Exploring Non-Insulin Therapies
in Type 1 Diabetes
Susan Cornell, BS, PharmD, CDE, FAPhA, FAADE
Associate Professor
Midwestern University - Chicago College of Pharmacy
Disclosures
Dr. Cornell:
Advanced Practitioner Advisory Board and Speakers Bureau: Novo Nordisk
Objectives
1. Explain the need for pharmacotherapy beyond insulin in type 1 diabetes
2. Describe how the mechanisms of action of newer non-insulin glucose-lowering agents differ from traditional insulin-based therapies.
3. Summarize the risks and benefits associated with newer non-insulin glucose-lowering agents in type 1 diabetes.
Pre-Assessment Question #1
Which of the following statements is true regarding type 1 diabetes?
A. T1D develops during childhood, adolescence or young adulthood.
B. Middle age and older adults can develop T1D
C. Insulin resistance is unusual in people with T1D.
D. Adding more insulin will “fix” insulin resistance
Pre-Assessment Question #2
Which of the following pharmacotherapy agents is indicted as adjunct to insulin in T1D?
A. Linagliptin
B. Metformin
C. Semaglutide
D. Sotogliflozin
Pre-Assessment Question #3
• Which is the transporter responsible for glucose and galactose absorption in the GI tract?
A. DPP-4
B. GLP-1
C. GLP-2
D. SGLT-1
E. SGLT-2
Type 1: Pathophysiology
• Type 1 results from an autoimmune disorder that destroys the pancreatic beta cells – Acute onset (???)
• Possible pre-diabetes in type 1 based on seroconversion
• 3 stages:– Genetic susceptibility
• Predisposition to the disease from a human leukocyte antigen- (HLA) related immunogenotype
– Autoimmunity
• Enterovirus (??)– Clinical diabetes
Standards of Medical Care in Diabetes-2018. Diabetes Care.
Type 1: Etiology
• Genetic
• Environmental– < 50% concordance in identical twins
– Pancreatic toxins
– Viruses
– Internal (Interleukin I; Tumor necrosis factors; Free radicals)
• Autoimmune – Begins years prior to symptoms
– Islet cell auto-antibodies (ICA’s)
– Insulin auto-antibodies (IAA’s)
– Auto-antibodies - Islet cell proteins
– Glutamic acid decarboxylase (GAD)
Natural history of Beta cell Defect in T1DM
Be
ta C
ell
Ma
ss %
Time ( yr )0
0
50
100
NormalInsulin
Impaired Insulin
Overt Diabetes
“Honeymoon”
20 %
Immunologic Abnormalities
ADA. Medical Management of Type 1 Diabetes, 6th ed., 2012.
Genetic Predisposition
Type 1 Diabetes• New-onset type 1 diabetes may occur at any age
– Classic type 1 diabetes is often thought of as a disorder of
childhood or young adulthood…BUT
– About half of all type 1 diabetes is diagnosed after age 301
• Adults represent 85% of the total population with type
1 diabetes2
– Adult onset type 1 can sometimes be mistaken for type 2
diabetes
1. Thomas NJM. European Association for the Study of Diabetes (EASD) 2016 Annual Meeting. Abstract 264.
2. Monaghan M, et al. Curr Diabetes Rev. 2015;11(4):239-250..
Adult Onset Type 1 Diabetes vs.
Type 2 Diabetes
• Adult-onset type 1 diabetes….
– May not express typical signs of insulin resistance common in type 2 diabetes (ie, no dyslipidemia, HTN, hyperuricemia, central obesity, etc.)
– Can be associated with other autoimmune endocrine/metabolic disorders (ie, thyroid disease, adrenal disorders, vitiligo, celiac disease, etc.)
– Often has no strong family history of diabetes
Classification and Treatment
• Leaders in Diabetes are calling for a change in how diabetes is
classified
– Focus should be ß-cell centric
• Opposed to Type 1, Type 1.5, Type 2, monogenic, etc.
