefficient glucose uptake
Liver
Secretes glucose during fasting periods to maintain
brain function; main site of gluconeogenesis (glucose
production in the body)
Increased endogenous glucose
secretion
Contributing Role
Adipose tissue (fat)
Stores small amounts of glucose for its own use. When
fat is broken down, glycerol is released, which is used
by the liver to produce glucose
Increased FFA production
Digestive tractDigests and absorbs carbohydrates and secretes
incretin hormonesDecreased incretin effect
Pancreatic alpha cells
Secrete glucagon, which stimulates hepatic glucose
production between meals and also helps suppress
insulin secretion during fasting periods
Increased glucagon secretion
Kidney
Reabsorbs glucose from renal filtrate to maintain
glucose at steady-state levels; also an important site for
gluconeogenesis (glucose production)
Increased glucose reabsorption
BrainUtilizes glucose for brain and nerve function
Regulates appetiteNeurotransmitter dysfunction
T2D, type 2 diabetes.
DeFronzo RA. Diabetes. 2009;58:773-795
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*P≤.05.
Nauck M, et al. Diabetologia. 1986;29:46-52.
The Incretin Effect Is Diminished
in Type 2 Diabetes
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Normal Glucose Tolerance
(n=8)
Type 2 Diabetes
(n=14)
IV Glucose
Oral Glucose
0 60 120 180
240
Pla
sm
a G
luc
os
e (
mg
/dL
)
180
90
0
0 60 120 180
Pla
sm
a G
luc
os
e (
mg
/dL
) 240
180
90
0
**
* **
* * *
0 60 120 180
C-P
ep
tid
e (
nm
ol/
L)
Time (min)
30
20
10
00 60 120 180
C-p
ep
tid
e (
nm
ol/
L)
Time (min)
30
20
10
0
Acute Insulin Response Is Reduced in
Type 2 Diabetes
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IRI, immunoreactive insulin.
Pfeifer MA, et al. Am J Med. 1981;70:579-588.
Pla
sm
a I
RI
(µU
/ml)
Time (minutes)
20 g glucose infusion
2nd phase1st
-300
20
40
60
80
100
0 30 60 90 120
120Normal (n=85)
Type 2 diabetes (n=160)
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Müller WA, et al. N Engl J Med. 1970;283:109-115.
Normal Glucose Homeostasis and Pre- and
Postmeal Insulin and Glucagon Dynamics
19
Premeal Postmeal
Insulin Insulin
Glucagon
HGP
Glucagon
HGP
Just enough glucose to meet metabolic
needs between meals
Modest postprandial increase with
prompt return to fasting levels
Glucose (mg %)
Glucagon (pg/mL)
Time (min)
-60 0 60 120 180 240
Meal120
90
60
30
0
140
130
120
110
100
90
Insulin (µU/mL)
360
330
300
270
240
110
80
Normal (n=11)
Hyperglycemia in Type 2 Diabetes Results from
Abnormal Insulin and Glucagon Dynamics
20
Premeal Postmeal
Insulin Insulin
Glucagon
HGP
Glucagon
HGP
FPG PPGGlucose (mg %)
Insulin (µU/mL)
Glucagon (pg/mL)
Time (min)
-60 0 60 120 180 240
Meal120
90
60
30
0
140
130
120
110
100
90
360
330
300
270
T2D (n=12)
Normal (n=11)
240
110
80
T2D, type 2 diabetes.
Müller WA, et al. N Engl J Med. 1970;283:109-115.
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Actions of GLP-1 and GIP
GLP-1
• Released from L cells in ileum and colon
• Stimulates insulin release from b-cell in a glucose-dependent manner
• Potent inhibition of gastric emptying
• Potent inhibition of glucagon secretion
• Reduction of food intake and body weight
• Significant effects on b-cell growth and survival
GIP
• Released from K cells in duodenum
• Stimulates insulin release from b-cell in a glucose dependent manner
• Minimal effects on gastric emptying
• No significant inhibition of glucagon secretion
• No significant effects on satiety or body weight
• Potential effects on b-cell growth and survival
21
Drucker DJ. Diabetes Care 2003;26:2929-2940.
