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Speaker Bureau
NovoNordisk
Sanofi
Objectives
Assess the burden of type 2 diabetes
Review current recommendations
Examine the clinical benefits and efficacy
GLP1 and SGLT2 therapy
Insulin analogs
Explore new glycemic monitoring systems
• 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
4
CDC. National diabetes statistics report, 2017. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf.
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.
Diabetes Morbidity and Mortality
The total cost of diabetes and prediabetes in the
U.S. is $322 billion.
Inpatient care is 43% of the total cost
People with diabetes have health care costs 2.3
times greater than those without diabetes.
$13,700 per year for people with diabetes ($7,900)
62% of cost is covered by government (CMS,
Medicaid and Military
The average price of insulin increased nearly 3
times between 2002 and 2013
Economic Costs
American Diabetes Association 2018
The Health Burden of Uncontrolled A1C
• Controlling A1C is a key
factor in managing
complications of diabetes.
• If A1C is left uncontrolled,
complications increase.
• Therapy effectiveness is
measured by Glycemic Control
(i.e., A1C, Interstitial Glucose).1
• A 1% reduction in A1C is
associated with reductions
in long-term complications
related to chronically
elevated blood glucose
levels.2
1. Standards of medical care in diabetes--2013. Diabetes Care. 2013;36 Suppl 1:S11-66.
2. Stratton IM. Association of glycaemia with macrovascular and
microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ.
2000;321(7258):405-412
For every 1% drop in A1c, there is an estimated
maximum cost savings of $4,100 annually
Amputations
MMicrovascular
Diabetes
related deaths
Heart Attack
St Stroke
A1c2
7NHANES, National Health and Nutrition Examination Survey.
Ali MK, et al. N Engl J Med. 2013;368:1613-1624.
NHANES 2007-2010
(N=1444)
Age (years) 18-44 45-64 ≥65 ≥65 18-44 45-64 ≥65
Target A1C (%) ≤6.5 ≤7.0 ≤7.0 ≤7.5 ≤7.0 ≤8.0 ≤8.0
Without complications With complications
37.0
52.057.1
69.4
39.4
57.1
74.6
0
10
20
30
40
50
60
70
80
90
100
Pa
tie
nts
wit
h d
iab
ete
s (
%)
A1c Achievement by Individualized Targets
8
1.5
1.8
1.7
1.5
0 0.5 1 1.5 2
Stroke
Myocardialinfarction
CVD death
All-cause death
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
Diabetes and Morbidity/Mortality
Classification & Diagnosis of Diabetes
• Classification
• Diagnostic Tests for Diabetes
• Categories of Increased Risk for Diabetes (Prediabetes)
• Type 1 Diabetes
• Type 2 Diabetes
• Gestational Diabetes
• Monogenic Diabetes Syndromes
• Cystic Fibrosis-Related Diabetes
• Post-transplantation Diabetes Mellitus
Classification and Diagnosis of Diabetes:
Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S13-S27
Clinical Recommendations
Diabetes
• DCCT: Trend toward lower risk of CVD events with
intensive control (T1D)
• EDIC: 57% reduction in risk of nonfatal MI, stroke, or
CVD death (T1D)
• UKPDS: nonsignificant reduction in CVD events (T2D).
• ACCORD, ADVANCE, VADT suggested no significant
reduction in CVD outcomes with intensive glycemic
control. (T2D)
American Diabetes Association Standards of Medical Care in Diabetes.
Glycemic targets. Diabetes Care 2017; 40 (Suppl. 1): S48-S56
A1c and CVD Outcomes
Classification and Diagnosis of Diabetes:
Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S13-S27
Criteria for the Diagnosis of Diabetes
• All children diagnosed with diabetes in the first 6 months of
life should have immediate genetic testing for neonatal
diabetes.
• Adults, diagnosed in early adulthood, who have diabetes
not characteristic of T1DM or T2DM that occurs in
successive generations (suggestive of an autosomal
dominant pattern of inheritance) should have genetic
testing for MODY.
• In both instances, consultation with a center specializing
in diabetes genetics is recommended to understand the
significance of these mutations and how best to approach
further evaluation, treatment, and genetic counseling.
Classification and Diagnosis of Diabetes:
Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S13-S27
Monogenic Diabetes Syndromes:Recommendations
Current Practice Guidelines
The A-B-C’s of Diabetes Care
ADA AACE
A1c <7% ≤6.5%
Fasting/preprandial glucose
(mg/dL)
80*-130 <110
Postprandial glucose (mg/dL) <180 <140†
Blood pressure (mm Hg) <140/90* <140/80
LDL-cholesterol (mg/dL) risk risk
HDL-cholesterol (mg/dL) >40/50 >35
Triglycerides (mg/dL) <150 <150
American Diabetes Association. Diabetes Care. 2016.
American Association of Clinical Endocrinologists. 2016
*Peak postprandial capillary plasma glucose†2-hour postprandial glucose‡LDL below 70 mg/dL in individuals with overt CV
Individualize A1c goal based upon age, co-morbidities, chronicity of disease
Lowest achievable A1c without hypoglycemia
BP < 130/80 may be appropriate for high risk patients.
