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Pharmacist Continuing Education - The Role of Non-Insulin Therapies in the Treatment of Type 1 Diabetes

12 Jan 2018 3:17 PM | Deleted user

The Role of Non-Insulin Therapies in the Treatment of Type 1 Diabetes

Authors: Sara Lingow, PharmD, PGY2 Ambulatory Care Pharmacy Resident
St. Louis College of Pharmacy/Saint Louis County
Department of Public Health

Justinne Guyton, PharmD, BCACP,
Assistant Professor, Pharmacy Practice
St. Louis College of Pharmacy

Program Number: 2017-12-09
Approval Dates: 2/7/2018 to 5/6/2018
Approved Contact Hours: One (1) CE(s) per LIVE session.
Submit Answers to CE Questions to Jim Andrews at: mshp@qabs.com


I. Describe the proposed role of GLP-1 receptor agonists and SGLT inhibitors in type 1 diabetes.

II. Identify adverse effects that may limit the use of GLP-1 receptor agonists or SGLT inhibitors.

III. Evaluate primary literature to determine the risks and benefits of both GLP-1 receptor agonist and SGLT inhibitor therapy in patients with type 1 diabetes.

IV. Select the best non-insulin therapy for a patient with type 1 diabetes who is not achieving glycemic control with insulin therapy alone.

Type 1 Diabetes Mellitus (T1DM) is characterized by autoimmune pancreatic β-cell destruction, leading to an insulin deficiency. Pancreatic α-cell dysfunction is also present, resulting in excess glucagon in both the fasting and postprandial state. Onset is most common during adolescence, but adults have also been diagnosed with T1DM. Patients with T1DM will have autoimmune markers present, and little to no residual C-peptide (a marker of insulin production).1,2

The Center for Disease Control and Prevention (CDC) estimates that 5 to 10% of patients with diabetes have type 1.3 Insulin is the mainstay of therapy for T1DM, as the characteristic β-cell destruction in T1DM results in minimal to no endogenous insulin production. While exogenous insulin is necessary, it does not account for the excess glucagon production or the altered gastric emptying rate in T1DM. Additionally, the two most common adverse effects of insulin are hypoglycemia and weight gain, which is of concern in patients with T1DM.2 A study published in 2015 found that patients in the United States with T1DM have an average A1C of 8.2%, with only 30% of patients achieving an A1c goal of less than 7%. Furthermore, 68% of patients are overweight or obese, diabetic ketoacidosis (DKA) occurs at a rate of 10% per year in some age groups, and severe hypoglycemia occurs at a rate of 9 – 20%.4 These data alone illustrates the need for alternative therapies to treat T1DM without risking further weight gain and hypoglycemia with insulin monotherapy.

In 2016 Schwartz and colleagues introduced the β-cell-centric classification schema of diabetes in which abnormal β-cell function is the common denominator for all types of diabetes. This model also identified ten other pathways of hyperglycemia, highlighting the idea that different treatment pathways can reduce hyperglycemia through different mechanisms in order to achieve glycemic goals.5 The ideal treatment regimen for a patient with T1DM would not only target the β-cell dysfunction, but also decrease blood glucose by targeting hyperglycemic pathways independent of β-cell function.

Pramlintide was FDA-approved for the treatment of T1DM in 2005.6 Pramlintide is an amylin analogue that delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety.7 Clinical trials showed that when pramlintide 30 or 60 mcg was administered subcutaneously three to four times daily, in addition to insulin therapy, the agent provided several positive benefits. The combination modestly lowered A1c, lowered the total daily dose (TDD) of insulin, and resulted in a decrease in body weight in patients with T1DM.8-10 Despite these benefits, pramlintide is rarely used in T1DM due to the multiple daily injections, significant nausea and vomiting, and overall cost of the medication. Metformin, dipeptidyl-peptidase-4 (DPP-4) inhibitors, and thiazolidinediones (TZD) have also been studied in T1DM, but have not shown clinically significant beneficial outcomes and therefore are not FDA-approved for treatment.2 The role of two other non-insulin classes of medications, sodium-glucose co-transporter (SGLT) inhibitors and glucagon-like-peptide 1 receptor agonists (GLP-1 RA), have been recently studied in T1DM. The remainder of this article will focus on a literature review of these agents with regard to lowering A1c, reducing insulin dose, and reducing body weight in patients with T1DM.

