Canadian Society of Internal Medicine Annual Meeting 2016 Montreal, QC

Canadian Society of Internal Medicine Annual Meeting 2016 Montreal, QC Choosing the Right Agent for your Patient with diabetes: Individualizing type 2 diabetes management in light of the expanding therapies available Kaberi Dasgupta, Associate Professor of Medicine, McGill University

Canadian Society of Internal Medicine Annual Meeting 2016 The following presentation represents the views of the speaker at the time of the presentation. This information is meant for educational purposes, and should not replace other sources of information or your medical judgment. K Dasgupta: Choosing the right agent for your diabetes patient 28 October 2016

Canadian Society of Internal Medicine Annual Meeting 2016 Conflict Disclosures I sit on the CDA 2018 pharmacotherapy in type 2 diabetes chapter. I have held and hold research grants from the CIHR, FRQS, Heart and Stroke Foundation, Canadian Diabetes Association, Lawson Foundation, Medavie Foundation, and Diabete Quebec. None of these place me in conflict. I study health behaviour change in type 2 diabetes, gestational diabetes, and hypertension. Some of the drugs, devices, or treatment modalities mentioned in this presentation are: All current classes of antihyperglycemic medications

1. Identify therapeutic options for patients on maximal doses of / intolerant to biguanides, sulfonylureas, and insulin 1. Compare and contrast the effects of the expanding options for anti-diabetic agents in diabetic patients, considering the risks of hypoglycaemia, body weight and other their side effects. 2. Interpret the evidence for cardiovascular outcomes for various hypoglycaemic agents 3. Recognize the impact of egfr on prescribing medications for type 2 diabetes.

Add another class of agent best suited to the individual (agents listed in alphabetical order): Class Relative A1C Lowering Hypoglycemia Weight Effect in Cardiovascular Outcome Trial Other therapeutic considerations Cost -glucosidase inhibitor (acarbose) Rare neutral to Improved postprandial control, GI sideeffects $$ Incretin agents: DPP-4 Inhibitors GLP-1R agonists to Rare Rare Neutral to Superior (Lira, ) Neutral (alo, saxa, sita) Neutral (lixi) Caution with saxagliptin in heart failure GI side-effects $$$ $$$$ Insulin Yes Neutral (glar) No dose ceiling, flexible regimens $- $$$$ Insulin secretagogue: Meglitinide Sulfonylurea Yes Yes Less hypoglycemia in context of missed meals but usually requires TID to QID dosing Gliclazide and glimepiride associated with less hypoglycemia than glyburide $$ $ SGLT2 inhibitors to Rare Superiority (empa in T2DM patients with clinical CVD) Genital infections, UTI, hypotension, dose-related changes in LDL-C, caution with renal dysfunction and loop diuretics, dapagliflozin not to be used if bladder cancer, rare diabetic ketoacidosis (may occur with no hyperglycemia) $$$ Thiazolidinediones Rare Neutral CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect $$ Weight loss agent None GI side effects $$$ (orlistat) guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 alo=alogliptin; Canadian Diabetes glar=glargine; Association saxa=saxagliptin; sita=sitagliptin; lixi=lixisenatide; empa=empagliflozin 201

The ominous octet (3) depicting the mechanism and site of action of antidiabetes medications based upon the pathophysiologic disturbances present in T2DM. View at: http://care.diabetesjournals.org/content/diacare/36/supplement_2/s127/f1.large.jpg Ralph A. DeFronzo et al. Dia Care 2013;36:S127-S138 2013 by American Diabetes Association

67 year old woman with type 2 diabetes diagnosed 15 years ago and hypertension for the past 10 years. Her A1C is 8.7%, blood pressure is 140/90 mm Hg in your office, and her LDL is 2.2 mmol/l. Her GFR is 45. Her BMI is 34 kg/m2, her waist circumference is 93 cm, and she walks her dog 20 minutes each day. Her current medications include a statin, ASA, perindoprilindapamide combination, metformin, and maximal doses of gliclazide MR. She had an MI 1 year ago. How would you manage this patient?

Glucose filtered, glucose resorbed (proximal tubule) Glucosuria if maximal transporter capacity exceeded SGLT2 inhibitors block reabsorption at higher glucose levels Glucose Glucose

Both sodium and glucose are excreted when SGLT2 is blocked View at: http://www.nature.com/nrd/journal/v9/n7/fig_tab/nrd3180_f1.html Chao EC, Henry RR. SGLT2 inhibition: A novel strategy for diabetes treatment. Nat Rev Drug Discov.2010;9:551 9

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes, Zinman and colleagues, Nov 2015 Population- High risk CVD Adults BMI < 45 kg/m2 GFR > 30 established CVD (MI, stroke, amputation, multivessel coronary artery disease, or CABG) Intervention/comparison Empagliflozin 10 mg vs. placebo Empagliflozin 20 mg vs. placebo Outcomes: CVD morbidity and mortality

Antihyperglycemics Metformin 74% Insulin 48% Sulfonylureas 43% DPP-4 inhibitor 11% TZD 4% GLP 1 agonist 3% Other cardioprotective ACE I/ARB 81% Beta blocker 65% Diuretic 44% Statin 77% ASA 83% Plavix 11%

Some A1C lowering View at: http://www.nejm.org/doi/full/10.1056/nejmoa1504720#t=article (fig 3) Zinman B et al. N Engl J Med 2015;373:2117-2128

