Faculty/Presenter Disclosure

Transcription

1 DIABETES UPATE 2016

2 Faculty/Presenter Disclosure Faculty/Presenter: tina kader Relationships with commercial interests: Grants/research support: BI; Sanofi Speaker s bureau/honoraria: eli lilly sanofi; medtronic; novonordisk;merck BMS; Astraxeneca;Jansen; Takeda Consulting fees: eli lilly sanofi; medtronic; novonordisk;merck Other: [insert company/organization name(s) here]

3 OBJECTIVES UPDATED GUIDELINES CASE PRESENTATION right agent for right patient SGLT2 INHIBITORS GLP 1 where do they fit in

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5 OBJECTIVES UPDATED GUIDELINES CASE PRESENTATION right agent for right patient SGLT2 INHIBITORS GLP 1 where do they fit in

6 guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association

7 Guideline Targets Achieved 60% 50% 57% % of patients 45% 30% 15% 36% 13% 0% A1c ( 7%) (n=5103) LDL ( 2.0 mmol/l) (n=5069) SBP/DBP (<130/80 mm HG) (n=5099) All 3 Endpoints (A1c, LDL, BP) (n=5104) Leiter LA et al. Can J Diabetes 2013; in press guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association

8 At Diagnosis, the Pathological Process of Type 2 Diabetes is Already Well Underway Postprandial plasma Pre-diabetes Diabetes glucose Fasting glucose Normal Therapy escalation Insulin resistance Normal Figure adapted from Kendall DM, et al. Am J Med 2009;122(6 Supp):S37-S50 Insulin secretion β-cell deficit Microvascular Time (years) Macrovascular complications

9 Diagnosis of Diabetes 2013 guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association FPG 7.0 mmol/l Fasting = no caloric intake for at least 8 hours or A1C 6.5% (in adults) Using a standardized, validated assay, in the absence of factors that affect the accuracy of the A1C and not for suspected type 1 diabetes or 2hPG in a 75-g OGTT 11.1 mmol/l or Random PG 11.1 mmol/l Random= any time of the day, without regard to the interval since the last meal 2hPG = 2-hour plasma glucose; FPG = fasting plasma glucose; OGTT = oral glucose tolerance test; PG = plasma glucose

10 Diagnosis of Prediabetes* 2013 Test Result Prediabetes Category Fasting Plasma Glucose (mmol/l) Impaired fasting glucose (IFG) 2-hr Plasma Glucose in a 75-g Oral Glucose Tolerance Test (mmol/l) Glycated Hemoglobin (A1C) (%) Impaired glucose tolerance (IGT) Prediabetes * Prediabetes = IFG, IGT or A1C % high risk of developing T2DM guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association

11 Individualizing A1C Targets 2013 Consider % if: which must be balanced against the risk of hypoglycemia guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright guidelines.diabetes.ca 2013 Canadian BANTING Diabetes Association ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association

12 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 PRIORITY: A1C 8.5% 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 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

13 Class -glucosidase inhibitor (acarbose) Incretin agents: DPP-4 Inhibitors GLP-1R agonists Add another class of agent best suited to the individual (agents listed in alphabetical order): Relative A1C Lowering Hypoglycemia Weight Effect in Cardiovascular Outcome Trial Other therapeutic considerations Rare neutral to Improved postprandial control, GI sideeffects to Rare Rare Neutral to Neutral (alo, saxa, sita) Neutral (lixi) Caution with saxagliptin in heart failure GI side-effects Insulin Yes Neutral (glar) No dose ceiling, flexible regimens $-$$$$ Cost $$ $$$ $$$$ Insulin secretagogue: Meglitinide Sulfonylurea Yes Yes Less hypoglycemia in context of missed meals but usually requires TID to QID dosing Gliclazide and glimepiride associated with less hypoglycemia than glyburide $$ $ SGLT2 inhibitors to Rare Superiority (empa in T2DM patients with clinical CVD) Genital infections, UTI, hypotension, 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; lixi=lixisenatide; empa=empagliflozin 2016

