DM-2 Therapy Update: GLP-1, SGLT-2 Inhibitors, and Inhaled Insulin, Oh My!

DM-2 Therapy Update: GLP-1, SGLT-2 Inhibitors, and Inhaled Insulin, Oh My! Kevin M. Pantalone, DO, ECNU, CCD Associate Staff Director of Clinical Research Department of Endocrinology Endocrinology and Metabolism Institute

Disclosures Speaker Bureau AstraZeneca, Merck, Novo Nordisk Consultant Novo Nordisk, Eli Lilly, Merck Research Support Novo Nordisk and Merck

Anti-diabetic Agents Used to be two main categories: Insulin sensitizers Insulin secretagogues However, the new agents do not fit nicely into these two categories Many of the new anti-diabetic agents work by novel mechanisms

Available Medications SGLT2 inhibitors

Hyperglycemia in Type 2 Diabetes

ADA/EASD Individualized Management Pick a Target Inzucchi SE et al. Diabetes Care. 2015;38:140 149.

Efficacy ( HbA1C) Hypoglycemia Weight Side Effects Cost Choosing a Therapy Individualize Care! Inzucchi SE et al. Diabetes Care. 2015;38:140 149. Inzucchi SE et al. Diabetes Care. 2012;35(6):1364-79. Inzucchi SE et al. Diabetologia. 2012;55(6):1577-96.

Drucker DJ. Diabetes Care. 2003;26:2929-2940.

Rachman J et al. Diabetologia. 1997:40:205-211.

Exenatide BID vs. Long-acting GLP-1 agonists Trials comparing exenatide BID with exenatide QW, liraglutide once daily, or dulaglutide once weekly, noted A1C reduction with daily or weekly GLP-1 agonists was significantly greater Treatment difference -0.3 to -0.7% Generally speaking, the long-acting GLP-1 agonists have similar or better tolerability Drucker DJ et al. Lancet. 2008;372(9645):1240. Buse JB et al. Lancet. 2009;374(9683):39. Blevins T et al. J Clin Endocrinol Metab. 2011;96(5):1301-10. Wysham C et al. Diabetes Care. 2014;37(8):2159-67.

Duration-6 Exenatide QW vs. Liraglutide -1.28% Exenatide 2 mg sc weekly Liraglutide 1.8 mg sc daily -1.48% Buse JB et al. Lancet. 2013;381(9861):117-24.

Duration-6 Exenatide QW vs. Liraglutide Exenatide once weekly did not meet its prespecified non-inferiority margin The most common side effects occurred more frequently in the liraglutide group: -Nausea (21 vs. 9%) -Diarrhea (13 vs. 6%) -Vomiting (11 vs. 4%) Weight loss was slightly greater in the liraglutide group (-3.57 and -2.68 kg) Buse JB et al. Lancet. 2013;381(9861):117-24.

Harmony-7 Albiglutide vs. Liraglutide Albiglutide: -initial dose 30 mg -titrated to 50 mg once weekly -0.78% Liraglutide: -initial dose 0.6 mg -titrated to 1.2 and then 1.8 mg daily 4 8 12 16 18 24 28 32 Week Pratley RE et al. Lancet Diabetes Endocrinol. 2014;2(4):289-97. -0.99%

Harmony-7 Albiglutide vs. Liraglutide Albiglutide did not meet its pre-specified noninferiority margin Injection-site reactions occurred in more patients given albiglutide than in those given liraglutide 12.9% vs. 5.4% However, GI events were higher with liraglutide treated patients than in those given albiglutide 49.0% vs. 35.9% Pratley RE et al. Lancet Diabetes Endocrinol. 2014;2(4):289-97.

AWARD-6 Dulaglutide vs. Liraglutide Dungan KM et al. Lancet. 2014;384(9951):1349-57.

