MANAGING DIABETES IN 2016 WHAT TO ADD, WHEN AND WHY?

Faculty: Maria Wolfs MD, MHSc, FRCPC Assistant Professor, University of Toronto Staff Endocrinologist, St. Michael's Hospital Relationships with commercial interests: Not Applicable Potential for conflict(s) of interest: Not Applicable

Mitigating Potential Bias All the recommendations involving clinical medicine are based on evidence that is accepted within the profession All scientific research referred to, reported, or used is in the support or justification of patient care Recommendations conform to the generally accepted standards.

Learning Objectives At the end of the session, participants will be able to: Identify patient factors that impact the addition of non-insulin pharmacotherapy in Type 2 Diabetes Discuss the glycemic and cardiovascular end-point evidence among non-insulin pharmacotherapies in Type 2 Diabetes Apply evidence based diabetes management to individual patient care

Diabetes increases CV risk 2-3 fold Lancet 2010; 375: 2215 22

Diabetes and heart failure Gilbert R Lancet 2015;385;2107-17

Absolute Risk of MI by Diabetes Status # of events per 1000 person years Booth, Kapral, Fung, Tu, Lancet. 2006;367:29-36

Yes No Does lowering glucose decrease the risk of microvascular complications? Maybe

Yes Does lowering glucose decrease the risk of microvascular complications?

Glycemic lowering trials ACCORD 2008 ADVANCE 2008 2014 5y FU VADT 2009 2015 10y FU DCCT 1993 2005 10y FU UKPDS-SU 1998 2008 10y FU UKPDS-MET 1998 2008 10y FU Kumamato 1995 2000 Mean age (y) 62 ± 7 66 ± 6 60 ± 9 27 54 ± 9 53 ± 8 48 ± 12 Duration DM (y) 10 8 11.5 2.6 New dx New dx 6.5 Baseline HbA1c 8.3 7.5 9.4 8.8 9 9 9.1 (%) Prior CV event (%) 35 32 40 None Excluded Excluded Excluded Study duration (y) 3.5 5 5.6 6.5 10 10.7 8 Int vs std HbA1c 6.4 vs 7.5 6.5 vs 7.3 6.9 vs 8.4 7.2 vs 9.1 7 vs 7.9 7.4 vs 8.0 7.2 vs 9.4 (%) Micro benefit Nephro Nephro Yes Yes No Yes Macro benefit Major harms Nonfatal MI (ARR 1%) Mortality (ARI 1%) No No (5y FU) No Yes (10y FU) No Yes (in EDIC) No Yes (10y FU) Yes Hypo Hypo Hypo Hypo Hypo Hypo Med Clin N Am 99 (2015) 47 67

Microvascular complications ACCORD 2008 ADVANCE 2008 2014 5y FU VADT 2009 2015 10y FU DCCT 1993 2005 10y FU UKPDS-SU 1998 2008 10y FU UKPDS-MET 1998 2008 10y FU Kumamato 1995 2000 Mean age (y) 62 ± 7 66 ± 6 60 ± 9 27 54 ± 9 53 ± 8 48 ± 12 Duration DM (y) 10 8 11.5 2.6 New dx New dx 6.5 Baseline HbA1c 8.3 7.5 9.4 8.8 9 9 9.1 (%) Prior CV event (%) 35 32 40 None Excluded Excluded Excluded Study duration (y) 3.5 5 5.6 6.5 10 10.7 8 Int vs std HbA1c 6.4 vs 7.5 6.5 vs 7.3 6.9 vs 8.4 7.2 vs 9.1 7 vs 7.9 7.4 vs 8.0 7.2 vs 9.4 (%) Micro benefit Nephro Nephro Yes Yes No Yes Macro benefit Major harms Nonfatal MI (ARR 1%) Mortality (ARI 1%) No No (5y FU) No Yes (10y FU) No Yes (in EDIC) No Yes (10y FU) Yes Hypo Hypo Hypo Hypo Hypo Hypo Med Clin N Am 99 (2015) 47 67