• Abnormal or genetically pre-disposed B-cells lead to:
– Insulin resistance
– Susceptibility to environmental influences
– Immune dysregulation
• Inflammation
Schwartz SS, et al. Diabetes Care 2016:39(2)
B-cell Centric Model
Age
Type 1
Type 2
Type 1.5
Not obese
Metabolic syndrome
HLADQB1
TCF7L2FTO
Auto-antibodies
Systemic inflammation
T-cells
C-peptide
Insulin treatment
Schwartz SS, et al. Diabetes Care 2016:39(2)
Choosing a Treatment Regimen for Managing Diabetes
Potential RisksHypoglycemia
Weight gainComplexity of Regimen
Other Side EffectsCost
Potential BenefitsImproved Glycemic
ControlDecreased Complications
Lack of Adverse EffectsEase of Use
Traditional Therapeutic Options for
Persons With Type 1 Diabetes
• Multiple daily injections of rapid acting insulin with
meals combined with basal insulin (basal bolus
regimens)
• Continuous subcutaneous insulin infusion via an
insulin pump
• Adjunctive therapy with pramlintide
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Insulin Therapy Not Always Sufficient to
Achieve Optimal Glucose Control
• Normal glucose regulation involves multiple hormones (eg, insulin, glucagon, amylin, incretins) and multiple organ systems (eg, pancreas, liver, stomach, brain)
• Insulin replacement therapy does not fully mimic the actions of insulin secreted by the pancreas in a healthy individual
• Insulin exposure in the liver is lower with exogenous replacement therapy compared to natural production, resulting in inadequate suppression of endogenous hepatic glucose production
• Higher doses of insulin may be required to achieve sufficient suppression of endogenous glucose production, but higher doses are associated with hypoglycemia and weight gain
Aronoff SL, et al. Diabetes Spectrum. 2004;17:183-190;
Brown L, et al. Sci Transl Med. 2010;2:27ps18; Lebovitz HE. Nat Rev Endocrinol. 2010;6:326-334.
Considerations in Drug Selection
• Patient factors to consider for T1DM
– A1c lowering needed
• Fasting, post-prandial or both
– Weight/Obesity
• Insulin resistance/metabolic syndrome
– Adding more insulin does NOT improve insulin resistance
– Cardiovascular disease
• Hypoglycemia
– Renal impairment
– Side effect profile
– Cost
• Available medication coverage
Glucose Lowering Comparison Among Select Drug Classes
Drug Class Route
Targets
insulin
resistance
Target Organs Weight Effect CVD BenefitsTarget Glucose:
FPG or PPG
A1c Reduction
%
MetforminOral Maybe Liver, possible GI tract Neutral to loss Yes or neutral FPG 1.5
DDP-4
inhibitorsOral No
α & β pancreatic cells, liver &
some GI tractNeutral Neutral PPG 0.5-0.7
SGLT-2
inhibitorsOral Maybe
Kidney,
possibly adipose fatLoss Yes or neutral Both 0.7 – 1.1
GLP-1
agonistsInjectable Yes
α & β pancreatic cells, liver, brain,
GI tract & some peripheral tissueLoss Yes or neutral
Short-acting—PPG
Long-acting—Both0.8-1.5
Note insulin resistance
Unger J, et al. Postgrad Med. 2010;122:145-57.Cornell S, et al. Postgrad Med. 2014;126(2):100-109.
Neurotransmitter
Dysfunction
Biguanides (Metformin)
DeFronzo RA. Diabetes.
2009;58(4):773-795.
19
Islet b-cell
Impaired
Insulin Secretion
Decreased Glucose
Uptake
Islet a-cell
Increased
Glucagon Secretion
IncreasedLipolysis
Increased Glucose
Reabsorption
Increased
Hepatic Glucose
Production
GI tract -microbiome
?
1) Decreases liver glucose production2) indirectly reduces insulin resistance3) Possible restoration of gut microbiome
Metformin in Type 1 Diabetes
• Metformin vs. placebo– No significant reduction in
A1C
– Significant improvement in body weight
– Significant reduction in total daily insulin dose
– CV parameters:• Increase in good cholesterol
(HDL)
• Decrease in bad cholesterol (LDL, TG)
• Adverse effects
– Caution in patients with renal
and hepatic dysfunction
• Not recommended if eGFR
30-45 mL/min/1.73 m2
• Contraindicated if eGFR
<30 mL/min/1.73 m2
– Most common side effects:
• Stomach and intestinal
distress
Harris K, et al. Targets and Therapy. 2018:11:159-173.
