Exploring Non-Insulin Therapies in Type 1 Diabetes

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 noninsulin 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)

Beta Cell Mass % Natural history of Beta cell Defect in T1DM Genetic Predisposition Immunologic Abnormalities 100 Normal Insulin Impaired Insulin Overt Diabetes 50 20 % Honeymoon 0 0 Time ( yr ) ADA. Medical Management of Type 1 Diabetes, 6th ed., 2012.

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 30 1 Adults represent 85% of the total population with type 1 diabetes 2 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 Type 1 Not obese HLA DQB1 Autoantibodies T-cells Insulin treatment Type 1.5 Type 2 Age Metabolic syndrome TCF7L2 FTO Systemic inflammation C-peptide Schwartz SS, et al. Diabetes Care 2016:39(2)

Choosing a Treatment Regimen for Managing Diabetes Potential Benefits Improved Glycemic Control Decreased Complications Lack of Adverse Effects Ease of Use Potential Risks Hypoglycemia Weight gain Complexity of Regimen Other Side Effects Cost

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 Note insulin resistance Drug Class Metformin Route Targets insulin resistance Target Organs Weight Effect CVD Benefits Target Glucose: FPG or PPG A1c Reduction % Oral Maybe Liver, possible GI tract Neutral to loss Yes or neutral FPG 1.5 DDP-4 inhibitors Oral No α & β pancreatic cells, liver & some GI tract Neutral Neutral PPG 0.5-0.7 SGLT-2 inhibitors Oral Maybe Kidney, possibly adipose fat Loss Yes or neutral Both 0.7 1.1 GLP-1 agonists Injectable Yes α & β pancreatic cells, liver, brain, GI tract & some peripheral tissue Loss Yes or neutral Short-acting PPG Long-acting Both 0.8-1.5 Unger J, et al. Postgrad Med. 2010;122:145-57. Cornell S, et al. Postgrad Med. 2014;126(2):100-109.

Biguanides (Metformin) GI tract - microbiome 1) Decreases liver glucose production 2) indirectly reduces insulin resistance 3) Possible restoration of gut microbiome Impaired Insulin Secretion Islet b-cell? Increased Lipolysis Islet a-cell Increased Glucagon Secretion Increased Glucose Reabsorption DeFronzo RA. Diabetes. 2009;58(4):773-795. Increased Hepatic Glucose Production Neurotransmitter 19 Dysfunction Decreased Glucose Uptake

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 m 2 Contraindicated if egfr <30 ml/min/1.73 m 2 Most common side effects: Stomach and intestinal distress Harris K, et al. Targets and Therapy. 2018:11:159-173.

DPP4 Inhibitors (Gliptins) Impaired Insulin Secretion Islet b-cell Decreased Incretin Effect Increased Lipolysis 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 Islet a-cell Increased Glucagon Secretion Increased Glucose Reabsorption Increased Hepatic Glucose Production Decreased Glucose Uptake DeFronzo RA. Diabetes. 2009;58(4):773-795. Neurotransmitter 21 Dysfunction

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: Comparison Dose/ frequency Efficacy (A1C lowering): monotherapy Efficacy (A1C lowering): combination therapy Renal dosing Approximate ex Vivo DPP-4 Inhibition, % (maximum) sitagliptin saxagliptin linagliptin alogliptin 100 mg once daily 5 mg once daily 5 mg once daily 25 mg once daily 0.6% 0.7% 0.4% 0.8% 0.7% 1.2% 0.7% 0.9% 50 mg daily (moderate) 25 mg daily (severe) 2.5 mg daily (moderatesevere) No dose adjustment necessary 12.5 mg daily (moderate) 6.25 mg daily (severe) 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 Impaired Insulin Secretion Increased Glucagon Secretion Islet a-cell Islet b-cell GI Tract/ Decreased Incretin Effect Increased Lipolysis 1) Enhances appropriate pancreatic beta cell (insulin and amylin) secretion 2) Pancreatic alpha cell (glucagon) suppression 3) liver glucose production 4) brain satiety 5) slows gastric emptying time 6) insulin uptake in peripheral tissue via weight loss Increased Glucose Reabsorption Increased Hepatic Glucose Production Decreased Glucose Uptake DeFronzo RA. Diabetes. 2009;58(4):773-795. Neurotransmitter 24 Dysfunction

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 Exenatide vs. no exenatide (2009) Liraglutide vs. no liraglutide (2012) Exenatide vs. no exenatide (2013) Exenatide vs. no exenatide (2014) Liraglutide vs. no liraglutide (2015) Liraglutide vs. no liraglutide (2016) Duration of intervention Wang W, et al. Diabetes Ther. 2017;8:727-738 A1c change (%) Weight change (kg) Bolus insulin change (units) 15 months -0.13-4.20-0.07-0.07 Total insulin change (units) 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

Differences in GLP-1 Agonists Exenatide BID Lixisenatide Liraglutide Exenatide QW Dulaglutide Semaglutide Short-acting Twice daily Short-acting Once daily Long-acting Once daily Long-acting Once weekly Long-acting Once weekly Long-acting Once 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. Can to 1.8 mg if needed 0.25 mg initially then to 0.5mg 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 m 2) <30 not recommended < 15 avoid 15 59 use caution and monitor No adjustment <30 not recommended No adjustment No adjustment 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 Impaired Insulin Secretion Islet b-cell 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) Increased Lipolysis Islet a-cell Increased Glucagon Secretion Increased Glucose Reabsorption Increased Hepatic Glucose Production Decreased Glucose Uptake DeFronzo RA. Diabetes. 2009;58(4):773-795. Neurotransmitter Dysfunction 29

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) Dapagliflozin 2 weeks -1.25-7.46 Total insulin change (units) 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.

SGLT2 Inhibitors: Renal Impairment Drug class Drug/Dose Reduce dose if: Contraindicated if: SGLT2 inhibitors Canagliflozin 100-300 mg daily egfr 45-59: 100 mg daily egfr <45mL/min/1.73 m 2 Dapagliflozin 5-10 mg daily Not recommended if egfr 30-60 egfr <30mL/min/1.73 m 2 Empagliflozin 10-25 mg daily Ertugliflozin 5-15 mg daily --- egfr <30mL/min/1.73 m 2 Not recommended if egfr 30-60 egfr <30mL/min/1.73 m 2 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

Sotagliflozin As Adjunct Therapy to Insulin in Type 1 Diabetes Efficacy and Safety Placebo (N = 17) Sotagliflozin (N = 16) P HbA 1c 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 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? scorne@midwestern.edu