Microvascular complications ACCORD 2008 ADVANCE 2008 2014 5y FU VADT 2009 2015 10y FU DCCT 1993 2005 10y FU UKPDS-SU 1998 2008 10y FU UKPDS-MET 1998 2008 10y FU Kumamato 1995 2000 Mean age (y) 62 ± 7 66 ± 6 60 ± 9 27 54 ± 9 53 ± 8 48 ± 12 Duration DM (y) 10 8 11.5 2.6 New dx New dx 6.5 Baseline HbA1c 8.3 7.5 9.4 8.8 9 9 9.1 (%) Prior CV event (%) 35 32 40 None Excluded Excluded Excluded Study duration (y) 3.5 5 5.6 6.5 10 10.7 8 1% in A1c = 40% microvascular complications Int vs std HbA1c 6.4 vs 7.5 6.5 vs 7.3 6.9 vs 8.4 7.2 vs 9.1 7 vs 7.9 7.4 vs 8.0 7.2 vs 9.4 (%) Micro benefit Nephro Nephro Yes Yes No Yes Macro benefit Major harms Nonfatal MI (ARR 1%) Mortality (ARI 1%) No No (5y FU) No Yes (10y FU) No Yes (in EDIC) No Yes (10y FU) Yes Hypo Hypo Hypo Hypo Hypo Hypo Med Clin N Am 99 (2015) 47 67

Yes No Does lowering glucose decrease the risk of macrovascular complications? Maybe

Maybe Does lowering glucose decrease the risk of macrovascular complications?

Macrovascular complications ACCORD 2008 ADVANCE 2008 2014 5y FU VADT 2009 2015 10y FU DCCT 1993 2005 10y FU UKPDS-SU 1998 2008 10y FU UKPDS-MET 1998 2008 10y FU Kumamato 1995 2000 Mean age (y) 62 ± 7 66 ± 6 60 ± 9 27 54 ± 9 53 ± 8 48 ± 12 Duration DM (y) 10 8 11.5 2.6 New dx New dx 6.5 Baseline HbA1c 8.3 7.5 9.4 8.8 9 9 9.1 (%) Prior CV event (%) 35 32 40 None Excluded Excluded Excluded Study duration (y) 3.5 5 5.6 6.5 10 10.7 8 Int vs std HbA1c 6.4 vs 7.5 6.5 vs 7.3 6.9 vs 8.4 7.2 vs 9.1 7 vs 7.9 7.4 vs 8.0 7.2 vs 9.4 (%) Micro benefit Nephro Nephro Yes Yes No Yes Macro benefit Major harms Nonfatal MI (ARR 1%) Mortality (ARI 1%) No No (5y FU) Med Clin N Am 99 (2015) 47 67 No Yes (10y FU) No Yes (in EDIC) No Yes (10y FU) Yes Hypo Hypo Hypo Hypo Hypo Hypo

Glycemic control and CV events Major Cardiovascular event 0.91 (0.84-0.99) Turnbull FM, et al. Diabetologia 2009; 52:2288 2298

Glycemic control and CV events Myocardial infarction 0.85 (0.76-0.94) Turnbull FM, et al. Diabetologia 2009; 52:2288 2298

Intensive Glycemic Control DM2 Benefit If No Hx of Vascular Disease History of macrovascular disease Absent History of microvascular disease Absent 0.84 (0.75-0.94) 0.89 (0.81-0.98) Turnbull FM, et al. Diabetologia 2009; 52:2288 2298

Rosiglitazone increases risk of MI Nissen SE, Wolski K. N Engl J Med 2007;356:2457-2471.

2008 U.S. FDA CV Safety Guidance for New Antihyperglycemic Agents Upper bound of the 95% CI for the estimated risk ratio of <1.3* Upper bound of the 95% CI for the estimated risk ratio of 1.3-1.8* Upper bound of the 95% CI for the estimated risk ratio of >1.8 Approvable: May be no need for postmarketing study Approvable: need for postmarketing study { Not approvable * With a reassuring point estimate for overall CV risk { Superiority Non-inferiority Non-inferiority { Inferior Underpowered Non-inferiority Boundary HR 1.3 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2.0 2.2 Hazard ratio Participants with higher CV risk 2 years of CV safety data Prospective, independent and blinded adjudication of CV events (include MACE)** Design and conduct should allow for future meta-analysis Hirshberg B, Raz I. Diabetes Care. 2011;34:S101-6.