Neurotransmitter Dysfunction
DPP4 Inhibitors (Gliptins)
21
Islet b-cell
ImpairedInsulin Secretion
Decreased GlucoseUptake
Islet a-cell
IncreasedGlucagon Secretion
IncreasedLipolysis
Increased GlucoseReabsorption
IncreasedHepatic Glucose Production
DecreasedIncretinEffect
1) Inhibits DPP-4 enzyme in the GI tract that breaks down GLP-1 resulting in ↑ endogenous GLP-1.
2) Enhances appropriate pancreatic beta cell (insulin and amylin) secretion
3) Pancreatic alpha cell (glucagon) suppression
4) ↓ liver glucose production
DeFronzo RA. Diabetes.
2009;58(4):773-795.
DPP4 Inhibitors in Type 1 Diabetes
• Meta-analysis of DPP4
inhibitors in T1DM:
– No significant reduction in
A1c
– Small reduction in total
daily insulin dose
• Most common side
effects:
– Stuffy, runny nose
– Headache
– Upper respiratory tract
infection
Harris K, et al. Targets and Therapy. 2018:11:159-173.
DPP4 Inhibitors: Comparisonsitagliptin saxagliptin linagliptin alogliptin
Dose/frequency
100 mg once daily
5 mg once daily
5 mg once daily
25 mg once daily
Efficacy (A1C lowering):
monotherapy 0.6% 0.7% 0.4% 0.8%
Efficacy (A1C lowering):
combination therapy 0.7% 1.2% 0.7% 0.9%
Renal dosing
50 mg daily (moderate)25 mg daily
(severe)
2.5 mg daily (moderate-
severe)
No dose adjustmentnecessary
12.5 mg daily (moderate)
6.25 mg daily (severe)
Approximate ex VivoDPP-4 Inhibition, %
(maximum)97 80 80 90
Baetta R. Drugs 2011;71:1441-1467; Deacon CF. Diabetes Obes Metab. 2011;13:7-18; Januvia® (sitagliptin) prescribing information; Onglyza®
(saxagliptin) prescribing information; Tradjenta® (linagliptin) prescribing information.; Nesina™ (alogliptin) prescribing information
Neurotransmitter Dysfunction
GLP-1 Agonists
24
Islet b-cellImpaired
Insulin Secretion
Decreased GlucoseUptake
Islet a-cell
IncreasedGlucagon Secretion
IncreasedLipolysis
Increased GlucoseReabsorption
IncreasedHepatic Glucose
Production
GI Tract/Decreased
Incretin Effect
1) Enhances appropriate pancreatic beta cell (insulin and amylin) secretion
2) Pancreatic alpha cell (glucagon) suppression
3) ↓ liver glucose production 4) ↑ brain satiety5) slows gastric emptying time6) ↑ insulin uptake in
peripheral tissue via weight loss
DeFronzo RA. Diabetes.
2009;58(4):773-795.
GLP-1 Agonists in Type 1 Diabetes
• Meta-analysis of GLP-1 agonists in T1DM:– No significant improvement in
A1C
– Increase in number of daily injections
• Weekly GLP-1 agonist product can be an option
– Reductions in:• Weight
– Waist circumference
• Hypoglycemia– Likely due to decrease in
total daily insulin dose
• Most common side
effects
– Weight loss
– Stomach upset
• Caution in patients at risk
for pancreatitis
Harris K, et al. Targets and Therapy. 2018:11:159-173.