Sodium-Glucose Co-Transporter-Inhibitors
The SGLT-2 receptor is located in the proximal tubule of the kidney and is responsible for 90% of renal glucose reabsorption. Inhibition of this transporter reduces reabsorption of filtered glucose, thereby increasing glucosuria and reducing plasma glucose concentrations.7 The SGLT-1 receptor is located both in the proximal renal tubule and in the proximal small intestine. In the proximal renal tubule, it is responsible for the remaining 10% of renal glucose reabsorption. In the small intestine, it is the primary transporter in glucose and galactose absorption. Inhibition of this receptor therefore prevents glucose absorption in the small intestine, and a small amount of reabsorption in the kidneys. 11,12 Because the mechanism of SLGT inhibitors are independent of beta-cell function, this drug class may offer A1c lowering benefit to patients with T1DM, both by increasing glucose excretion in the kidney through SGLT-1 and-2 inhibition, and preventing glucose absorption in the small intestine through SGLT-1 inhibition.2 Currently, only SGLT-2 inhibitors are available in the United States. Known adverse effects of SGLT inhibitors include lipid abnormalities, genital infections, hypotension, and euglycemic diabetic ketoacidosis.7 A list of all available agents and their respective average wholesale prices can be found in Appendix I, Table 1. The first studies of SGLT inhibitors in patients with T1DM were limited by small sample size and a short duration. However, a few key findings warrant the necessity of future trials. Reduction in A1c, varying from -0.24% to -0.7%, a significant decrease in body weight, and a decrease in TDD were all seen in preliminary literature. While these benefits were apparent, patients receiving SGLT inhibitors also experienced more episodes of ketoacidosis and genital infections. 11,13-16

Two new, larger scale, landmark clinical trials were recently published in September 2017 evaluating the role of SLGT inhibitors in T1DM. The DEPICT-1 trial evaluated the role of dapagliflozin, an SGLT-2 inhibitor added to insulin therapy in 833 patients with T1DM. The primary outcome, change in A1c at 24-weeks, favored treatment with both dapagliflozin 5 mg (-0.42%) and dapagliflozin 10 mg (-0.45%) compared to placebo (p<0.0001). Severe hypoglycemia occurred in 21 (8%), 19 (6%) and 19 (7%) of the patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups respectively. Adjudicated definite diabetic ketoacidosis occurred in four (1%), five (2%), and three (1%) patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups respectively. This trial was still relatively short in duration, and excluded patients at a higher risk for hypoglycemia and DKA, however, it still offers promising benefit of an SGLT-2 inhibitor in addition to insulin for patients with T1DM who are not achieving glycemic goals.17

The inTandem 3 trial was also published in September 2017. This trial evaluated the role of sotagliflozin, an SLGT-1 and SLGT-2 inhibitor, in 1402 patients with T1DM. The primary outcome targeted both efficacy and safety endpoints, assessing the number of patients to achieve an A1c < 7.0% without hypoglycemia or DKA. Two hundred of the patients in the sotagliflozin group (28.6%) achieved this primary outcome, while only 107 (15.2%) patients in the placebo group achieved the outcome (p<0.001). This resulted in a number needed to treat of eight patients. Conversely, there were also more patients in the sotagliflozin group who did not meet the A1c goal and had at least one episode of DKA compared to placebo (16 patients (2.3%) vs. 13 patients (1.8%) respectively, p <0.003). This resulted in a number needed to harm of 50 patients. This trial was also relatively short in duration at only 24 weeks, excluded patients with a recent history of DKA or hypoglycemia, and demonstrated an increased risk of DKA in the treatment group.12