Ominous Octet
Ralph DeFronzo, MD, Banting Lecture 2008
Glucose Monitoring
Fingerstick checks
Medicare coverage
1 time daily
3 times daily with insulin
More often if PA
Times to check
Fasting vs post meals
Random
CGM (Dexcom/Libre) approved to use for dosing
Glucose Monitoring
Glucose Monitoring
BG Meter Readings
9PM 6PM3PM12PM9AM6AM3AM
Time of Day
Glu
co
se
( m
g/d
L)
CGM Reveals Insights Beyond BGs and A1C
Midnight Midnight
100
40
200
300
400
Target Glucose Range
A1C: 7.5
Meter Avg: 100 SD: 40
SG Avg: 154 SD: 102 Continuous Glucose Sensor Reading
Glucose Monitoring 8.9%
Glucose Monitoring
Glucose Monitoring
• Continuous glucose monitoring (CGM)
– Personal CGM
• Continuous glucose monitoring – Diagnostic
– At least 3 days of data, review and written report
– Blinded or open view
– Reimbursable by CMS and Commercial Insurance
Anti-Hyperglycemic Agents
Class % A1c Hypoglycemia Weight Cost
Sulfonylureas 1.5 Yes Gain $
“Glitinides” 1 to 1.5 Yes Gain $$
TZD’s 0.5 to 1.4 No Gain $$
Amylin-mimetics 0.5 to 1.0 No Loss $$$
Incretin – GLP1 0.5 to 1.0 No Loss $$$
Biguanides 1.5 No Neutral $
Alpha-gluc inhib 0.5 to 0.8 No Neutral $
DPP-IV Inhibitors 0.6 to 0.8 No Neutral $$$
SGLT 2 0.7 to 0.9 No Loss $$$
AACE Recommendations
AACE Guidelines 2018
AACE Guidelines
AACE Guidelines 2018
ADA Clinical GuidelinesAntihyperglycemia therapy recommendations
American Diabetes Association Dia Care 2017;40:S64-S74
American Diabetes Association Standards of Medical Care in Diabetes.
Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74
Considerations for Therapy
PROVIDERAge, Co-morbid conditionsChronicity of diseaseAppropriate goal settingEfficacy of the treatmentSafety and TolerabilityMetformin first line Complementary actionsGlucose monitoringComplexity of planEducation and Life styleTime commitment
PATIENT
What are personal goals
Health Beliefs/Quality of
Life
Routine of Daily Living
Support System
Knowledge and Resources
Side Effects
Willingness to check BS
Fear of Failure
Fear of Insulin
Hypoglycemia
Cost/insurance coverage
Newer AHAs Can Be Used in Combination With Many
Agents at Different Stages of T2DM Progression1-5
Combination OptionsNewer AHAs
DPP-4 Inhibitors GLP-1 RAs SGLT2 Inhibitors
Metformin
Sulfonylureas
Thiazolidinediones
α-Glucosidase inhibitors
Insulin
DPP-4 inhibitors — Should not be used
GLP-1 RAs Should not be used — a
SGLT2 inhibitors —
• May use newer AHAs as monotherapy if metformin is contraindicated/not tolerated
• May add most newer AHAs to insulin to improve prandial control or may add insulin to
regimens with newer AHAsb
a Inzucchi—no data available for
recommendation.b See prescribing information for indicated use
of individual GLP-1 RAs with insulin.1
1. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA;
2. Garber AJ, et al. Endocr Pract. 2015;21:438-447; 3. Inzucchi SE, et al. Diabetes
Care. 2015;38:140-149; 4. ADA. Diabetes Care. 2015;38
(suppl 1):S1-S93; 5. Handelsman Y, et al. Endocr Pract. 2015;21(suppl 1):1-87.
• Overall hypoglycemia risk is greater when combined with SU or insulin—
consider decreasing SU/insulin dose to reduce hypoglycemia risk3
• Incidence of severe hypoglycemia is low (≤ 1% with no SU or insulin; ≤ 5%
with SU or insulin)3
Newer AHAs Are Good Options for
Minimizing Risk of Hypoglycemia1,2
Range of Overall Hypoglycemia Incidence in Clinical Trials, % of participants3
Class With Non-SU
OADs
With SU
± Any Other OADs
With Basal Insulin
± OADs
DPP-4 inhibitors 0-8 7-23 15-31
GLP-1 RAs 1-11 8-40 9-25a
SGLT2 inhibitors 1-6 6-43 20-49
a EXN QW and DULA have not been assessed in combination
with basal insulin; hypoglycemia incidence with DULA in
combination with prandial insulin was 80%-85%.
1. Garber AJ, et al. Endocr Pract. 2015;21:438-447. 2. Inzucchi SE, et al. Diabetes Care. 2015;38:140-149.
3. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.