Systematic Review & Meta-Analysis: Effects of Insulin + GLP-1 agonists in
treating Type 1 Diabetes
Drug Duration of intervention
A1c change (%)
Weight change (kg)
Bolus insulin change (units)
Total insulin change (units)
Exenatide vs. no exenatide (2009)
15 months -0.13 -4.20 -0.07 -0.07
Liraglutide vs. no liraglutide (2012)
12 months -0.5 No data No data No data
Exenatide vs. no exenatide (2013)
12 months -0.5 -6.60 No data -0.42
Exenatide vs. no exenatide (2014)
12 months -0.1 -4.20 -0.08 -0.07
Liraglutide vs. no liraglutide (2015)
24 weeks -0.2 -6.50 -0.05 -0.05
Liraglutide vs. no liraglutide (2016)
12 weeks -0.33 -1.70 No data No data
Wang W, et al. Diabetes Ther. 2017;8:727-738
Differences in GLP-1 Agonists Exenatide BID Lixisenatide Liraglutide Exenatide QW Dulaglutide Semaglutide
Short-actingTwice daily
Short-actingOnce daily
Long-actingOnce daily
Long-actingOnce weekly
Long-actingOnce weekly
Long-actingOnce weekly
Dose 5 & 10 mcg 10 & 20 mcg 0.6, 1.2 & 1.8 mg 2 mg 0.75 & 1.5 mg 0.25, 0.5 & 1.0 mg
within 30-60 min of am/pm meal
within 60 min of same meal
0.6mg initially then ↑ to 1.2 mg.
0.25 mg initially then ↑ to 0.5mg
Can ↑ to 1.8 mg if needed
Can ↑ to 1.0 mg
if needed
Max dose 10mcg BID 20mcg daily 1.8mg daily 2mg weekly 1.5mg weekly 1.0mg weekly
Half- life 2-4 hours 2-4 hours 13 hours 5 days 5 days 7 days
Homology to GLP-1
53% 50% 97% 53% 90% 94%
Antibodies 44% 69.8% 8.6% 44% 2% 1%
Byetta®. Bydureon®. Prescribing information. Wilmington, DE: AstraZeneca Pharmaceuticals LP. Victoza®. Ozempic®. Prescribing information. Plainsboro, NJ: Novo Nordisk Inc.
Trulicity® Prescribing information. Indianapolis, IN: Eli Lilly and Company. Adlyxin® Prescribing information. Sanofi-US, LLC.
GLP-1 Agonists: Renal
Dosing
Exenatide (Byetta)
Lixisenatide(Lyxumia)
Liraglutide (Victoza)
Exenatide QW(Bydureon)
Dulaglutide (Trulicity)
Semaglutide(Ozempic)
Renal dosing:
(eGFR -mL/min/1.73 m2)
<30 not
recommended
< 15 avoid
No adjustment
<30 not
recommendedNo
adjustment
No adjustment15–59
use caution and monitor
Byetta®. Bydureon®. Prescribing information. Wilmington, DE: AstraZeneca Pharmaceuticals LP. Victoza®. Ozempic®. Prescribing information. Plainsboro, NJ: Novo Nordisk Inc. Trulicity® Prescribing information. Indianapolis, IN: Eli Lilly and Company. Adlyxin® Prescribing information. Sanofi-US, LLC.
Neurotransmitter Dysfunction
SGLT-2 Inhibitors
29
Islet b-cell
ImpairedInsulin Secretion
Decreased GlucoseUptake
Islet a-cell
IncreasedGlucagon Secretion
IncreasedLipolysis
Increased GlucoseReabsorption
IncreasedHepatic Glucose Production
GI Tract/Decreased
Incretin Effect
?
1) ↓ renal glucose reabsorption in proximal tubule of kidney
2) Some ↓ in body fat (possibly due to SGLT-1 inhibition)
DeFronzo RA. Diabetes.
2009;58(4):773-795.
SGLT-2 Inhibitors in Type 1 Diabetes
• Meta-analysis of SGLT-2 inhibitors in T1DM:
– Overall trends toward reductions in:
• FPG
• Daily average glucose
• Mean amplitude of glucose excursion
• Total daily insulin dose
• Weight
– Waist circumference
• Most common side effects:– Weight loss
– Decrease in blood pressure
– Vaginal and male genital infections
– UTI
– Frequent urination
– Increased risk of ketoacidosis
Harris K, et al. Targets and Therapy. 2018:11:159-173.
SGLT2 Inhibitors in Type 1 Diabetes: Comparison
Drug Duration of intervention
A1c change (%)
FPG change (mg/dl)
Weight change (Kg)
Total insulin change (units)
Dapagliflozin 2 weeks -1.25 -7.46
Canagliflozin 18 weeks -0.27 -0.55 -2.80 -2.65
Empagliflozin 4 weeks -0.40 -1.69 -1.56 -6.20
Sotagliflozin 4 weeks -0.29 -3.20 -2.20 -6.50
Harris K, et al. Targets and Therapy. 2018:11:159-173.