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Renal Glucose Reabsorption
in Type 2 Diabetes
• Sodium-glucose cotransporters 1 and 2 (SGLT1
and SGLT2) reabsorb glucose in the proximal
tubule of kidney
– Ensures glucose availability during fasting periods
• Renal glucose reabsorption is increased in type 2
diabetes
– Contributes to fasting and postprandial hyperglycemia
– Hyperglycemia leads to increased SGLT2 levels, which
raises the blood glucose threshold for urinary glucose
excretion
23
Wright EM, et al. J Intern Med. 2007;261:32-43.
90% of glucose
SGLT1
(180 L/day) (90 mg/dL) = 162 g glucose per day
10% of glucose
Glucose
No Glucose
S1
S3
Normal Renal Handling of Glucose
24
SGLT2
Abdul-Ghani MA, et al. Endocr Pract. 2008;14:782-790.
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Increased SGLT2 Protein Levels Change
Glucose Reabsorption and Excretion Thresholds
25
TmG, glucose transport maximum.
Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14:782-790.
27090
Ren
al
Glu
co
se R
eab
so
rpti
on
TmG
180
TmG
Blood Glucose Concentration (mg/dL)
Reabsorption
increases
27090 180
Blood Glucose Concentration (mg/dL)
Excretion
threshold
increases
Ren
al
Glu
co
se E
xcre
tio
n
Reabsorption Excretion
Hypothalamic Dopaminergic Tone
and Autonomic Imbalance
26
In diabetes:
Low dopaminergic tone in
hypothalamus in early morning
Sympathetic tone
HPA axis tone
Hepatic gluconeogenesis
FFA and TG
Insulin resistance
Inflammation/hypercoagulation
Impaired glucose metabolism
Hyperglycemia
Insulin resistance
Adverse cardiovascular pathology
20Fonseca V. Dopamine Agonists in Type 2 Diabetes. New York, NY: Oxford University Press; 2010.
Cincotta AH. In: Hansen B, Shafrir E, eds. Insulin Resistance and Insulin Resistance Syndrome. New York, NY: Taylor &
Francis; 2002:271-312.
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AACE Comprehensive Care PlanComprehensive Care Plan
Disease
managemen
t from a
multidisciplin
ary team
Antihypergly
cemic
pharmacoth
erapy
Comprehen
sive
diabetes
self-
education
for the
patient
Therapeutic
lifestyle
change
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
27
THERAPEUTIC LIFESTYLE
CHANGE
Glycemic Management of Type 2 Diabetes
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Components of Therapeutic Lifestyle
Change
• Healthful eating
• Sufficient physical activity
• Sufficient sleep
• Avoidance of tobacco products
• Limited alcohol consumption
• Stress reduction
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
29
AACE Recommendations:
Therapeutic Lifestyle Changes
Parameter Treatment Goal
Weight loss(for
overweight and
obese patients)
Reduce by 5% to 10%
Physical activity150 min/week of moderate-intensity exercise (eg, brisk
walking) plus flexibility and strength training
Diet
• Eat regular meals and snacks; avoid fasting to lose
weight
• Consume plant-based diet (high in fiber, low
calories/glycemic index, and high in
phytochemicals/antioxidants)
• Understand Nutrition Facts Label information
• Incorporate beliefs and culture into discussions
• Use mild cooking techniques instead of high-heat
cooking
• Keep physician-patient discussions informal30
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
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AACE Recommendations: Medical
Nutritional Therapy
• Consistency in day-to-day carbohydrate intake
• Adjusting insulin doses to match carbohydrate intake (eg, use of carbohydrate counting)
• Limitation of sucrose-containing or high-glycemic index foods
• Adequate protein intake
• “Heart-healthy” diets
• Weight management
• Exercise
• Increased glucose monitoring
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
31
ANTIHYPERGLYCEMIC
THERAPY
Glycemic Management of Type 2 Diabetes
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Noninsulin Agents for DM2Class Primary Mechanism of Action Agent(s) Available as
a-Glucosidase
inhibitors
• Delay carbohydrate absorption
from intestine
Acarbose
Miglitol
Precose or generic
Glyset
Amylin analogue
• Decrease glucagon secretion
• Slow gastric emptying
• Increase satiety
Pramlintide Symlin
Biguanide• Decrease HGP
• Increase glucose uptake in muscleMetformin
Glucophage or
generic
Bile acid
sequestrant
• Decrease HGP?