Newer AHAs Decrease Postprandial Glucose Levels
When Added to Basal Insulin
1. Wilding JPH, et al. Diabetes Care. 32;2009:1656-1662.
2. Arnolds S, et al. Diabetes Care. 2010;33:1509-1515.
19
-34-42-50.0
-25.0
0.0
25.0
ΔP
PG
, m
g/d
L
Improved PPG With an SGLT2 Inhibitor
Added to Basal Insulin1
Placebo
DAPA 5 mg
DAPA 10 mg
Improved PPG With a DPP-4 Inhibitor
or GLP-1 RA Added to Basal Insulin2
250
200
150
100
50
0 -60
-30
15
30
45
120
150
180
210
300
-15
60
90
240
270
360
Mean
Blo
od
Glu
co
se,
mg
/dL
Nominal Time From Meal, min
GLAR + MET + EXN BID
GLAR + MET
GLAR + MET + SITA
SGLT2 Inhibitors Improve Glycemic Control
at All Stages of T2DM Progression
SGLT2 Inhibitors Lead to More Urinary Glucose
Excretion at Lower Blood Glucose Levels
• SGLT2 reabsorbs glucose from
glomerular filtrate in the renal
tubule1
• Reabsorbed glucose is returned to
circulation1
• As BG increases, SGLT2 is “filled”,
and glucose spills into urine1,2
– Healthy individuals: ≈ 170 mg/dL
– Individuals with T2DM: ≈ 200 mg/dL
1. Chao E, Henry R. Nature Rev Drug Discov. 2010;9:551-559.
2. DeFronzo RA, et al. Diabetes Care. 2013;36:3169-3176.
SGLT2 inhibitors effectively “saturate”
SGLT2 at lower BG levels1
So glucose is spilled into urine at
lower BG levels (lower threshold)
and is not returned to circulation1
Bowman’s
capsule
Return
to
circulation
Urinary excretion
Glucose
SGLT2Proximal
renal
tubule
SGLT2 Inhibitors Improve Glycemic Control
at All Stages of T2DM Progression
-1.0-0.9
-1.1
-0.7
-0.9-0.8
-0.9 -0.9-0.8 -0.8 -0.8
-0.7
-2.0
-1.5
-1.0
-0.5
0.0
0.5Monotherapy
Added toMET
Added to 2AHAs
Added toInsulin
Mean
Δ A
1C
Fro
m B
L, %
US FDA. Drugs@FDA.
http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA
P < .001 vs PBO for all
Duration, wk:
BL A1C, %:
26
8.0
CANA (300 mg) DAPA (10 mg) EMPA (25 mg)
24
8.0
24
7.9
26
8.0
24
7.9
24
7.9
26
8.1
24
8.1
24
8.1
18
8.3
24
8.6
18
8.3
SGLT2 Inhibitor Added to Incretin Therapy—
Post Hoc Analysis of CANVAS Data at Week 18a
a Baseline A1C, 8.1% for both groups; baseline BMI, 37.4 kg/m2 for GLP-1 RA group and 32.3 kg/m2 for DPP-4 inhibitor group.
-1.0
-0.6
-1.1
-0.8
-1.5
-1.0
-0.5
0.0
0.5
Δ A
1C
, %
(Pla
ceb
o s
ub
tracte
d)
Fulcher G, et al. Diabetes Obes Metab. 2015 Oct 9. [Epub ahead of print].
-2.5-2.3
-3.2-3.0
-4
-3
-2
-1
0
1
Δ B
W, %
(Pla
ceb
o s
ub
tracte
d)
CANA 100 mg + GLP-1 RA (n = 35)
CANA 300 mg + GLP-1 RA (n = 30)
CANA 100 mg + DPP-4 inhibitor (n = 103)
CANA 300 mg + DPP-4 inhibitor (n = 111)
With
GLP-1 RA
With
DPP-4 inhibitor
With
GLP-1 RA
With
DPP-4 inhibitor
Among patients not taking insulin or an insulin secretagogue, 1 patient in each of
incretin therapy + CANA 300 mg groups reported hypoglycemia (no severe events).
SGLT2 Inhibitors: Considerations for
Individualized AHA Selection
Therapeutic
Consideration1-2
Characteristics Relative to
Therapeutic Consideration1-3
A1C change ‒0.5% to ‒1.0%
Weight change ‒1.5 to ‒2.0 kg (‒3.0 to ‒4.0 lb)
Risk of hypoglycemia Low (increased with SU or insulin)
Adverse events Genital mycotic infections, urinary tract infections
Administration Oral, once daily
Glucose monitoring Not needed unless used with SU or insulin
Accessibility Consider patient resources
1. Mayo Clinic. Diabetes medication choice. Take-home brochure for patients.
http://shareddecisions.mayoclinic.org/files/2011/08/Diabetes-brochure.pdf; 2. Shillington AC, et al. Patient Prefer
Adherence. 2015;9:609-617; 3. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA;
4. US FDA. Drug safety communication. http://www.fda.gov/downloads/drugs/drugsafety/ucm446954.pdf.
Key patient education points3,4: Possible mycotic and urinary tract infections;
potential risk of hypotension—need for adequate fluid; potential risk of allergic
reaction; increased risk of hypoglycemia with SU or insulin; signs and
symptoms of acidosis, bladder cancer (DAPA); potential fracture risk and
hyperkalemia (CANA)
SGLT2 Inhibitor Safety in the Context of
Patient Characteristics/Traitsa
Clinical Concerns Safety Considerations or Actions
Pregnancy/ nursing • Pregnancy Category C
• Discontinue drug or nursing
Older patients • No dose adjustment based on age
• Consider renal function, reduced vascular volume, hypotension
High or low systolic BP • Hypotension in patients with low SBP or being treated with diuretic,
ACE inhibitor, or ARB
Renal insufficiency • Contraindicated in severe renal impairment, ESRD, or dialysis
• See recommended dose adjustments
• Hypotension risk
Hepatic insufficiency • CANA and DAPA: mild to moderate—no dose adjustment; severe—
CANA not recommended, assess individual risk with DAPA
• EMPA may be used
Genital mycotic/urinary
tract infections
• Treat as usual
• GMI—most had 1 event; more common in people with a history
All patients—monitor
for potential risks
• Impaired renal function, hyperkalemia, hypersensitivity, fracture
(CANA), bladder cancer (DAPA), increased LDL-C (treat as usual)
a No SGLT2 inhibitors are indicated for pediatric patients (< 18
years), and for patients who have had a hypersensitivity reaction
to an agent, the agent is contraindicated.