Peiper T, et al. Diabetes Obes Metab. 2015;10:928-935.
Drug class Drug/Dose Reduce dose if: Contraindicated if:
SGLT2 inhibitors Canagliflozin100-300 mg daily
eGFR 45-59: 100 mg daily
eGFR<45mL/min/1.73 m2
Dapagliflozin5-10 mg daily
Not recommended if eGFR 30-60
eGFR<30mL/min/1.73 m2
Empagliflozin10-25 mg daily
--- eGFR<30mL/min/1.73 m2
Ertugliflozin5-15 mg daily
Not recommended if eGFR 30-60
eGFR<30mL/min/1.73 m2
SGLT2 Inhibitors: Renal Impairment
American Diabetes Association (ADA). Diabetes Care. 2018;41(Suppl 1):S1.
Package Insert: Steglatro. https://www.steglatro.com
Dual SGLT1/SGLT2 Inhibitor
Sotagliflozin (LX4211) for type 1 and type 2 diabetes
SGLT1 is a transporter responsible for glucose and galactose absorption in the GI tract and glucose reabsorption in the kidneys (though to a lesser extent than SGLT-2)
PCT = proximal convoluted tubule; PST = proximal straight tubule
Dual SGLT1/SGLT2 Inhibitor
• Sotagliflozin as adjunct to insulin in T1DM
• Randomized, double-blind trial to assess:– Safety
– Insulin dose
– Glycemic control
• Dual SGLT1 & SGLT2 inhibition with sotagliflozin:– Improved glycemic control
– Reduced bolus insulin dose
– Weight loss
– No increased hypoglycemia
Sands AT, et al. Diabetes Care. 2015;38:1181-1188
Efficacy and SafetyPlacebo(N = 17)
Sotagliflozin(N = 16)
P
HbA1c change from baseline (%) −0.06 −0.55 0.002
FPG change from baseline assessed at day 29 (mg/dL) 39.0 −18.6 0.15
Daily bolus insulin change from baseline assessed at days 3–27 (%) −6.4 −32.0 0.007
Daily basal insulin change from baseline assessed at days 3–27 (%) 0.2 −2.4 0.53
Total daily insulin change from baseline assessed at days 3–27 (%) −0.7 −15.3 0.029
Mean body weight change from baseline assessed at day 29 (kg) 0.5 −1.7 0.005
Seated systolic blood pressure change from baseline assessed at day 29 (mmHg) −3.9 −4.9 0.45
Patients with serious adverse effects (both with DKA) 0 2 N/A
Hypoglycemic events (SMBG ≤70 mg/dL, baseline–day 36) 354 304 N/A
Documented symptomatic hypoglycemia (SMBG ≤70 mg/dL, baseline–day 36) 185 162 N/A
Sotagliflozin As Adjunct Therapy to
Insulin in Type 1 Diabetes
Sands AT, et al. Diabetes Care. 2015;38:1181-1188
Summary
• People with T1DM can have insulin resistance/metabolic syndrome
• Use of select T2DM drugs in people with T1DM can help with insulin resistance through:– Weight loss– Reduction in total daily insulin dose
• Potential for reduction in hypoglycemic episodes
• Promising agents include:– Dual SGLT-1/SGLT-2 inhibitors– SGLT-2 inhibitors– GLP-1 agonists– Metformin
Post-Assessment Question #1
Which of the following statements is true regarding type 1 diabetes?
A. T1D develops during childhood, adolescence or young adulthood.
B. Middle age and older adults can develop T1D
C. Insulin resistance is unusual in people with T1D.
D. Adding more insulin will “fix” insulin resistance
Post-Assessment Question #2
Which of the following pharmacotherapy agents is indicted as adjunct to insulin in T1D?
A. Linagliptin
B. Metformin
C. Semaglutide
D. Sotogliflozin
Post-Assessment Question #3
• Which is the transporter responsible for glucose and galactose absorption in the GI tract?
A. DPP-4
B. GLP-1
C. GLP-2
D. SGLT-1
E. SGLT-2
Thank you for your time and
attention.
What questions can I answer for you?