The data from these two recent landmark trials confirm the benefits of A1c reduction, weight loss, and reduction in total daily insulin doses with SGLT inhibitors seen in preliminary literature. Furthermore, the literature does not show an increased risk of hypoglycemia with these agents, though both trials excluded patients at baseline with a recent history of severe hypoglycemia. However, these benefits do not come without the risk of ketoacidosis, and should therefore not be used in patients with a history of, or at an increased risk for DKA. Additionally, the cost of these newer, brand-name agents may introduce an additional barrier (Appendix I, Table 1). Future trials that are longer in duration and specifically evaluate the safety of these medications in patients with T1DM are essential. Additionally, future studies should be designed so that the primary outcome is patient-related, evaluating the benefit of this class in prevention or delay of microvascular and/or macrovascular diabetic complications.

Glucagon-Like-Peptide-1 Receptor Agonists (GLP-1 RA)
Human GLP-1 is a peptide that, in conjunction with glucose-dependent insulinoptropic polypeptide (GIP), is responsible for over 90% of the increased insulin secretion seen from an oral glucose load. GLP-1 is secreted from L-cells, located in the intestine and colon, in response to meals. Human GLP-1 levels rise shortly after food ingestion, enhancing insulin secretion, suppressing glucagon secretion, slowing gastric emptying and reducing food intake by increasing satiety.18 GLP-1 receptor agonists are analogs of human GLP-1 which increase glucose-dependent insulin secretion, delay inappropriate glucagon secretion, increase β-cell growth and replication, delay gastric emptying, and decrease food intake. The proposed benefit of GLP-1 receptor agonists in T1DM is mostly related to the mechanistic avenues independent of β-cell function. However, the potential to improve residual β-cell function and increase glucose-dependent insulin secretion may be beneficial early on in the diagnosis of T1DM. The most common adverse effects of GLP-1 receptor agonists include gastrointestinal disturbances, such as nausea and vomiting, increased heart rate, and headache. This class should not be used in patients with a personal or family history of thyroid cancer or multiple endocrine neoplasia syndrome (MENS).7,19 A list of available GLP-1 receptor agonists and their respective costs are available in (Appendix I, Table 2).

Preliminary literature evaluating the role of GLP-1 RAs in T1DM are largely inconclusive. Most trials had a small sample size and duration ranged from four to 26 weeks, with the exception of one 56-week trial. The results of the trials were variable regarding A1c reduction (-0.3 to -2.3%), weight loss (-0.5 kg to 6 kg), and reduction in TDD of insulin up to 20%. While the results of these earlier studies suggest potential benefit of this class, many were retrospective, open-label, or observational, limiting their usefulness.20-26. The ADJUNCT-ONE trial, published in 2016, evaluated the role of liraglutide added to treat-to-target insulin with regard to effects on A1c, insulin requirement, and body weight in patients with T1DM. The trial was a double-blind, randomized controlled trial including 1,398 adults with a duration of 52 weeks. Subjects were randomized in a 3:1 fashion to receive either liraglutide 0.6 mg, 1.2 mg, 1.8 mg or placebo added to insulin. At 52 weeks, liraglutide at both the 1.8 mg and 1.2 mg doses significantly reduced A1c compared to placebo (-0.54% and -0.49% vs. -0.34% respectively). Reduction in total daily insulin dose also significantly favored liraglutide at the 1.8 mg and 1.2 mg doses when compared to placebo (-5% and -2% vs. +4% respectively). Reduction in weight was significant for all three treatment groups compared to placebo. While benefits were seen at the higher doses of liraglutide, they were accompanied by an increased rate of symptomatic hypoglycemic events. The rate of symptomatic hypoglycemia events observed was 16.5/patient-year of exposure (PYE) and 16.1/PYE in the liraglutide 1.8 mg and 1.2 mg groups, respectively compared with a rate of only 12.3/PYE in the placebo group (p<0.05). Additionally, liraglutide 1.8 mg was associated with a higher rate of hyperglycemic episodes with ketosis. Gastrointestinal adverse effects were notable in all liraglutide groups. In the subgroup analysis, ADJUNCT-ONE authors identified that patients with residual C-peptide levels (n=17%) at baseline had a greater decrease in A1c with liraglutide 1.8 mg and 1.2 mg compared to those without residual C-peptide at baseline at the same dose. Additionally, patients with residual C-peptide experienced fewer episodes of hypoglycemia or hyperglycemia with ketosis.27