US FDA. Drugs@FDA.
http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.
SGLT2 Inhibitors – Approved Monotherapy or Combination
Drug Starting Dose Max dose GFR
Canaglifozin 100 mg 300 mg GFR >60
d/c if GFR consistently < 45
UGE* 100 grams
Dapagliflozin 5 mg 10 mg GFR > 60
d/c if GFR consistently between
30 and 60
UGE* 70 grams
Empaglifozin 10 mg 25 mg GFR > 45
d/c if GFR consistently < 45
UGE 70 grams
Ertuglifozin 5 mg 1.5 mg GFR > 60
d/c if GFR consistently between
30 and 60
UGE* 70 grams
*UGE – Urinary glucose excretion rate
SGLT2 Inhibitors - Adverse Reactions & Precautions
Common Adverse reactionsGenital Mycotic Infections
UTI
Dry mouth
Dehydration
Increased Urination
Constipation
Headache
Warnings and precautionsNot recommended in renal failure or dialysis
Not recommended in Type 1 diabetes
DKA
Can cause hyperkalemia
Monitor renal function (remember GFR drop during first 12 weeks, comes back
to baseline.
Consider risk for amputation
Patient Education
• Meta-analysis demonstrated no increased CV event risk in clinical trials3
• Reported effects on CVD risk factors4,b
– Decreased body weight (≈ 3%-4%)
– Decreased systolic blood pressure (≈ 4-7 mm Hg)
– Modest increases in LDL-C—successfully treated using standard of care
Cardiovascular Risk and Potential for
Cardiovascular Benefit With SGLT2 Inhibitors
Agent—TrialLong-Term CV Safety Trials in Populations at
Increased CV Risk
Empagliflozin—EMPA-REG
OUTCOME1
Significant effects for EMPA vs placebo1
• Lower primary composite outcome rate (P = .04)a
• 38% reduction in risk of death from CV causes
• 35% reduction in risk of hospitalization for heart failure
• 32% reduction in risk of death from any cause
Canagliflozin—CANVAS2 • 14% CV risk reduction, 40% decrease in renal decline
• Increase risk of amputation
Dapagliflozin2 • Anticipated completion 20192
a Primary composite outcome—death from CV
causes, nonfatal MI, nonfatal stroke.a None of the agents listed are approved for weight
reduction or treatment of hypertension.4
1. Zinman B, et al; EMPA-REG OUTCOME Investigators. N Engl J Med. 2015
Sep 17. [Epub ahead of print]; 2. ClinicalTrials.gov. http://www.clinicaltrials.gov;
3. Vasilakou D, et al. Ann Intern Med. 2013;159:262-274; 4. US FDA. Drugs@FDA.
http://www.accessdata.fda.gov/ Scripts/cder/DrugsatFDA.
Recent Safety Information for SGLT2 Inhibitors
Ketoacidosis
• Predictable, detectable, and
preventable/mitigable safety concern1
• Reports in T1DM and T2DM2-4
– FAERS: 20 cases 2013-2014, most
with T2DM2
– CANA trials: 6 of 12 cases with
autoimmune diabetes3
– Incidental reports: 7 with T1DM,
2 with T2DM4
• SGLT2 inhibitors are not approved for
use in patients with T1DM5
• Inform patients/caregivers of
symptoms (eg, nausea/vomiting,
anorexia, greater thirst, confusion)1
• Evaluate if symptoms—discontinue
SGLT2 inhibitor if confirmed1
Effects on Bone5
• Label update for CANA—ongoing
evaluation of other agents in class
• Potential risk of bone fracture based
on pooled data (9 trials)
– 1.1, 1.4, and 1.5 events per 100 P-Y for
placebo, 100 mg, and 300 mg
– As early as 12 weeks
– Decreased bone mineral density
reported in a clinical trial (0.3%-1.2%
in total hip and lumbar spine)a
• Consider factors that may increase
fracture risk before starting CANA—
inform patients of these factors
a Double-blind, placebo-controlled trial (N = 714; age
55- 80 y) to fulfill postmarketing requirement.
1. Rosenstock R, Ferrannini E. Diabetes Care. 2015;38:1638-1642.
2. US FDA. Drug safety communication.
http://www.fda.gov/downloads/drugs/drugsafety/ucm446954.pdf.
3. Erondu N, et al. Diabetes Care. 2015;38(9):1680-1686.
4. Peters A, et al. Diabetes Care. 2015;38(9):1687-1693.
5. US FDA. FDA drug safety communication.
http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm.
Nauck MA, et al., J Clin Endocrinol Metab. 1986;63:492-498.
Pratley RE et al. Rev Diabet Stud. 2008;5:73-94.
Glu
cose, m
g/d
L
Insulin
, pm
ol/L
Time, min
200 400
0
50
100
150
-30 0 30 60 90 120150 180210 210Time (min)
0
100
200
300
-30 0 30 60 90 120 150 180
Oral Glucose Tolerance Test and Matched IV Infusion
Measurement of the Incretin Effect
OralIntravenous
OralIntravenous
Summary of GLP-1:Effects in Humans
Flint A et al. J Clin Invest. 1998;101:515-520. Larsson H et al. Acta Physiol Scand. 1997;160:413-422. Nauck MA et al. Diabetologia. 1996;39:1546-1553. Drucker DJ. Diabetes. 1998;47:159-169.