• Increase incretin levels?Colesevelam WelChol
DPP-4 inhibitors
• Increase glucose-dependent
insulin secretion
• Decrease glucagon secretion
Alogliptin
Linagliptin
Saxagliptin
Sitagliptin
Nesina
Tradjenta
Onglyza
Januvia
Dopamine-2 agonist • Activates dopaminergic receptors Bromocriptine Cycloset
Glinides • Increase insulin secretionNateglinide
Repaglinide
Starlix or generic
Prandin
36
DPP-4, dipeptidyl peptidase; HGP, hepatic glucose production.
Garber AJ, et al. Endocr Pract. 2015;21:438-447.
Inzucchi SE, et al. Diabetes Care. 2015;38:140-149. Continued on next slide
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Noninsulin Agents
Available for T2D
Class Primary Mechanism of Action Agent(s) Available as
GLP-1 receptor
agonists
• Increase glucose-dependent
insulin secretion
• Decrease glucagon secretion
• Slow gastric emptying
• Increase satiety
Albiglutide
Dulaglutide
Exenatide
Exenatide XR
Liraglutide
Tanzeum
Trulicity
Byetta
Bydureon
Victoza
SGLT2 inhibitors• Increase urinary excretion of
glucose
Canagliflozin
Dapagliflozin
Empagliflozin
Invokana
Farxiga
Jardiance
Sulfonylureas • Increase insulin secretion
Glimepiride
Glipizide
Glyburide
Amaryl or generic
Glucotrol or generic
Diabeta, Glynase,
Micronase, or generic
Thiazolidinediones
• Increase glucose uptake in muscle
and fat
• Decrease HGP
Pioglitazone
Rosiglitazone
Actos
Avandia
GLP-1, glucagon-like peptide; HGP, hepatic glucose production; SGLT2, sodium glucose cotransporter 2.
Garber AJ, et al. Endocr Pract. 2015;21:438-447.
Inzucchi SE, et al. Diabetes Care. 2015;38:140-149. Continued from previous slide
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Depicted are patient and disease factors used to determine optimal A1C targets.
American Diabetes Association Clin Diabetes 2019;37:11-34
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• Use GFR in place
of creatinine
• Can initiate
Metformin if GFR is
> 45
• Can remain on it if
GFR is > 30
Metformin Guidelines Have
Changed
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Pharmacologic Therapy for Type 2 Diabetes.9.5 Metformin is the preferred initial pharmacologic agent for
the treatment of type 2 diabetes. A
9.6 Once initiated, metformin should be continued as long as it
is tolerated and not contraindicated; other agents, including
insulin, should be added to metformin. A
9.7 Long-term use of metformin may be associated with
biochemical vitamin B12 deficiency, and periodic
measurement of vitamin B12 levels should be considered
in metformin-treated patients, especially in those with
anemia or peripheral neuropathy. BPharmacologic Approaches to Glycemic Treatment:
Standards of Medical Care in Diabetes - 2019. Diabetes Care 2019;42(Suppl.
1):S90-S102
Pharmacologic Therapy for Type 2 Diabetes.
9.8 The early introduction of insulin should be considered if
there is evidence of ongoing catabolism (weight loss), if
symptoms of hyperglycemia are present, or when A1C
levels (>10% [86 mmol/mol)] or blood glucose levels (≥300
mg/dL [16.7 mmol/L)] are very high. E
9.9 Consider initiating dual therapy in patients with newly
diagnosed type 2 diabetes who have A1C ≥1.5% (12.5
mmol/mol) above their glycemic target. E
9.10 A patient-centered approach should be used to guide the
choice of pharmacologic agents. Considerations include
comorbidities (atherosclerotic cardiovascular disease, heart
failure, chronic kidney disease), hypoglycemia risk, impact
Pharmacologic Approaches to Glycemic Treatment:
Standards of Medical Care in Diabetes - 2019. Diabetes Care 2019;42(Suppl.
