exploring non-insulin therapies in type 1 diabetes non... · glucagon secretion increased lipolysis...

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


Which of the following pharmacotherapy agents is indicted as adjunct to insulin in T1D?

A. Linagliptin

B. Metformin

C. Semaglutide

D. Sotogliflozin


• 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


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


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


GLP-1 Agonists

24

Islet b-cellImpaired

Insulin Secretion


Islet a-cell


IncreasedLipolysis


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


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


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


12 months -0.5 -6.60 No data -0.42


12 months -0.1 -4.20 -0.08 -0.07


24 weeks -0.2 -6.50 -0.05 -0.05


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



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.


SGLT-2 Inhibitors

29

Islet b-cell

ImpairedInsulin Secretion


Islet a-cell


IncreasedLipolysis


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)


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


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


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


Empagliflozin10-25 mg daily

--- eGFR<30mL/min/1.73 m2

Ertugliflozin5-15 mg daily

Not recommended if eGFR 30-60


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


Which of the following pharmacotherapy agents is indicted as adjunct to insulin in T1D?

A. Linagliptin

B. Metformin

C. Semaglutide

D. Sotogliflozin


• 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?

[email protected]

mailto:[email protected]

exploring non-insulin therapies in type 1 diabetes non... · glucagon secretion increased lipolysis...

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