Blood pressure lowering View here: http://care.diabetesjournals.org/content/diacare/38/3/420.full.pdf Fig 1 Ilkka Tikkanen et al. Dia Care 2015;38:420-428 2015 by American Diabetes Association

Primary and Secondary Cardiovascular Outcomes. Zinman B et al. N Engl J Med 2015;373:2117-2128

Genital infections Vulvovaginal infections Balanitis Candida Adverse Events. Zinman B et al. N Engl J Med 2015;373:2117-2128

Canagliflozin (Invokana) Dapagliflozin (Forxiga) In Europe these and empagliflozin are available in combination with metformin From CDA website, 2016:

Rare but life threatening cases have occurred in type 2 diabetes patient taking SGLT2 inhibitors Glucose levels may not be as high as expected for DKA Context Low insulin production or increased need Symptoms Nausea and vomiting Abdominal pain Thirst Tachypnea Confusion Medscape, Internal Medicine European Medicines Agency, 2016

A. In whom should we use empagliflozin? All patients with type 2 diabetes? Those with established CVD? Those with creatinine clearance above 30? All patients with renal injury? What other antihyperglycemic agents should be used first? A. Is this a class effect?

Secreted by intestinal mucosa (ileum, distal colon) Half-life under two minutes enzyme dipeptidyl peptidase-iv (DPP-IV) Stimulates insulin secretion Slows gastric emptying Short half-life in circulation Liraglutide 97% structurally similar to GLP-1 Longer half life because of a fatty chain for binding with proteins

Manning and colleagues, Physiology, Published 5 January 2015 Vol. 30 no. 1, 50-62 View here: http://physiologyonline.physiology.org/content/30/1/50 Fig 2

Type 2 diabetes 18 years BMI < 45 kg/m2 GFR > 30 established CVD with 1 or more of: MI Stroke Amputation Multivessel coronary artery disease CABG EMPAreg eligibility A1C 7% 50 years with 1 Coronary heart disease Cerebrovascular disease Peripheral vascular disease Chronic kidney disease stage 3 or greater 60 years with 1 Microalbuminuria/Proteinuria Hypertension with LVH LV systolic or diastolic dysfunction Chronic kidney disease stage 3 or greater Ankle-brachial index < 0.9 LEADER eligibility

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes, Marso and colleagues, Aug 2016 Intervention/comparison 1.8 mg liraglutide injection once daily vs. placebo following run-in period Stratified randomization by GFR (< 30 ) Outcomes Composite Death from cardiovascular causes Nonfatal MI Nonfatal stroke Coronary revascularization Hospitalization for unstable angina Hospitalization for heart failure

Primary Composite Outcomes in Various Demographic and Clinical Subgroups. View here http://www.nejm.org/doi/full/10.1056/nejmoa1603827#t=article Table 1 Marso SP et al. N Engl J Med 2016;375:311-322 View here http://www.nejm.org/doi/full/10.1056/nejmoa1603827#t=article Fig 2 Marso SP et al. N Engl J Med 2016;375:311-322 View here http://www.nejm.org/doi/full/10.1056/nejmoa1603827#t=article Table 2 Marso SP et al. N Engl J Med 2016;375:311-322

Exenatide Lixisenatide Dulaglutide Albiglutide Semaglutide

Once/week GLP-1 agonis

In whom would you use a GLP-1 agonist? Which one? Why?

DPP 4 saxagliptin and heart failure

Population Type 2 diabetes 35 to 75 years of age with A1C > 6.5% MI, stroke, PTCA, CABG, PVD, Intervention vs. Control Pioglitazone vs. placebo

Population No type 2 diabetes HOMA-IR > 3 Ischemic stroke or TIA Intervention vs Control Pioglitazone vs. Placebo Outcome Fatal or nonfatal stroke or MI

Many agents lower A1C to similar extent DeFronzo provides evidence that durability of glycemic control differs across agents Studying the impact of combo therapy

The effect of sulfonylurea (glibenclamide = glyburide) and metformin therapy on the plasma HbA1c concentration in newly diagnosed T2DM subjects in UKPDS. Conventionally treated diabetic subjects received diet plus exercise therapy (113,114). View here: http://care.diabetesjournals.org/content/36/supplement_2/s127.figures-only Fig 3 Ralph A. DeFronzo et al. Dia Care 2013;36:S127-S138 2013 by American Diabetes Association

Durability of glycemic control with sulfonylureas. View here: http://care.diabetesjournals.org/content/36/supplement_2/s127.figures-only Fig 4 Ralph A. DeFronzo et al. Dia Care 2013;36:S127-S138 2013 by American Diabetes Association

Durability of glycemic control with TZDs. Summary of studies examining the effect of TZDs versus placebo or versus active comparator on HbA1c in T2DM subjects. View here: http://care.diabetesjournals.org/content/36/supplement_2/s127.figures-only Fig 5 Ralph A. DeFronzo et al. Dia Care 2013;36:S127-S138 2013 by American Diabetes Association

Population Newly diagnosed type 2 diabetes patients Intervention Combination: Pioglitazone, metformin, exenatide Comparison Sequential: metformin, then sulfonylurea, then insulin Outcome A1C 134 patients (preliminary): 2.7% vs. 2.2% reduction at 2 years with 1.5 vs 4 kg loss and less hypos

If you were diagnosed with type 2 diabetes, what would you do?