1):S90-S102
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Copyright ADA & EASD 2018
Copyright ADA & EASD 2018
Presence of cardiovascular disease is compelling indication
Step 1: Assess cardiovascular disease
Pharmacologic Therapy for Type 2 Diabetes.9.11 Among patients with type 2 diabetes who have established
atherosclerotic cardiovascular disease, sodium-glucose
cotransporter 2 inhibitors, or glucagon-like peptide 1
receptor agonists with demonstrated cardiovascular disease
benefit (Table 9.1) are recommended as part of the
antihyperglycemic regimen. A
9.12 Among patients with atherosclerotic cardiovascular
disease at high risk of heart failure or in whom heart failure
coexists, sodium-glucose cotransporter 2 inhibitors are
preferred. C
9.13 For patients with type 2 diabetes and chronic kidney
disease, consider use of a sodium-glucose cotransporter 2
inhibitor or glucagon-like peptide 1 receptor agonist shown
Pharmacologic Approaches to Glycemic Treatment:
Standards of Medical Care in Diabetes - 2019. Diabetes Care 2019;42(Suppl.
1):S90-S102
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Pharmacologic Therapy for Type 2 Diabetes.9.14 In most patients who need the greater glucose-lowering
effect of an injectable medication, glucagon-like peptide 1
receptor agonists are preferred to insulin. B
9.15 Intensification of treatment for patients with type 2
diabetes not meeting treatment goals should not be
delayed. B
9.16 The medication regimen should be reevaluated at regular
intervals (every 3-6 months) and adjusted as needed to
incorporate new patient factors (Table 9.1). EPharmacologic Approaches to Glycemic Treatment:
Standards of Medical Care in Diabetes - 2019. Diabetes Care 2019;42(Suppl.
1):S90-S102
Copyright ADA & EASD 2018
Copyright ADA & EASD 2018
Consensus Recommendation—new since 2015
Consider important comorbidities that should influence the choice of a particular glucose-lowering medication
Among patients with type 2 diabetes with established atherosclerotic cardiovascular disease (ASCVD), sodium-glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide 1 (GLP-1) receptor agonists with proven cardiovascular benefit are recommended as part of glycaemic management
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Copyright ADA & EASD 2018
Copyright ADA & EASD 2018
Clinical Inertia
Clinical inertia: failure of healthcare providers to initiate or intensify therapy when indicated, due to:
• overestimation of care provided
• use of “soft” reasons to avoid intensification of therapy
• lack of education, training, and practice organzation aimed at achieving therapeutic goals
Copyright ADA & EASD 2018
CHOOSING GLUCOSE-LOWERING MEDICATION IN THOSE WITH ESTABLISHED ASCVD OR CKD
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Copyright ADA & EASD 2018
If ASCVD Predominates:GLP-1 receptor agonist with proven cardiovascular benefit
•Liraglutide > semaglutide > exenatide LAR
SGLT2 inhibitor with proven cardiovascular benefit
•Empagliflozin > canagliflozin
Copyright ADA & EASD 2018
CHOOSING GLUCOSE-LOWERING MEDICATION IN THOSE WITH ESTABLISHED HF OR CKD
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Copyright ADA & EASD 2018
Copyright ADA & EASD 2018
Among patients with ASCVD in whom HF coexists or is of concern, SGLT2 inhibitor are recommended
Rationale: Patients with T2D are at increased risk for heart failure with reduced or preserved ejection fraction
Significant, consistent reductions in hospitalization for heart failure have been seen in SGLT2 inhibitor trials
Caveat: trials were not designed to adjudicate heart failure
Majority of patients did not have clinical heart failure at baseline
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Copyright ADA & EASD 2018
Copyright ADA & EASD 2018
Consensus Recommendation:
For patients with type 2 diabetes and CKD, with or without cardiovascular disease, consider the use of an SGLT2 inhibitor shown to reduce CKD progression or, if contraindicated or not preferred, a GLP-1 receptor agonist shown to reduce CKD progression .