AWARD-6 Dulaglutide vs. Liraglutide The most common GI AEs were Nausea (20% in dulaglutide group vs. 18% in liraglutide group) Diarrhea 12% vs. 12% Vomiting 7% vs. 8% AE related rates of study drug discontinuation between the two groups were similar (6% in each group) Dungan KM et al. Lancet. 2014;384(9951):1349-57.

What to choose? Among the long-acting agents, patient preference and payer coverage are important considerations Among the longer-acting GLP-1 agonists, small differences in glucose control favor once-daily liraglutide to exenatide once weekly and albiglutide Glycemic control appears to be similar with liraglutide and dulaglutide

Tolerability Long-acting GLP-1 Other Considerations Means of injection Differences in device GFR Exenatide not recommended in patients with CrCl <30 ml/minute or end-stage renal disease (ESRD)

GLP-1 Agonists Benefits Weight loss Low (no) risk of hypoglycemia Improved glycemic control Reduction in systolic BP? In-vivo increase B-cell growth/replication? Reduce CV risk Side Effects/Adverse Reactions Nausea, vomiting, diarrhea, injection site reactions

Warnings Thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), were noted in rats, but human relevance remains uncertain Contraindicated in patients with a personal or family history of MTC and in patients with MEN2 Routine serum calcitonin measurements, or thyroid ultrasounds, are of uncertain value, and not recommended

Warnings Pancreatitis: In clinical trials, there were more cases of pancreatitis among GLP-1-treated patients than among comparator-treated patients If pancreatitis is suspected, GLP-1 therapies and other potentially suspect drugs should be discontinued GLP-1 agonists should not be restarted if pancreatitis is confirmed. Use with caution in patients with a history of pancreatitis Serious hypoglycemia: Can occur when GLP-1 agonists are used with an insulin secretagogue or insulin Consider lowering the dose of the insulin or insulin secretagogue to reduce the risk of hypoglycemia

Sodium-glucose co-transporter 2 (SGLT2) inhibitors Dapagliflozin, Canagliflozin, Empagliflozin Block the glucose reabsorption function of the kidney, resulting in the excretion of excess glucose up to 10% of daily calorific intake in patients' urine Dokken B. Diabetes Spectr. 2012;25:29-36.

Renal Threshold for Glucose is Increased in Patients with DM-2 Defronzo RA. Diabetes Care. 2013;36:3169-3176.

DM-2 Maladaptation: The kidney has a 32% increased capacity for glucose reabsorption vs. the healthy patient Healthy SGLT2 Inhibitor DM-2 Mogensen CE. Scand J Clin Lab Invest. 1971; 28: 101 109. Abdul-Ghani MA, Defronzo RA. Endocr Pract. 2008;14:782-790. Rahmoune H et al. Diabetes. 2005; 54: 3427 3434. Vestri S et al. J Membr Biol. 2001;182: 105 112. Bays H. Curr Med Res Opin. 2009;25:671-681. Defronzo RA. Diabetes Care. 2013;36:3169-3176.

Renal Threshold for Glucose with SGLT2 inhibition SGLT-2

SGLT2 inhibitors Benefits Weight loss Low (no) risk of hypoglycemia Improved Glycemic control Reduction in systolic BP (~ 5 mmhg) CV risk reduction? Risks/Negatives Slight increase in LDL cholesterol Hypotension Intravascular volume contraction UTIs, genital mycotic infections Bladder Cancer (???) Breast Cancer (???) DKA (euglycemic)

Dapagliflozin Bladder Cancer Across 22 clinical studies, newly diagnosed cases of bladder cancer were reported in 0.17% of dapagliflozin treated patients and 0.03% of placebo or comparator-treated patients

Dapagliflozin Bladder Cancer After excluding patients in whom exposure to study drug was < 1 year at the time of diagnosis of bladder cancer, there were 4 cases with dapagliflozin and no cases with placebo/comparator Study arms were balanced at baseline with respect to bladder cancer risk factors and hematuria Bottom line, there were too few cases to determine whether the emergence of these events were related to dapagliflozin

SGLT2 and Alpha Cells It has been demonstrated that SGLT2 is expressed in glucagon-secreting alpha cells of the pancreatic islets Inhibition of SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion Bonner C et al. Nature Medicine 2015; 21:512 517.