Case Mr. Singh 59 year old man Self-employed contractor A1c 6.3% 75g OGTT Fasting glucose 6.2 mmol/l (<6.1) 2hr glucose 8.9 mmol/l (<7.8)

Goldenberg R, Punthakee Z, Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada:Definition, Classification and Diagnosis of Diabetes, Prediabetes and Metabolic Syndrome. Can J Diabetes 2013;37(suppl 1):S61-S68. Diagnosis of Prediabetes Test Result Prediabetes Category Fasting Plasma Glucose (mmol/l) 2-hr Plasma Glucose in a 75-g Oral Glucose Tolerance Test (mmol/l) Glycated Hemoglobin (A1C) (%) 6.1-6.9 Impaired fasting glucose (IFG) 7.8 11.0 Impaired glucose tolerance (IGT) 6.0-6.4 Prediabetes

What is his risk of progressing to diabetes in the next five years? 25% 50% 75% 100%

Progression to diabetes FPG of 6.1 to 6.9 mmol/l + A1C of 6.0% to 6.4% predictive of 100% progression to type 2 diabetes over 5-year period Heianza Y Diabetic Med 20012;29;e279 e285 Zhang X et al. Diabetes Care. 2010;33:1665-1673

What would you do next? Reassess with labs in 6 months Refer to local diabetes education centre (DEC) Refer to endocrinologist Start metformin Start acarbose

Diabetes Prevention Program Trial Metformin 31% Lifestyle 58% Diabetes Prevention Program (DPP) Research Group. N Engl J Med 2002;346:393-403.

Acarbose progression to DM2 by 25% 25% Chiasson JL, et al. Lancet 2002;359:2072-77.

Metformin Medication Coverage on ODB Formulary Cost for 30 Day Supply Metformin 500mg tablets Glumetza (extended release metformin) Yes 1 g BID - $7 No 1g (2x500mg tabs) daily - $35 2 g (2x1000mg tabs) daily - $73 Henry Halapy, RPh, Diabetes Pharmacist, St. Michael s Hospital 2015

Metformin and risk of MI 0.90 (0.74-1.09) Boussageon R et al. PLoS Med 2012. 9(4): e1001204. doi:10.1371/journal.pmed.1001204

Metformin

Mr. Singh 4 years later 63 year old contractor Attended local DEC x 2 visit Widowed gained 5 kg Metformin 1 g bid Labs A1c 7.6% egfr > 60 ml/min ACR 1.2 mg/mmol

What would you do next? Refer to local diabetes education centre (DEC) Refer to endocrinologist Acarbose Secretagogue (e.g. Gliclazide MR) DPP4 inhibitor (e.g. Sitagliptin) SGLT2 inhibitor (e.g. Canagliflozin, Empagliflozin) Incretin (e.g. Liraglutide)

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 α-glucosidase inhibitor (acarbose) Rare Neutral to Improved postprandial control, GI side-effects $$ DPP-4 Inhibitors Rare Neutral to alo, saxa, sita: Neutral Caution with saxagliptin in heart failure $$$ GLP-1R agonists to Rare lira: Superiority in T2DM patients with clinical CVD lixi: Neutral 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 empa: Superiority in T2DM patients with clinical CVD 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) $$$

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 α-glucosidase inhibitor (acarbose) Rare Neutral to Improved postprandial control, GI side-effects $$ DPP-4 Inhibitors Rare Neutral to alo, saxa, sita: Caution with saxagliptin in heart failure $$$ α-glucosidase Neutral inhibitor GLP-1R agonists to Rare lira: Superiority GI side-effects $$$$ in T2DM patients with clinical CVD lixi: Neutral Insulin Yes Neutral (glar) No dose ceiling, flexible regimens $-$$$$ Insulin secretagogue: Meglitinide Sulfonylurea Yes Yes Less hypoglycemia in context of missed meals but usually requires TID to QID dosing Gliclazide and glimepiride associated with less hypoglycemia than glyburide $$ $ SGLT2 inhibitors to Rare empa: Superiority in T2DM patients with clinical CVD 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) $$$