Several of these medications have demonstrated renal benefit and cardiovascular benefit and should be considered as part of treatment
Copyright ADA & EASD 2018
CKD ConsiderationsFor SGLT2-i adequate eGFR differs between countries and compounds
SGLT2-i are registered as glucose-lowering agents to be started if eGFR>45-60 ml/min/1.73m2 and stopped at eGFR 45-60, as glucose-lowering effect declines with eGFR
SGLT2-i CVOTs included patients with eGFR>30, and there were no excess adverse events in subjects with eGFR<60
For GLP-1 RA gastrointestinal side effects increase with declining renal function
GLP-1 RA are not recommended in end stage renal disease due to limited experience
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Copyright ADA & EASD 2018
*CI, confidence interval; HR, hazard ratio
Wanner et al. N Engl J Med 2016;375:323-34
HR=0.54*, 95% CI: 0.40;0.75p<0.001
Month
Cum
ula
tive p
robability o
f event
(%)
0 6 12 18 24 30 36 42 48
0
1
2
3
4
5
6
7
8
Empagliflozin
EMPA-REGTime to first renal event (secondary outcome)Doubling of the serum creatinine level, the initiation of renal-replacement therapy, or death from renal disease
Copyright ADA & EASD 2018
LEADER Time to first renal event (secondary outcome)
Macroalbuminuria, doubling of serum creatinine, ESRD, renal death
The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard
regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI:
confidence interval; ESRD: end-stage renal disease; HR: hazard ratio.
Marso SP et al. N Engl J Med 2016;375:311–322
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Copyright ADA & EASD 2018
Copyright ADA & EASD 2018
Summary
Consider the presence or absence of ASCVD, CKD and HF
Start with metformin if tolerated, then:
In patients with ASCVD a GLP-1 RA or SGLT2-i is recommended
In patients with ASCVD and HF SGLT2-i is recommended
In patients with CKD, with or without ASCVD consider an SGLT2-i
Agents with proven benefit are preferred
ASCVD, CKD and HF affects choice of additional glucose lowering medication
Copyright ADA & EASD 2018
Copyright ADA & EASD 2018
New Since 2014
MetforminUS and EU Labels were revised in 2016 for use when eGFR is reduced
InsulinsDegludec (long acting) approved in the US (approved earlier in EU)Fast-acting insulin aspart approved in US and EUBiosimilars have become available for glargine and lisproConcentrated forms of several have become availableInhaled insulin (US)
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Copyright ADA & EASD 2018
Copyright ADA & EASD 2018
New Since 2014
SGLT2 InhibitorsErtugliflozin approved in US and EUCombination products approved (with metformin or DPP4 inhibitors)Cardiovascular outcomes trials with empagliflozin, canagliflozin (and dapagliflozin)
complete with broad benefits on cardiorenal outcomes
GLP-1 Receptor AgonistsTwo agents were approved: lixisenatide (in US 2016, EU 2013), semaglutideCombination products approved (with long-acting insulins)Cardiovascular outcomes trials with liraglutide, semaglutide and exenatide
extended-release complete with cardiovascular benefitsNew safety data is reassuring regarding pancreatitis and pancreatic cancer
New ADA Recommendation
In most cases of type 2 Diabetes, the
first injectable agent should be a GLP-1
receptor agonist
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Cardiovascular Risk Reduction with Icosapent Ethyl for HypertriglyceridemiaDeepak L. Bhatt, M.D., M.P.H., P. Gabriel Steg, M.D., Michael Miller, M.D., Eliot A. Brinton, M.D., Terry A. Jacobson, M.D., Steven B. Ketchum, Ph.D., Ralph T. Doyle, Jr., B.A., Rebecca A. Juliano, Ph.D., Lixia Jiao, Ph.D., Craig Granowitz, M.D., Ph.D.
DL Bhatt et al. N Engl J Med 2019;380:11-22.