DKA and SGLT2 inhibitors SGLT2 inhibitors, by increasing glucagon, may exploit a state of hypo-insulinemia, and if the insulin deficiency is sufficient enough, precipitate DKA, even if the glycemic control does not deteriorate We need to pay more attention to the patients we choose to put on SGLT2 inhibitors, particularly the leaner DM-2 patients and those with very high A1Cs, either of which could represent a significant state of insulin deficiency

Clinical Trial Data: DKA Empagliflozin: 17 randomized studies (Phase 1-3 studies) 8,588 T2D patients, only 3 cases of DKA were reported, <0.1% Canagliflozin: The incidence of DKA in phase 3 studies, and the additional randomized, controlled canagliflozin studies conducted by Janssen, was <0.1%. Overall these studies include more than 17,000 patients Dapagliflozin: Phase IIB/III (21 studies), only 1 case of DKA was reported in the total 5936 dapagliflozin treated T2D patients (6547.2 patient years), <0.1%

DKA and SGLT2 inhibitors: Conclusions The available (limited) data suggests that we may need to be more selective and thorough in our determination of who is prescribed SGLT2 inhibitors High A1Cs at baseline, high-risk of volume of contraction, and unusual/atypical cases of DM2, may require further investigation Should closely monitor DM1 patients in whom SGLT2 inhibitors are prescribed off-label

Zinman B, et al. for the EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015; published on-line September 17, 2015.

Zinman B, et al. for the EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015; published on-line September 17, 2015.

SGLT2 Inhibitors Drug Dose GFR (ml/minute/1.73 m2) Canagliflozin 100 mg 45-60 100 mg, 300 mg >60 Dapagliflozin 5 mg, 10 mg > 60 Empagliflozin 10 mg, 25 mg >45

Inhaled Insulin, Round 2!

Randomized, open-label, parallel-group study, of adult T2D and poor glycemic control despite insulin therapy, with or without oral antidiabetes drugs Rosenstock J et al. Lancet. 2010;375(9733):2244-53.

Change from Baseline in A1C at 52 Weeks At Week 52, the reduction in A1C with Afrezza was non-inferior to the reduction with insulin (Pre-specified non-inferiority margin of 0.4%) Rosenstock J et al. Lancet. 2010;375(9733):2244-53.

A1C 7% at 24 Weeks At Week 52, the percentage of patients with A1C 7% was similar across both treatment groups Rosenstock J et al. Lancet. 2010;375(9733):2244-53.

Body Weight at 52 Weeks Rosenstock J et al. Lancet. 2010;375(9733):2244-53.

Significant Adverse Events > 5% Inhaled Insulin N 323 Biaspart Insulin N 331 Upper Resp Tract Inf 39 (12%) 24 (7%) Hypoglycemia 155 (48%) 228 (69%) Cough 106 (33%) 20 (6%) Rosenstock J et al. Lancet. 2010;375(9733):2244-53.

A Bong is No Longer Required.

SC vs. Inhaled Afrezza insulin cartridges contain an absolute quantity of insulin greater than the designated quantity on the cartridge, reflecting the reduced bioavailability of insulin delivered via the pulmonary route versus the subcutaneous route. The Afrezza 4 unit cartridge actually contains 10 units of insulin, but has the approximate effect of 4 units of subcutaneously administered rapid acting insulin. The Afrezza 8 unit cartridge actually contains 20 units of insulin but has an approximate effect of 8 units of subcutaneously administered rapid acting insulin.

Effect of Technosphere inhaled Insulin on PFT s

Conclusions Individualize Care Consider the newer classes of antidiabetic medications to help patients obtain glycemic control