StomachRegulates gastric
emptying
Central nervous systemPromotes satiety and
reduction of appetite
Liver
Glucagon reduces
hepatic glucose output
α cell
Glucagon secretion
post-meal
β cellEnhances secretion of
glucose-dependent insulinPotential increase in β-
cell mass
Comparing GLP-1 RAs in T2DM:
Head-to-Head Trialsa
Long Acting vs Twice Daily
-1.1b
-1.6b -1.5b
-0.8-0.9
-1.0
-2.0
-1.0
0.0
ΔA
1C
, %
Once Weekly vs Once Daily
-1.3
-0.8
-1.4-1.5b
-1.0
-1.4
-2.0
-1.0
0.0
ΔA
1C
, %
a Mean T2DM duration 7-9 y; background
therapy ≥ 2 oral AHAs for most patients
(except DURATION-5 and AWARD-6).b P < .05 between groups.
1. Buse JB, et al. Lancet. 2009;374:39-47; 2. Blevins T, et al. J Clin Endocrinol
Metab. 2011;96:1301-1310; 3. Wysham C, et al. Diabetes Care. 2014;37:2159-2167;
4. Buse JB, et al. Lancet. 2013;381:117-124; 5. Pratley RE, et al. Lancet Diabetes
Endocrinol. 2014;2:289-297; 6. Dungan KM, et al. Lancet. 2014;384:1349-1357.
LEAD-61 DURATION-52 AWARD-13
EXN BID 10 µg LIRA 1.8 mg EXN QW 2.0 mg ALBI 50 mgDULA 1.5 mg
DURATION-64HARMONY-75 AWARD-66
Non-
inferiority
not met Non-
inferior
Nausea
incidence, %
EXN QW2,4 ALBI5 LIRA1,4-6 DULA3,6 EXN BID1,2,3
9-14 10 18-29 20-28 26-35
GLP-1 RAs May Be Alternatives to Prandial Insulin
for Basal Insulin Intensification: Head-to-Head Trials
a 30 weeks; BL A1C, 8.2%-8.3%.b 26 weeks; BL A1C, 7.7%.c 26 weeks; BL A1C, 8.4%-8.5%.
1. Diamant M, et al. Diabetes Care. 2014;37:2763-2773.
2. Mathieu C, et al. Diabetes Obes Metab. 2014;16:636-644.
3. Rosenstock J, et al. Diabetes Care. 2014;37:2317-2325.
−1.1−0.7 −0.8
−1.1
−0.4−0.7
-2
-1
0
1
ΔA
1C
Fro
m
Ra
nd
om
iza
tio
n,
%
• Other outcomes for GLP-1 RAs vs prandial insulin
– Lower rate of hypoglycemia
– Higher rate of GI adverse effects (eg, nausea)
– Weight loss vs weight gain
Added to GLAR1,a
NoninferiorP = .0024
ASP QDLIS TIDLIRA QD ALBI QWEXN BID
Added to IDEG2,b Added to GLAR3,c
Noninferior
GLP-1 RAs: Considerations for
Individualized AHA Selection
Therapeutic
Consideration1-3
Characteristics Relative to
Therapeutic Consideration1-3
A1C change ‒0.5% to ‒1.6%
Weight change ‒1.5 to ‒6.0 kg (‒3.0 to ‒13.2 lb)
Risk of hypoglycemia Low (increased with SU or insulin)
Adverse events Gastrointestinal,a headache (EXN BID, EXN QW,
LIRA, DULAG, SEM), injection site reaction (EXN QW)
Administration Injected—twice daily, once daily, once weeklya
Glucose monitoring Not needed unless used with SUs or insulin
Accessibility Consider patient resources
a Varies with agent.
1. Mayo Clinic. Diabetes medication choice. Take-home brochure for patients.
http://shareddecisions.mayoclinic.org/files/2011/08/Diabetes-brochure.pdf.
2. Shillington AC, et al. Patient Prefer Adherence. 2015;9:609-617.
3. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.
Key patient education points3: possible GI AEs; injection technique; potential
risk of pancreatitis, thyroid tumors
US FDA–Approved GLP-RAs
Agent1 Administration (subcutaneous injection)1 Needle1,2
Exenatide BIDTwice daily, within 1 hour prior to 2 main
meals but ≥ 6 hours apart
Advise patient
regarding sizea
Liraglutide Once daily, any time of dayAdvise patient
regarding sizea
Exenatide QW Once weekly, any time of day Supplied (23 G)
Dulaglutide Once weekly, any time of day Supplied (29 G)
Lixisenatide Once daily, 1 hour prior to first mealAdvise patient
regarding sizea
1. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.