Alpha-glucosidase inhibitors Medication Coverage on ODB Formulary Cost for 30 Day Supply Alpha-glucosidase inhibitors Acarbose (Glucobay ) LU code 175 failed treatment with other drugs 176 in combination with other drugs 50mg tabs TID $24 100 mg tabs TID - $34 Henry Halapy, RPh, Diabetes Pharmacist, St. Michael s Hospital 2015

Acarbose and CV events Myocardial infarction Hanefeld M et al. Eur Heart J 2004;25(1):10-16

Acarbose GI side effect slow titration! Week Breakfast Lunch Dinner 1 - - 25 2-25 25 3 25 25 25 4 25 25 50 5 25 50 50 6 50 50 50

Acarbose

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 α-glucosidase inhibitor (acarbose) Rare Neutral to Improved postprandial control, GI side-effects $$ Insulin secretagogues DPP-4 Inhibitors Rare Neutral to alo, saxa, sita: Caution with saxagliptin in heart failure Neutral $$$ GLP-1R agonists to Rare lira: Superiority in T2DM patients with clinical CVD lixi: Neutral 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 empa: Superiority in T2DM patients with clinical CVD 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) $$$

Insulin secretagogues Medication Coverage on ODB Formulary Cost for 30 Day Supply Insulin secretagogues Glyburide Yes 10 mg BID - $4 Gliclazide (Diamicron ) Yes 160 mg BID - $7 Gliclazide MR (Diamicron MR ) Yes 4 x 30mg MR tabs - $11 2 x 60mg MR - $15 Glimepiride (Amaryl ) No 8 mg daily - $59 Repaglinide (Gluconorm ) EAP i.e. Section 8 4 mg QID -$58 Nateglinide (Starlix ) No 180 mg TID - $106 Henry Halapy, RPh, Diabetes Pharmacist, St. Michael s Hospital 2015

Sulphonylureas and CV events Outcome # trials OR 95% CI p Mortality 37 1.22 1.01-1.49 0.047 MACE 30 1.08 0.86-1.36 0.52 Stroke 16 1.28 1.03-1.60 0.026 MI 23 0.88 0.75-1.04 0.13 CV death 23 1.40 0.87-2.26 0.17 Monami M et al. Diabetes, Obesity & Metabolism; 2013; 15:938-953

Mr. Singh 4 years later 63 year old contractor Attended local DEC x 2 visit Widowed gained 5 kg Metformin 1 g bid Labs A1c 7.6% egfr > 60 ml/min ACR 1.2 mg/mmol

Mr. Singh 6 years later 69 year old retired man Metformin 1g bid Gliclazide MR 60mg bid Recent diagnosis of CAD and CHF Labs A1c 7.9% egfr 68 mmol/min ACR 2.4 mg/mmol

What would you do next? Refer to local diabetes education centre (DEC) Refer to endocrinologist DPP4 inhibitor (e.g. Sitagliptin) SGLT2 inhibitor (e.g. Empagliflozin) Incretin (e.g. Liraglutide)

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 α-glucosidase inhibitor (acarbose) Rare Neutral to Improved postprandial control, GI side-effects $$ DPP-4 Inhibitors Rare Neutral to alo, saxa, sita: Neutral Caution with saxagliptin in heart failure $$$ GLP-1R agonists to Rare lira: Superiority in T2DM patients with clinical CVD lixi: Neutral GI side-effects $$$$ Insulin SGLT2 inhibitors Yes Neutral (glar) No dose ceiling, flexible regimens $-$$$$ Insulin secretagogue: Meglitinide Yes $$ Sulfonylurea 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 empa: Superiority in T2DM patients with clinical CVD 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) $$$

SGLT2 Inhibitors

SGLT2 Inhibitors Medication Coverage on ODB Formulary Cost for 30 Day Supply SGLT-2 Inhibitors Canagliflozin (Invokana ) Dapaglifozin (Forxiga ) Empagliflozin (Jardiance ) Yes 100 mg daily - $78 300 mg daily - $78 Yes 5 mg daily - $91 10 mg daily - $91 Yes 10 mg daily - $92 25 mg daily - $92 Henry Halapy, RPh, Diabetes Pharmacist, St. Michael s Hospital