The ADJUNCT-TWO trial, published shortly after ADJUNCT-ONE in 2016, evaluated the efficacy and safety of liraglutide added to a capped insulin dose in patients with T1DM. This was a 26-week randomized, double-blind trial enrolling 835 patients randomized in a 3:1 fashion to receive liraglutide 0.6 mg, 1.2 mg, 1.8 mg or placebo added to capped insulin. At 26-weeks, there was a statistically significant reduction in A1c with all three doses of liraglutide compared to placebo (-0.35%, -0.23%, -0.24% and +0.01% for liraglutide 1.8 mg, 1.2 mg, 0.6 mg and placebo respectively). Reduction in total daily dose of insulin and body weight also significantly favored all three liraglutide doses. The highest rate of symptomatic hypoglycemia was unexpectedly seen in the liraglutide 1.2 mg arm. Like the ADJUNCT-ONE trial, hyperglycemia with ketosis was seen most often in the liraglutide 1.8 mg arm. The subgroup analysis of ADJUNCT-TWO revealed that, similar to the ADJUNCT-ONE findings, patients with residual C-peptide (15%) at baseline also showed a greater reduction in A1c with liraglutide 1.8 mg compared to those without residual C-peptide.28

ADJUNCT-ONE and ADJUNCT-TWO are the largest trials available to date to evaluate liraglutide in T1DM. While the results of both trials are favorable with regard to A1c reduction, weight loss, and reduction in insulin doses, the treatment arms did show an increased risk of dose-dependent hypoglycemia and hyperglycemia with ketosis as well as gastrointestinal adverse events. Similar to the SGLT inhibitors, all available GLP-1 RAs are brand-name with a high price tag, often limiting their use (Appendix I, Table 2). Future studies focused on patient-oriented evidence that matters, such as prevention of microvascular or macrovascular outcomes, would be beneficial to truly determine their clinical utility.

When to Choose an SLGT Inhibitor or GLP-1 RA in T1DM?
A patient with T1DM may be a good candidate for an SLGT inhibitor if overweight or obese and interested in an oral agent in addition to an insulin regimen. Duration of diabetes does not appear to be a factor affecting efficacy of SGLT inhibitors in T1DM. This class may be considered in patients who are at risk for hypoglycemia, as the recent clinical trials did not show an increase rate of hypoglycemia in the treatment groups. This class should be avoided in patients with a recent history of, or who are at high risk for, a DKA episode. On the other hand, a GLP-1 RA may be the best option to add on in a patient with newer-onset T1DM, residual β-cell function, or residual C-peptide levels, as the preliminary literature and subgroup analyses show the most benefit in this population. Obese and overweight patients with T1DM may benefit from the weight loss properties, and the class should be used with caution in patients at a higher risk of DKA or hypoglycemic events, as the recent evidence showed a higher incidence of these adverse effects. Overall, the benefits of both classes in addition to insulin therapy in T1DM appear to be promising. However, due to the potential for adverse effects, in addition to cost, lack of FDA-approval, and lack of insurance coverage, the practicality of using either class is relatively low at this time.