2. Lilly USA, LLC. https://www.trulicity.com/healthcare-professionals-glp-1-ra-therapy-and-administration.aspx.
Semaglutide Once weekly, any time of day Supplied (32 G)
GLP-1 RAs: Dosing
Lixisenitide
10 mg once
daily for 14 day20 mg once
daily
20 mg
once daily
Renal & hepatic impairment: use
caution – limited experience
Drug Initial Titrate Max Dose Adjustments
Exenatide IR
5 mcg BID
within 60 mins
of a meal
(> 6H between
doses)
↑ to 10 mcg
after 1
month
10 mcgRenal impairment: CrCl 30-50
mL/min: use caution; CrCl < 30
mL/min not recommended
Hepatic impairment: not studied
Exenatide ER 2 mg once
weeklyN/A
2 mg once
weekly
Liraglutide
0.6 mg once
daily
1.2 mg once
daily per
week
1.8 mg
once daily
Renal & hepatic impairment: use
caution – limited experience
Dulaglutide
0.75 mg once
weekly
↑ to 1.5 mg
once weekly
if inadequate
response
1.5 mg
once
weekly
Renal impairment: use caution
when initiating or escalating doses
Hepatic impairment: use with
caution
Semaglutide0.25 mgs once
weekly
↑ to 0.50 mg
weekly
1.0 mg
weekly
Monitor renal and hepatic function,
observe changes in retinopathy
Dosing of GLP-RAs
GLP-1 RA Safety in the Context of
Patient Characteristics and Traitsa
Clinical Concerns Safety Consideration or Actions
Pregnancy/nursing • Pregnancy Category C (EXN BID and EXN QW registries)
• Discontinue drug or nursing
Older patients (≥ 65 years) • No safety or effectiveness differences vs younger patients
• Consider renal function
Endocrine tumors • Contraindicated if personal/family history of MTC or personal
history of MEN2
• Boxed warning of potential risk of C-cell tumors
• Except EXN BID & LIXI – short acting GLP1
Renal insufficiency • See recommended dose adjustments
• Possible risk of impairment related to hypovolemia
Liver disease • LIRA and DULA: limited clinical experience—use caution
• EXN BID, EXN QW, ALBI: not expected to affect clearance
Severe GI disease • Slowed gastric emptying—may also affect drug absorption
• Contraindicated in pancreatitis
All patients—monitor for
potential risks
• Acute pancreatitis, renal impairment related to hypovolemia,
hypersensitivity
a No GLP-1 RAs are indicated for pediatric patients (< 18 years),
and for patients who have had a hypersensitivity reaction to an
agent, the agent is contraindicated.
US FDA. Drugs@FDA.
http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.
Some Limitations for Use of GLP-1 RAs in Patients
With Renal Impairment
a CrCl < 30 mL/min.b CrCl 30-50 mL/min.
US FDA. Drugs@FDA.
http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.
GLP-1 RARecommendations for Use in
Patients With Renal Impairment
EXN BID or
EXN QW
• Should not be used in severe renal impairmenta or ESRD
• Use with caution in moderate renal impairmentb or transplant
LIRA • No recommended dose adjustment
• Use with caution in renal impairment
DULA
SEMA
• No recommended dose adjustment
• Use with caution in renal impairment—monitor renal function
and severe GI adverse effects
• No direct nephrotoxicity has been demonstrated with GLP-1 RAs
• Cases of altered renal function have been reported—most were in
conjunction with nausea, vomiting, or hypovolemia
• Meta-analysis of short-term GLP-1 RA trialsa demonstrated NO increased risk
of MACE, acute MI, stroke, all-cause mortality, or CV death vs comparators3
• Additional reported effects on CVD risk factors and CV function
– Decreased systolic blood pressure (≈ 2-5 mm Hg)4-6
– Increased mean heart rate (≈ 1-4 bpm), except EXN BID—long-term clinical
effects of heart rate increase have not been established7,8
What about Cardiovascular Risk
With GLP-1 RAs in Patients With T2DM
Agent—Trial Long-Term CV Safety Trials in
Populations at Increased CV Risk
Lixisenatide—ELIXA1,2 Noninferior to PBO for CV safety2
Liraglutide—LEADER1 CV risk reduction compared to PBO1
Exenatide QW—EXSCEL1 Noninferior to PBO for CV safety
Dulaglutide—REWIND1 Anticipated completion April 20191
a ALBI, EXN BID,
EXN QW, LIRA, and
TASPO; most trials 24-
52 wk.
1. ClinicalTrials.gov. http://www.clinicaltrials.gov; 2. Sanofi. http://www.news.sanofi.us/2015-06-08-
Sanofis-Lyxumia-lixisenatide-Demonstrated-Cardiovascular-Safety-in-People-with-Type-2-Diabetes-and-
High-CV-Risk; 3. Monami M, et al. Diabetes Obes Metab. 2014;16:38-47; 4. Moretto T, et al. Clin Ther.
2008;30:1448-1460; 5. Garber A, et al. Lancet. 2009;373:473-481;
6. Sun F, et al. Diabetes Res Clin Pract. 2015;110:26-37; 7. US FDA. Drugs@FDA.
http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA; 8. Gill A, et al. Cardiovasc Diabetol. 2010;9:6.
Hypoglycemia
Hypoglycemia Defined
Level Glycemic Criteria Description
Glucose alert value
level 1
≤70 mg/dl Sufficiently low for Rx with
fast acting CHO and
insulin adjustment
Clinically significant
hypoglycemia
Level 2
<54 mg/dl Sufficiently low to indicate
serious, clinically
important hypoglycemia
Severe hypoglycemia
Level 3
No specific glucose
threshold
Hypoglycemia associated
with sever cognitive
impairment.
