DIABETES DEBATE - IS NEW BETTER?

DIABETES DEBATE - IS NEW BETTER? WHAT MEDICATION CLASS AFTER METFORMIN TO CONTROL BLOOD SUGAR Dr. Lydia Hatcher, MD, CCFP, FCFP, CHE, D-CAPM Associate Clinical Professor of Family Medicine, McMaster Chief of Family Medicine, St Josephs Healthcare, Hamilton CMEaway TM by Sea Courses 2017

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OBJECTIVES Following this program, participants will: 1. Know the target for glycemic control 2. List classes of glucose lowering agents 3. Articulate benefits and drawbacks of each class 4. Respond to argument of why or why not use newer agents

CASE STUDY - KATHERINE 59 year old teacher Diagnosed with Type 2 DM three years ago. 5 kg weight gain as she went through menopause. Despite early interventions with diet and exercise and progressive doses of metformin her weight has increased by 1 kg in the last year HgA1c risen to 7.3%.

CASE STUDY - KATHERINE Current meds: Metformin 1000 mg bid Citalopram 20 mg od Ramipril 10 mg od Simvastatin 40 mg od ECASA 81 mg od BP 130/84 All her other blood work is within target with a normal renal function

WHAT WOULD YOU DO WITH RESPECT TO HER GLYCEMIC CONTROL? a) Increase metformin to 2.5 grams/day? b) Make no medication changes but use this as an opportunity for encouraging continued lifestyle change? c) Accept that this is close enough and make no changes to avoid therapeutic turbulence d) Add another agent? e) Send the patient to Certified Diabetes Educator to make the decision?

WHAT DO THE GUIDELINES SAY ABOUT TARGETS?

CDA 2013 GUIDELINES: INDIVIDUALIZING A1C TARGETS 7% >7% A target A1C 6.5% may be considered in some patients with T2DM to further lower the risk of nephropathy and retinopathy, which must be balanced against the risk of hypoglycemia Most patients with type 1 and type 2 diabetes 7 % Consider A1C target 7.1 8.5% if: Limited life expectancy High level of functional dependency Extensive coronary artery disease at high risk of ischemic events Multiple comorbidities History of recurrent severe hypoglycemia Hypoglycemia unawareness Longstanding diabetes and difficulty achieving A1C 7% despite effective doses of multiple antihyperglycemic agents, including intensified basalbolus insulin therapy CDA: Canadian Diabetes Association. CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.

ASSUME YOU WERE GOING TO ADD ANOTHER AGENT WHICH WOULD YOU CHOOSE? a) Alpha-glucosidase inhibitor b) DPP-4 inhibitor c) GLP-1 agonist d) Insulin e) Secretagogue f) SGLT-2 Inhibitor g) TZD

WHAT DO THE GUIDELINES SAY?

AT DIAGNOSIS OF TYPE 2 DIABETES L I F E S T Y L E Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin A1C <8.5% If not at glycemic target (2-3 mos) Start / Increase metformin A1C ³8.5% Start metformin immediately Consider initial combination with another antihyperglycemic agent If not at glycemic targets Symptomatic hyperglycemia with metabolic decompensation Initiate insulin +/- metformin Add another agent best suited to the individual by prioritizing patient characteristics: PATIENT CHARACTERISTIC PRIORITY: Clinical Cardiovascular Disease Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Cardiovascular disease or multiple risk factors Comorbidities (renal, CHF, hepatic) Preferences & access to treatment CHOICE OF AGENT SGLT2 inhibitor with demonstrated CV outcome benefit Consider relative A1C lowering Rare hypoglycemia Weight loss or weight neutral Effect on cardiovascular outcome See therapeutic considerations, consider egfr See cost column; consider access 2016 See next page

Add another class of agent best suited to the individual (agents listed in alphabetical order): Class Relative A1C Lowering Hypoglycemi a Weight Effect in Cardiovascular Outcome Trial Other therapeutic considerations Cost a-glucosidase inhibitor (acarbose) Rare Neutral to Improved postprandial control, GI side-effects $$ DPP-4 Inhibitors Rare Neutral to alo, saxa, sita: Neutral GLP-1R agonists to Rare lira: Superiority in T2DM patients with clinical CVD lixi: Neutral Caution with saxagliptin in heart failure $$$ GI side-effects $$$$ Insulin Yes Neutral (glar) No dose ceiling, flexible regimens $-$$$$ Insulin secretagogue: Meglitinide Sulfonylurea Yes Yes SGLT2 inhibitors to Rare empa: Superiority in T2DM patients with clinical CVD Less hypoglycemia in context of missed meals but usually requires TID to QID dosing Gliclazide and glimepiride associated with less hypoglycemia than glyburide Genital infections, UTI, hypotension, doserelated changes in LDL-C, caution with renal dysfunction and loop diuretics, dapagliflozin not to be used if bladder cancer, rare diabetic ketoacidosis (may occur with no hyperglycemia) $$ $ $$$ Thiazolidinediones Rare Neutral CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect Weight loss agent (orlistat) None GI side effects $$$ $$ alo=alogliptin; glar=glargine; saxa=saxagliptin; sita=sitagliptin; lira=liraglutide; lixi=lixisenatide; empa=empagliflozin 11/2016

ALPHA-GLUCOSIDASE INHIBITOR Advantages Modest A1c lowering Relatively inexpensive Weight neutral to lowering Hypoglycemia rare Disadvantages GI intolerance Adapted from 2016 CDA guidelines