CV outcomes SGLT2 Inhibitor Courtesy of A. Y. Y. Cheng 2016

Empagliflozin and CV Outcomes Primary outcome CV death 14% 38% Death from any cause 32% CHF hospitalization 35% Zinman B et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1504720

Genital infections Genital infections 5% male balanitis (if not circumcised) 10% female 200-300ml more urine per day (1 extra void) Zinman B et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1504720

SGLT2 Inhibitor CV end point studies CANVAS CANagliflozin cardiovascular Assessment Study Estimated Study Completion Date June 2017 DECLARE-TIMI 58 Dapagliflozin Effect on CardiovascuLAR Events Estimated Primary Completion Date April 2019

SGLT2 Inhibitor safety data Euglycemic DKA Decreased insulin dose Decreased renal clearance of ketone bodies SGLT2 inhibitors increase glucagon secretion http://www.fda.gov/drugs/drugsafety/ucm446845.htm Increased risk of fractures and bone loss Canagliflozin studies http://www.fda.gov/drugs/drugsafety/ucm461449.htm

Incretin therapies

Incretin therapies GLP-1 t ½ 90 seconds DPP4 degrades GLP-1

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 α-glucosidase inhibitor (acarbose) DPP-4 Inhibitors Rare Neutral to Improved postprandial control, GI side-effects $$ GLP-1R agonist Rare Neutral to alo, saxa, sita: Caution with saxagliptin in heart failure $$$ Neutral GLP-1R agonists to Rare lira: Superiority in T2DM patients with clinical CVD lixi: Neutral 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 empa: Superiority in T2DM patients with clinical CVD 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) $$$

Incretin therapies Medication Coverage on ODB Formulary Cost for 30 Day Supply GLP-1 agonists Liraglutide (Victoza ) Dulaglutide (Trulicity ) Exenatide (Byetta ) No 1.2mg sc daily - $169 1.8mg sc daily - $253 No 0.75mg sc weekly - $277 1.5mg sc weekly - $277 No 5-10mcg sc BID - $144

LEADER Liraglutide 0.87 (0.78-0.97) ARR 1.9% NNT 52 N Engl J Med 2016;375:311-22.

SUSTAIN-6 Semaglutide 0.74 (0.58-0.95) ARR 2.3% NNT 43 N Engl J Med 2016;375:1834-44.

CV outcomes GLP-1 RA Courtesy of A. Y. Y. Cheng 2016

GLP-1 Agonists

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 α-glucosidase inhibitor (acarbose) Rare Neutral to Improved postprandial control, GI side-effects $$ DPP-4 Inhibitors Rare Neutral to alo, saxa, sita: Neutral Caution with saxagliptin in heart failure $$$ GLP-1R agonists to Rare lira: Superiority in T2DM patients GI side-effects $$$$ DPP-4 with inhibitors clinical CVD lixi: Neutral Insulin Yes Neutral (glar) No dose ceiling, flexible regimens $-$$$$ Insulin secretagogue: Meglitinide Sulfonylurea Yes Yes Less hypoglycemia in context of missed meals but usually requires TID to QID dosing Gliclazide and glimepiride associated with less hypoglycemia than glyburide $$ $ SGLT2 inhibitors to Rare empa: Superiority in T2DM patients with clinical CVD 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) $$$

Incretin therapies Medication Coverage on ODB Formulary Cost for 30 Day Supply DPP-IV inhibitors Sitagliptin (Januvia ) Saxagliptin (Onglyza ) Linagliptin (Trajenta ) Yes 25mg daily - $89 50mg daily - $89 100 mg daily -$89 Yes 2.5mg daily - $71 5mg daily - $85 Yes 5mg daily - $77

DPP4 Inhibitors + metformin Medication Coverage on ODB Formulary Cost for 30 Day Supply Combination pills Janumet (sitagliptin + metformin) Janumet XR (sitagliptin + sustained release metformin) Komboglyze (saxagliptin + metformin) Jentodueto (linagliptin + metformin) Yes 50/500mg BID - $96 50/850mg BID - $96 50mg/1000mg BID - $96 Yes 50/1000mg 2 tabs together once daily - $96 Yes 2.5mg/500mg BID - $76 2.5mg/850mg BID - $76 2.5mg/1000mg BID - $76 Yes 2.5mg/500mg BID - $80 2.5mg/850mg BID - $80 2.5mg/1000mg BID - $80