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In REDUCE-IT, the risk of the key secondary composite end point of cardiovascular death, nonfatal myocardial infarction, or nonf
Fatal and nonfatal ischemic events were lower in the icosapent ethyl group than in the placebo group, including a 20% lower r
The benefits were observed against a background of appropriate statin use among patients who had a median LDL cholesterol lev
• The revised standards now recommend that
icosapent ethyl (Vascepa, Amarin) be
considered to reduce CV risk for patients with
diabetes who have atherosclerotic CVD or
other CV risk factors and who are prescribed
a statin and have controlled LDL cholesterol
but persistently elevated triglycerides. The
recommendation is based on findings from the
REDUCE-IT trial, which found that icosapent
ethyl was superior to placebo for reducing risk
for ischemic events in patients with elevated
triglycerides at high CV risk despite statin
therapy.
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• Degludec (Tresiba)
• Glargine U300 (Toujeo)
• Fiasp
• Combination basal insulin
+ GLP1 Xultophy and
Soliqua
• Inhaled insulin (Affreza)
New Insulins
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Summary
• New recommendations for type 2 diabetics
with established cardiovascular disease
• New guidelines for metformin
• New insulins
• New GLP-1s
• GLP-1 are recommended as first injectable
• I did not include everything
• The only hope for diabetes is for technology to
outpace apathy
References
• AACE 2019 Diabetes Management Algorithm
• ADA 2019 Standards of Care
• N Engl J Med 2019; 380:347-357
• DOI: 10.1056/NEJMoa1812389
• June 13, 2019
• N Engl J Med 2019; 380:2295-2306
• DOI: 10.1056/NEJMoa1811744
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Renal Outcomes with Empagliflozin Over
3.2 Years
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EMPA-REG RENAL
(N=7020)
Arrows = relative risk reduction.
*Doubling of SCr + eGFR ≤45 mL/min/1.73 m2, initiation of renal replacement therapy, or death from renal disease.
CI, confidence interval; eGFR, estimated glomerular filtration rate; SCr, serum creatinine.
Wanner C, et al. N Engl J Med. 2016;375:323-334.
18.8
12.7
0.
4.8
9.5
14.3
19.
23.8
Incident or worsening nephropathy
Pati
en
ts (
%) 39%
P<0.0019.7
5.5
0.
2.5
5.
7.5
10.
12.5
Post-hoc composite outcome*
Pati
en
ts (
%)
44%P<0.001
16.2
11.2
0.
4.3
8.5
12.8
17.
21.3
Progression to macroalbuminuria
Pati
en
ts (
%)
38%P<0.001
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Clinical Outcomes with Liraglutide
93
LEADER
(N=9340)
*CV death, nonfatal MI (including silent MI), or nonfatal stroke.
CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
Marso SP, et al. N Engl J Med. 2016:375:311-322.
Clinical Outcomes with Liraglutide
94
LEADER Adverse Events Leading to
Discontinuation
Marso SP, et al. N Engl J Med. 2016:375:311-322.
Event Liraglutide (%)
(n=4668)
Placebo (%)
(n=4672)
P value
Any adverse event 9.5 7.3 <0.001
Serious adverse event 4.1 5.2 0.01
Nausea 1.6 0.4 <0.001
Vomiting 0.7 <0.1 <0.001
Diarrhea 0.6 0.1 <0.001
Increased lipase level 0.3 0.2 0.43
Abdominal pain 0.2 0.1 0.03
Decreased appetite 0.2 <0.1 0.01
Abdominal discomfort 0.2 0 0.002
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Mann JF et al. N Engl J Med 2017;377:839-848.
Mann JF et al. N Engl J Med 2017;377:839-848.
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Mann JF et al. N Engl J Med 2017;377:839-848.
SUSTAIN 6(TRIAL TO EVALUATE CARDIOVASCULAR AND OTHER LONG-TERM
OUTCOMES WITH SEMAGLUTIDE IN SUBJECTS WITH TYPE 2
DIABETES)
Clinical Outcomes with Antihyperglycemic Agents
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Marso SP et al. N Engl J Med 2016;375:1834-1844.
Marso SP et al. N Engl J Med 2016;375:1834-1844.
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Clinical Outcomes with Semaglutide
101
SUSTAIN 6 Selected Adverse Events
Marso SP, et al. N Engl J Med. 2016:375:1834-1844.