Requires external
assistance for recovery
American Diabetes Association Clinical Recommendations 2018
Treatment of Hypoglycemia
15 Grams CHO
4 oz juice or soda
Glucose tabs
Gum drops
NO CHOCOLATE
Recheck BS in 15”
If BS less than 50, may
need 30 gms
Glucagon for severe
hypoglycemiaBlood Sugar less than 70
What’s New With Insulin
Classification of Insulins
BASAL or BACKGROUND
Intermediate-acting
i
NPH
1st Generation analogs Detemir, Glargine
Concentrated long acting Glargine U300
Degladec U100 and U200
Other Basal U500 Regular
Classification of Insulins
BOLUS or MEAL TIME
Short acting
i
Regular U100
Rapid Acting
Fast Acting
Aspart
Lispro U100 and U200)
Glulisine
Aspart with Vit B3 and Amino
Acid
Classification of Insulin Types
Mixed Insulins/ Biphasic
NPH/Regular Humulin® 70/30, 50/50,
Novolin® 70/30
Aspart protamine suspension/
aspart
NovoLog® Mix 70/30
Lispro protamine suspension
/ lispro
Humalog®
Mix 75/25, 50/50
Time Action of Insulins
Insulin Onset Peak Duration
Aspart (AA VB3)
Aspart LisproGlulisine
2.5 minutes
10–20 minutes
1.5 hours
1–2 hours
3-5 hours
3–5 hours
Regular
Inhaled
30 to 60 minutes
10 to 12 minutes
2-4 hours
1-3 hours
6–10 hours
3 – 4 hours
Lispro U 200 10 -20 minutes 1-2 hours 3 -5 hours
NPH 1–2 hours 4–8 hours 10–20 hours
Detemir Glargine
1–2 hours Almost Flat up to 24 hours
Glargine U300 1-2 hr, 3-5 days SS Flat Up to 36 hours
Deglutec 30 to 90 minutes
3-5 days SS
Flat Up to 42 hours
1. Palumbo PJ. Cleveland Clin J Med. 2004;71:385-403; 2. Physicians’ Desk Reference® 2006. Montvale, NJ: Thomas PDR; 2006; 3. Weyer C, et al.
Diabetes Care. 1997;20:1612-14. PI Lilly, PI Novo, PI Sanofi 2018
Time Action of Insulins
American Diabetes Association Clin Diabetes 2018;36:14-37
©2018 by American Diabetes Association
Insulin Therapy for Type 2 Diabetes(ADA)
AACE Guidelines 2018
Before You Start Insulin
Does the patient check blood glucose levels? Min 3-5 consecutive days of readings necessary for medication
decision making
Does the patient understand and is adherent to
current therapy?
Are BG readings reviewed with patient?
Who will teach the patient to administer and
manage insulin?
Is there a follow-up plan? Re-evaluate treatment response
Patient ability
Nursing availability or diabetes educator
Ensure proper technique
Glargine U300
FDA approved February 25, 2015
• Three times as concentrated as glargine U100
• Longer duration of action (up to 36 hrs ) than glargine U100; half-life about 19 hours
• Less variable plasma insulin exposure as U100
• Similar safety and efficacy profile as U100
• 450 units in each pre-filled syringe
• Stable for 42 days at room temperature
Toujeo® (package insert) Bridgewater, NJ Sanofi-Aventis US LLC: 2015
Studies: Glargine U300Edition Studies- Non-Inferiority
Type 2 DM
26 week open-label randomized controlled study
Intervention
U300 once daily + bolus insulin +/- metformin (n=404)
U100 once daily + bolus insulin +/- metformin (n=400)
Results
U300 arm average A1c reduction of 0.9%
U100 arm average A1c reduction 0.87%
U300 arm utilized 11% more basal insulin
No differences in body weight
Toujeo® (package insert).Sanofi-Aventis U.S. LLC; 2015.Ritzel RA et al. European Association for the Study of Diabetes congress, 2014, abstract 963.
Glargine U300 Dosing
Insulin Naïve Patients
Starting Dose of U300 Frequency
Type 1 DM 0.2-0.4 units/kg/day ½ to 1/3 TTD
Once Daily
Type 2 DM 0.2 units/kg/day Once Daily
Insulin Experienced Patients - Conversions
Insulin Conversion Frequency
Once daily long acting (U-100) to U300
1:1** Once Daily
Twice daily NPH to U300 Decrease total daily dose of NPH by
20%
Once Daily
Toujeo® (package insert).Sanofi-Aventis U.S. LLC; 2015.
Glargine U200
Toujeo® (package insert).Sanofi-Aventis U.S. LLC; 2015.
Degladec U100 and U200
FDA approved September 25, 2015
Formation of multi-hexamers
Prolonged action profile, duration longer than 42 hours
Half-life of about 25 hours
Flat PD/PD profile of both U100 and U200 formulations
U 200 delivers in 2 units increments up to160 units total dose.
(600 units/pen)
U 100 delivers in 1 unit increments up to 80 units
(300 units /pen)
Insulin degludec met it’s primary endpoint of lowering A1c
26 week trial with insulin naïve Type 2 patients
-1.18% reduction with degludec U200 A1c 7%
-1.22% reduction with glargine U100 A1c 6.9%
Insulin degludec lasts 42 hours and possibly longer in some patients.
Insulin degludec showed greater reductions in hypoglycemic events when
compared to insulin glargine.
“A Trial Comparing the Safety and Efficacy of Insulin Degludec and Insulin Glargine, With or Without OADs in Subjects With Type 2 Diabetes
(SWITCH 2).” ClinicalTrials.gov. Novo Nordisk A/S, Dec. 2015. Web. 2 Feb. 2016.
(BEGIN®: Low Volume) Gough SCL, Bhargava A, Jain R, Mersebach H, Rasmussen S, Bergenstal RM. Diabetes Care. 2013;36(9):2536-2542.