CV outcomes DPP4 inhibitor Courtesy of A. Y. Y. Cheng 2016

Scirica BM et al. N Engl J Med 2013;369:1317-1326. SAVOR-TIMI 53 Saxagliptin and CV events Hospitalization for Heart Failure 3.5% 2.8% 1.27 (1.07-1.51) 0.007

Heart Failure Hospitalization with DPP4i 1.14 (0.97 1.34)

DPP4 Inhibitors and CV endpoints Linagliptin CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA ) Estimated Study Completion Date: September 2018

DPP4 Inhibitor pancreas safety data Study arms SAVOR-TIMI 53 1,2 EXAMINE 3 TECOS 4 Placebo n=8,212 Saxaglptinn =8,220 Placebo n=2,679 Alogliptin n=2,701 Placebo n=7,339 Sitagliptin n=7,332 Acute 16 22 8 12 12 23 pancreatitis (n) Chronic pancreatitis 6 2 4 5 0 4 (n) Malignancy (%) 4.4 3.9 1.9 2.0 4.0 3.7 Pancreatic cancer (n) 12 5 0 0 14 9 1 Scirica BM et al. N Engl J Med. 2013;369:1317-2; 3 White WB et al. N Engl J Med. 2013;369:1327-35 2 Raz I et al. Diabetes Care. 2014;37:2435-41 4 Green JB et al. N Engl J Med. 2015. doi: 10.1056/NEJMoa1501352

DPP4 Inhibitor safety data Pancreatitis Insufficient data should be discontinued if pancreatitis confirmed should not be started if history of pancreatitis Pancreatic cancer monitoring for and reporting of pancreatic adverse effects by FDA and European Societies Joint pain http://www.fda.gov/drugs/drugsafety/ucm459579.htm

DPP4 - Inhibitors

Mr. Singh 69 year old retired man Metformin 1g bid Gliclazide MR 60mg bid Recent diagnosis of CAD and CHF Labs A1c 7.9% egfr 68 mmol/min ACR 2.4 mg/mmol

What would you do next? Refer to local diabetes education centre (DEC) Refer to endocrinologist DPP4 inhibitor (e.g. Sitagliptin) SGLT2 inhibitor (e.g. Empagliflozin) Incretin (e.g. Liraglutide)

Mr. Singh 4 years later 73 year old man Metformin 1 g bid Gliclazide MR 60 mg bid Empagliflozin 10 mg Labs A1c 7.2% egfr 44 ml/min ACR 4.2 mg/mmol

Which medications need adjustment for his renal impairment? Metformin Gliclazide MR Canagliflozin

Which medications need adjustment for renal impairment? Metformin Gliclazide MR Canagliflozin

Mr. Singh 3 months later 73 year old man Metformin 500 mg bid Gliclazide MR 60 mg bid Labs A1c 8.2 % egfr 42 ml/min

Refer to local DEC What would you do next? Refer to endocrinologist Start basal insulin (e.g. 10 units hs) Start mixed insulin Start linagliptin

Which oral medication should be discontinued with basal insulin? Metformin Secretagogues Acarbose DPP4 inhibitors SGLT2 inhibitors Incretins (e.g. liraglutide) Thiazoladinediones

Which oral medication should be discontinued with basal insulin? Metformin off label in Canada Secretagogues off label in Canada Acarbose DPP4 inhibitors linagliptin not approved SGLT2 inhibitors Incretins (e.g. liraglutide) Thiazoladinediones

Which oral medication should be discontinued with mixed insulin? Metformin Secretagogues Acarbose DPP4 inhibitors SGLT2 inhibitors Incretins (e.g. liraglutide) Thiazoladinediones

Which oral medication should be discontinued with mixed insulin? Metformin off label use in Canada Secretagogues Acarbose DPP4 inhibitors linagliptin not approved SGLT2 inhibitors Incretins (e.g. liraglutide) off label use Thiazoladinediones