Event Semaglutide 1 mg (%)
(n=822)
Placebo 1 mg (%)
(n=825)
Any adverse event 89.1 89.2
Serious adverse event 33.6 36.1
Gastrointestinal disorder 52.3 35.2
Diarrhea 18.4 10.5
Nausea 21.9 8.1
Vomiting 14.8 4.1
Acute pancreatitis 0.4 1.1
Gallbladder disorder 3.2 2.8
Cholelithiasis 2.1 1.5
Acute cholecystitis 0 0.2
Severe or symptomatic hypoglycemia 21.7 21.0
Injection site reaction 1.1 1.5
Neoplasm (any) 10.8 8.4
Any malignant 4.9 4.2
Malignant pancreatic 0.1 0.2
• Compared with placebo, the once-
weekly GLP-1 receptor agonist
dulaglutide reduced major adverse
cardiovascular events in adults with
type 2 diabetes with and without
established cardiovascular disease,
making the agent the first type 2
diabetes agent to demonstrate CV
superiority in a broad type 2 diabetes
population.
• In the REWIND CV outcomes trial,
dulaglutide (Trulicity) was associated
with significantly reduced major
adverse cardiovascular events, a
composite endpoint of CV death, non-
fatal myocardial infarction or non-fatal
stroke, meeting the primary efficacy
objective, according to the release.
REWIND: Dulaglutide reduces CV
risk in type 2 diabetes without CVD
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• The REWIND trial is distinct
from other CV outcome trials
due to the limited number of
people with established CV
disease who participated in the
trial, according to Lilly. Of the
9,901 REWIND participants,
only 31% had established CVD.
Additionally, REWIND had a
median follow-up period of
more than 5 years, the longest
for a CV outcome trial in the
GLP-1 receptor agonist class,
according to the release.
REWIND
ORIGINAL ARTICLE
Canagliflozin and Renal Outcomes in
Type 2 Diabetes and Nephropathy• Vlado Perkovic, M.B., B.S., Ph.D., Meg J. Jardine, M.B., B.S., Ph.D., Bruce
Neal, M.B., Ch.B., Ph.D., Severine Bompoint, B.Sc., Hiddo J.L. Heerspink,
Pharm.D., Ph.D., David M. Charytan, M.D., Robert Edwards, M.P.H., Rajiv
Agarwal, M.D., George Bakris, M.D., Scott Bull, Pharm.D., Christopher P.
Cannon, M.D., George Capuano, Ph.D., Pei-Ling Chu, Ph.D., Dick de Zeeuw,
M.D., Ph.D., Tom Greene, Ph.D., Adeera Levin, M.D., Carol Pollock, M.B., B.S.,
Ph.D., David C. Wheeler, M.D., Yshai Yavin, M.B., Ch.B., Hong Zhang, M.D.,
Ph.D., Bernard Zinman, M.D., Gary Meininger, M.D., Barry M. Brenner, M.D.,
and Kenneth W. Mahaffey, M.D.et al., for the CREDENCE Trial Investigators*
June 13, 2019
N Engl J Med 2019; 380:2295-2306
DOI: 10.1056/NEJMoa1811744
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SD Wiviott et al. N Engl J Med 2019;380:347-357.
SD Wiviott et al. N Engl J Med 2019;380:347-357.
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SD Wiviott et al. N Engl J Med 2019;380:347-357.
SD Wiviott et al. N Engl J Med 2019;380:347-357.
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V Perkovic et al. N Engl J Med 2019;380:2295-2306.
V Perkovic et al. N Engl J Med 2019;380:2295-2306.
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V Perkovic et al. N Engl J Med 2019;380:2295-2306.
Original Article
Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes
Stephen D. Wiviott, M.D., Itamar Raz, M.D., Marc P. Bonaca, M.D., M.P.H., Ofri Mosenzon, M.D., Eri T. Kato, M.D., M.P.H., Ph.D., Avivit Cahn, M.D., Michael G.
Silverman, M.D., M.P.H., Thomas A. Zelniker, M.D., Julia F. Kuder, M.A., Sabina A. Murphy, M.P.H., Deepak L. Bhatt, M.D., M.P.H., Lawrence A. Leiter, M.D., Darren K. McGuire, M.D., John P.H. Wilding, M.D., Christian T. Ruff, M.D., M.P.H., Ingrid A.M.