Degladec Trials
Degladec Tresiba® Switch from other basal insulin unit for unit
Insulin naïve type 2 patients, begin with 10 units
Insulin naïve type 1 patients begin with ⅓ to ½ TDD
Titrate dose every 3 – 4 days
May have increase in BG levels initially
Once opened it lasts for 8 weeks at room temperature
A missed a dose of degludec can be given during waking hours upon
discovering the missed dose. Ensure that at least 8 hours have elapsed
between degludec injections.
Starting Degladec U100 and U200
Tresiba Package Insert NovoNordisk 2015-2016
Degladec
Tresiba Package Insert NovoNordisk 2015-2016
U500 Concentrated Insulin
5 times more concentrated
Used for those taking more than 200–300 units TDD
Use syringe with conversion dose
High Risk for Error
Need for education and re-enforcement
Now in pen device
Emerging Basal Insulin-GLP-1 RA
Fixed-Ratio Co-formulations
-1.9 -1.8-1.4 -1.6
-1.3-2
-1
0
Δ A
1C
, %
-0.5 -1.0
1.6c
0.5d
-3.0c-5
0
5
Δ B
W, kg
a 26-wk open-label, treat-to-target, RCT; N = 1663 (insulin
naive); BL A1C, 8.3%; BL wt, 87.2 to 87.4 kg; b 24-wk open-
label, treat-to-target, RCT; N = 323 (insulin naive); BL A1C,
8.01% to 8.06%; BL wt, 90.26 to 91.70 kg; c P < .001 vs IDEG-
LIRA; d P < .001 vs GLAR-LIXI.
1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2:885-893.
2. Rosenstock J, et al. Diabetologia. 2014;57(suppl 1) [abstract 241].
LIRA1,aIDEG-LIRA1,a GLAR2,bIDEG1,a GLAR-LIXI2,b
• ≤ 3 severe hypoglycemic episodes per group
• Lower rate of hypoglycemia with LIRA vs IDEG or IDEG-LIRA (overall and nocturnal)1
• Lower rate of hypoglycemia with GLAR-LIXI than with GLAR (overall)2,d
Noninferior to IDEG
Superior to LIRA
Superior
to GLAR
A1C < 7%, % 81 60c 65c 84 78
Degladec/liraglitude Combination
combination of insulin degludec and liraglutide
indicated as an adjunct to diet and exercise in adults
with type 2 diabetes mellitus inadequately controlled
on basal insulin (less than 50 units daily) or liraglutide
(less than or equal to 1.8 mg daily)
Average A1c of 7% achieved in trial
Lowers both FPG and PPG
Less units of insulin needed
Low rates of hypoglycemia
Degladec/liraglitude
Dosing
Recommended dosage is 16 to 50 units
daily
Titrate every 3 to 4 days
Prescribing information: Package Insert Novo Nordisk 2017
U100 glargine/lixisenatide Combination
combination of insulin U100 glargine and lixisenatide
indicated as an adjunct to diet and exercise in adults
with type 2 diabetes mellitus inadequately controlled
on basal insulin (less than 60 units daily) or
lixisenatide
Average A1c of 6.9% achieved in trial as compared
to glargine alone – 7.5%
Lowers both FPG and PPG
Less units of insulin needed
Low rates of hypoglycemia
U100 glargine/lixisenatide
Prescribing information: Package Insert Sanofi 2017
U100 glargine/lixisenatide
Prescribing information: Package Insert Sanofi 2017
Starting dose of glargine/lixi is 15 units daily for previous
insulin dose of 30 units or less
Starting dose of glargine/lixi is 30 units daily for previous
insulin dose of 31 units or more
Titrate: every week
New Technologies
8
2
Goal of Every Insulin Regimen: Mimic Insulin Delivery of Healthy Pancreas
12am 3am 7am 12pm 6pm 9pm
Time of Day
LunchBreakfast Dinner Snack
Insulin
Secre
tion
Multiple Daily Injections
(Rapid-Acting and Long-Acting Insulins)
Long-Acting
InsulinRapid-Acting Insulin
Example of a Basal Profile
Basal rates can be
decreased
Basal rates can be
programmed to increase
for dawn phenomenon
Higher rate can be
programmed if
needed after dinner
Pumps can be programmed to deliver basal insulin at different rates
throughout the day according to each patient’s unique requirements
12am
Insu
lin
In
fus
ion
Rate
2am 4am 6am 8am 10am 12pm 2pm 4pm 6pm 8pm 10pm 12am
Time of Day
Basal infusion
Lenhard MJ, Reeves GD. Continuous subcutaneous insulin infusion. Arch Intern Med. 2001;161:2293-2300. Reused with permission.
Pumps are Designed for Multiple Basal Rates
Insulin Pumps Offer More Information
Putting it all Together – Case Study
Glucose Monitoring A1c 8.7%
Glucose Monitoring A1c 8.7%
Insulin to Carb Ratio
Correction
Wrap Up
Gylcemic Targets and BS Lowering Therapies:
Individualized to patient – Risk vs benefit, CVD DataDecisions made in partnership with the patientUse of current ADA and AACE guidelines
Cornerstone of treatment
Meal planning, exercise and educationMetformin is optimal 1st line agentCombination therapy – dual or triple, quadruple
Technology
Use newer meters that can be downloadedContinuous glucose monitoring Insulin pump therapy may be beneficial for type 2 diabetes
Overall Goal
Improve well-being, reduce symptoms/ prevent complications
Ultimately most patients will require combination therapy withtwo, three or more agents.
Questions?
Answers
THANK
YOU