DPP-4 INHIBITOR Advantages Good A1c lowering Available as combination therapy Weight neutral to lowering Hypoglycemia rare Disadvantages Expense Adapted from 2016 CDA guidelines

GLP-1 AGONIST Advantages Good Excellent A1c lowering Hypoglycemia rare Disadvantages Expense Injection Weight reduction in most GI side effects Adapted from 2016 CDA guidelines

INSULIN Advantages Excellent A1c lowering Inexpensive insulin s are available Disadvantages Hypoglycemia risk Injection Weight gain Adapted from 2016 CDA guidelines

SECRETAGOGUE Advantages Good A1c lowering Inexpensive/covered Disadvantages Hypoglycemia risk Weight gain Adapted from 2016 CDA guidelines

SGLT-2 INHIBITOR Advantages Good A1c lowering Disadvantages Expense Weight loss Mycotic infections + UTI s Hypoglycemia rare Slight BP lowering Interpreted through 2016 CDA guideline format

TZD Advantages Good A1c lowering Hypoglycemia rare Relatively inexpensive Combo drug available Disadvantages Cardiovascular signals (Rosi) Weight gain Edema Adapted from 2016 CDA guidelines

Antihyperglycemic agents and Renal Function CKD Stage: 5 4 3 2 1 egfr (ml/min/1.73 m 2 ): <15 15 29 30 59 60 89 90 Insulin Secretagogues Alpha-glucosidase Inhibitor GLP-1R agonists Biguanide DPP-4 inhibitors Acarbose Not recommended 25 Canagliflozin 25 45 100 mg 60* Dapagliflozin 60 Empagliflozin 45 60* Thiazolidinediones 30 Contraindicated Not recommended Caution and/or reduce dose * = do not initiate if egfr <60 ml/min Adapted from: Product Monographs as of March 2016 Harper W et al. Can J Diabetes 2015;39:440. Metformin 30 60 Alogliptin Not recommended 6.25 mg 30 12.5 mg 50 Linagliptin 15 Saxagliptin 15 2.5 mg 50 Sitagliptin 25 mg 30 50 mg 50 Albiglutide 50 Dulaglutide 50 Exenatide (BID/QW) 30 50 Liraglutide 30 50 Gliclazide/Glimepiride 15 30 SGLT2 inhibitors Glyburide 30 50 Repaglinide Safe No dose adjustment but close monitoring of renal function 11/2016

SECOND-LINE AGENTS FOR GLYCEMIC CONTROL FOR TYPE 2 DIABETES: ARE NEWER AGENTS BETTER? According to our model, all regimens resulted in similar LYs and QALYs regardless of glycemic control goal, but the regimen with sulfonylurea incurred significantly lower cost per QALY and resulted in the longest time to insulin dependence. An HbA1c goal of 7% (53 mmol/mol) produced higher QALYs compared with a goal of 8% (64 mmol/mol) for all regimens. Zhang et al. Diabetes Care Feb 2014

YES Fewer side effects especially weight gain More thorough testing and safety data More metabolically sensible mechanisms Less risk for hypoglycemia

NO We really don t know the long term safety Expense not justified The majority of people tolerate these just as well There is no evidence for improved outcomes

RECOMMENDATION 4 4. In adults with type 2 diabetes with clinical cardiovascular disease in whom glycemic targets are not met, an antihyperglycemic agent with demonstrated cardiovascular outcome benefit should be added to reduce the risk of major cardiovascular events (Grade 1, Level 1A for empagliflozin ; Grade 1, Level 1A for liraglutide if age 50 years; Grade D, Consensus for liraglutide if age <50 years). 11/2016

LINK BETWEEN HYPOGLYCEMIA AND ACUTE CV EVENTS IN T2DM 57 Retrospective, observational study assessing association between hypoglycemia and acute CV events 3.1% patients had hypoglycemia during evaluation period Patients with hypoglycemia had 79% higher odds for acute CV events vs. patients with no hypoglycemia Johnston SS et al. Diabetes Care 2011; 34:1164-70

RECOMMENDATION 5 5. Choice of additional pharmacological agents should be individualized taking into consideration [Grade D, consensus] Patient Characteristics Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Clinical cardiovascular disease Co-morbidities (renal, CHF, hepatic) Preferences of the patient Access to treatment Agent Characteristics BG lowering efficacy and durability Risk of inducing hypoglycemia Effect on weight Effect on cardiovascular outcomes Side effects Contraindications Cost and coverage 2016

BACK TO OUR CASE

CASE STUDY - KATHERINE 59 year old teacher Diagnosed with Type 2 DM three years ago. 5 kg weight gain as she went through menopause. Despite early interventions with diet and exercise and progressive doses of metformin her weight has increased by 1 kg in the last year HgA1c risen to 7.3%.

CASE STUDY - KATHERINE Current meds: Metformin 1000 mg bid Citalopram 20 mg od Ramipril 10 mg od Simvastatin 40 mg od ECASA 81 mg od BP 130/84 All her other blood work is within target with a normal renal function

DID ANYONE CHANGE THEIR MIND?

WHAT WOULD WE DO?

CONCLUSION In most patients with Type 2 DM start with lifestyle and metformin The decision on a second agents should depend on individual patient characteristics, preference, and co morbidity

QUESTIONS?