Gause-Nilsson, M.D., Ph.D., Martin Fredriksson, M.D., Ph.D., Peter A. Johansson, M.Sc., Anna-Maria Langkilde, M.D., Ph.D., Marc S. Sabatine, M.D.,
M.P.H., for the DECLARE–TIMI 58 Investigators
N Engl J MedVolume 380(4):347-357
January 24, 2019
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Study Overview
• In a randomized trial of patients with type 2 diabetes, treatment with dapagliflozin, an SGLT2 inhibitor that promotes glucosuria, did not result in a higher or lower rate of cardiovascular death, myocardial infarction, or stroke than placebo but did result in a lower rate of hospitalization for heart failure.
Major Cardiovascular and Renal Outcomes and Death from Any Cause.
Wiviott SD et al. N Engl J Med 2019;380:347-357
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Key Efficacy Outcomes and Their Components.
Wiviott SD et al. N Engl J Med 2019;380:347-357
Major Subgroup Analyses of the Primary Efficacy Outcomes.
Wiviott SD et al. N Engl J Med 2019;380:347-357
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Baseline Characteristics of the Patients.
Wiviott SD et al. N Engl J Med 2019;380:347-357
Safety Events.
Wiviott SD et al. N Engl J Med 2019;380:347-357
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Conclusions
• In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure.
• Empagliflozin
• Luraglutide
• Canagliflozin
Three Diabetic Drugs Now Have an
FDA Indication to Decrease Risk of
Cardiovascular Death
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Lipid Management:Other Combination Therapy.
10.28 Combination therapy (statin/fibrate) has not been shown
to improve atherosclerotic cardiovascular disease
outcomes and is generally not recommended. A
10.29 Combination therapy (statin/niacin) has not been shown
to provide additional cardiovascular benefit above statin
therapy alone, may increase the risk of stroke with
additional side effects, and is generally not recommended.
A
Cardiovascular Disease and Risk Management:
Standards of Medical Care in Diabetes - 2019. Diabetes Care 2019;42(Suppl.
1):S103-S123
Comprehensive Medical Evaluation and Assessment of Comorbidities:
Standards of Medical Care in Diabetes - 2019. Diabetes Care 2019;42(Suppl.
1):S34-S45
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Copyright ADA & EASD 2018
Copyright ADA & EASD 2018
Importance of Glycaemic Control
Averting symptomatic hyperglycaemia
Substantial and enduring reduction in microvascular complications• 50-76% reduction DCCT with A1c 7% vs 9%• 25% reduction UKPDS with A1C 7% vs 7.9%• Greatest benefit with reduction from higher levels of A1C
Uncertainty regarding macrovascular benefit of BG control in T2D
Benefits emerge slowly while harms of glucose control medications can be more immediate
Copyright ADA & EASD 2018
Copyright ADA & EASD 2018
Considerations
ASCVD is defined differently across trials• Established CVD (e.g. MI, stroke, revascularization procedure)• Very high cardiovascular risk
Each cardiovascular outcomes trial, while large, is a single experiment
It is not always clear whether differences in trial findings within a drug class are related to trial design or to true differences in the individual medications
• Where evidence suggests a hierarchy, this is noted
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Copyright ADA & EASD 2018
Copyright ADA & EASD 2018
Conclusions
Hospitalization for heart failure was reduced consistently with SGLT2-i in two trials but was a secondary outcome
For patients with type 2 diabetes and CKD, with or without cardiovascular disease, consider the use of an SGLT2 inhibitor shown to reduce CKD progression or, if contraindicated or not preferred, a GLP-1 receptor agonist shown to reduce CKD progression
• Studies of HF or CKD as primary outcome are ongoing with SGLT2-i.
Copyright ADA & EASD 2018
Copyright ADA & EASD 2018
Conclusions
Given the new evidence of outcomes benefit with the use of specific glucose lowering medications in patients with established ASCVD, an important early step in this new approach is to consider the presence or absence of ASCVD, CKD and heart failure.
In patients with ASCVD, studies have demonstrated benefit on cardiovascular outcomes, and some GLP-1 RA and SGLT2-i are recommended in these patients
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