Paradigm Shift
Over the past few years there has been a shift in framework for managing diabetes. Landmark trials such as the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) demonstrated that the longer amount of time patients with T1DM spend meeting glycemic goals, the lower risk of long-term microvascular and macrovascular complications.29,30 Newer trials, such as LEADER and EMPA-REG, have shown cardiovascular benefit (and even renal benefits) with specific drug classes in patients with type 2 diabetes within 3 to 5 years.21,32 Perhaps, there is more to prevention of complications in patients with diabetes than merely meeting glycemic goals. Future trials evaluating the prevention of microvascular and macrovascular complications with SLGT inhibitors and GLP-1 RAs in the treatment of T1DM have the potential to transform the current treatment algorithms.

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14. Pieber TR, Famulla S, Eilbracht J, et al. Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1). Diabetes Obes Metab. 2015;17(10):928-35.
15. Henry RR, Thakkar P, Tong C, Polidori D, Alba M. Efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes. Diab Care. 2015;38(12):2258-65.
16. Kuhadiya ND, Ghanim H, Mehta A, et al. Dapagliflozin as additional treatment to liraglutide and insulin in patients with type 1 diabetes. J Clin Endocrinol Metab. 2016;101(9):3506-15.
17. Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017;[online first]:1-13.
18. Triplitt CL, Repas T, Alvarez C. Diabetes Mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; Accessed October 05, 2017.
19. American Diabetes Association. Classification and diagnosis of diabetes. Sec 8. In Standards of Medical Care in Diabetes 2017. Diab Care 2017;40(Suppl. 1):S64-S74
20. Kielgast U, Krarup T, Holst JJ, Madsbad S. Four weeks of treatment with liraglutide reduces insulin dose without loss of glycemic control in type 1 diabetic patients with and without residual beta-cell function. Diab Care. 2011;34(7):1463-8.
21. Kuhadiya ND, Malik R, Bellini NJ, et al. Liraglutide as additional treatment to insulin in obese patients with type 1 diabetes mellitus. Endocr Pract. 2013;19(6):963-7.
22. Hari kumar KV, Shaikh A, Prusty P. Addition of exenatide or sitagliptin to insulin in new onset type 1 diabetes: a randomized, open label study. Diabetes Res Clin Pract. 2013;100(2):e55-8.
23. Traina AN, Lull ME, Hui AC, Zahorian TM, Lyons-Patterson J. Once-weekly exenatide as adjunct treatment of type 1 diabetes mellitus in patients receiving continuous subcutaneous insulin infusion therapy. Can J Diabetes. 2014;38(4):269-72.
24. Frandsen CS, Dejgaard TF, Holst JJ, Andersen HU, Thorsteinsson B, Madsbad S. Twelve-Week Treatment With Liraglutide as Add-on to Insulin in Normal-Weight Patients With Poorly Controlled Type 1 Diabetes: A Randomized, Placebo-Controlled, Double-Blind Parallel Study. Diab Care. 2015;38(12):2250-7.
25. Dejgaard TF, Fransden CS, Hansen TS, et al. Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2016;4:221-32

26. Kuhadiya ND, Dhindsa S, Ghanim H, et al. Addition of Liraglutide to Insulin in Patients With Type 1 Diabetes: A Randomized Placebo-Controlled Clinical Trial of 12 Weeks. Diab Care. 2016;39(6):1027-35.

27. Mathieu C, Zinman B, Hemmingsson JU, et al. Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE Treat-To-Target Randomized Trial. Diab Care. 2016;39(10):1702-10.

28. Ahrén B, Hirsch IB, Pieber TR, et al. Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Subjects With Type 1 Diabetes: the ADJUNCT TWO Randomized Trial. Diab Care. 2016;39:1693-1701
29. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-86.
30. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643-53.
31. Marso SP, Daniels GH, Brown-Frandsen K et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.
32. Zinman B, Wanner C, Lachin JM. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015l373(22):2117-28
33. Micromedex Solutions. Ann Arbor (MI): Truven Health Analytics; publication year [5 October 2017]. Available from: www.micromedexsolutions.com.

Appendix I: 

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