14 Antihyperglycemic agents and Renal Function CKD Stage: egfr (ml/min/1.73 m 2 ): < Insulin Secretagogues Alpha-glucosidase Inhibitor GLP-1R agonists Biguanide DPP-4 inhibitors SGLT2 inhibitors Acarbose Not recommended 25 Canagliflozin mg 60* Dapagliflozin 60 Empagliflozin 45 Thiazolidinediones 30 Adapted from: Product Monographs as of March 2016 Harper W et al. Can J Diabetes 2015;39:440. Metformin Alogliptin Not recommended 6.25 mg mg 50 Linagliptin 15 Saxagliptin mg 50 Sitagliptin 25 mg mg 50 Albiglutide 50 Dulaglutide 50 Exenatide (BID/QW) Liraglutide** 50 Gliclazide/Glimepiride Glyburide Repaglinide Contraindicated 30 Not recommended 60* Caution and/or reduce dose * = do not initiate if egfr <60 ml/min Safe 2016

15 guidelines.diabetes.ca BANTING ( ) diabetes.ca

16 Who Should Receive Statins? (regardless of baseline LDL-C) yrs old or Macrovascular disease or Microvascular disease or DM >15 yrs duration and age >30 years or Warrants therapy based on the 2012 Canadian Cardiovascular Society lipid guidelines Among women with childbearing potential, statins should only be used in the presence of proper preconception counseling & reliable contraception. Stop statins prior to conception. guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association

17 Vascular Protection Checklist 2013 A A1C optimal glycemic control (usually 7%) B BP optimal blood pressure control (<130/80) C Cholesterol LDL 2.0 mmol/l if decided to treat D Drugs to protect the heart (regardless of baseline BP or LDL) A ACEi or ARB S Statin A ASA if indicated E Exercise / Eating healthily regular physical activity, achieve and maintain healthy body weight S Smoking cessation guidelines.diabetes.ca BANTING ( ) diabetes.ca Copyright 2013 Canadian Diabetes Association

18 OBJECTIVES UPDATED GUIDELINES CASE PRESENTATION right agent for right patient SGLT2 INHIBITORS GLP 1 where do they fit in

19 Meet Juan-Garcia 61 years old Diagnosed 6 years ago BMI: 31 kg/m 2 Weight: 95 kg Occupation: supervisor Lifestyle: busy

20 Juan-Garcia s History Treated with metformin and gliclazide MR for 5 years, but A1C has crept up to 9.2% WHAT ARE OPTIONS Bedtime insulin Glp1 agonist dpp4 inhibitor Sglt2 inhibitor

21 GLYBERIDE METFORMIN (took years to get approved in the states)

22 erglycemic Medications Alpha-glucosidase Inhibitors Delay the absorption of glucose from starch and sucrose Biguanides Reduce hepatic gluconeogenesis Insulin Secretagogues Sulfonylureas and meglitinides stimulate insulin secretion SGLT2 Inhibitors Reduce the reabsorption of glucose by the kidneys : glucosuria Liver Adipose Tissues Muscles Pancreas Kidneys Intestine Thiazolidinediones Improve insulin resistance DPP-4 Inhibitors and GLP-1R Agonists Increase insulin secretion, inhibit glucagon secretion

23 secretagogues biguanides dpp4 inhibitors glp1 agonists slgt2 inhibitors tzd alphaglucosidase inhibitors basal insulin basal plus mdi

24 Drugs with Different Mechanisms of Action are Required to Address the Numerous T2DM Pathophysiological Defects The ominous octet 1-3 GLP-1 RA; TZDs, DPP4i, SU GLP-1 RA; DPP4i; TZDs Decreased insulin secretion β Decreased incretin effect Increased lipolysis GLP-1 RA; DPP4i Increased glucagon secretion Hyperglycemia Increased glucose reabsorption SGLT2 inhibitors Metformin, Increased TZDs, HGP GLP-1 RA Neurotransmitter dysfunction GLP-1 RA Decreased glucose uptake TZDs, metformin HGP, hepatic glucose production

25 OBJECTIVES UPDATED GUIDELINES CASE PRESENTATION right agent for right patient SGLT2 INHIBITORS GLP 1 where do they fit in

26 GLP-1 Receptor Agonists (albiglutide, exenatide, exenatide QW, dulaglutide, liraglutide) Advantages Reduce postprandial glucose A1C lowering 1.0% as add-on to MET Significant weight loss Reduction in SBP Rare hypoglycemia Available as once weekly option (albiglutide, dulaglutide, exenatide QW) MET: metformin; MEN2: multiple endocrine neoplasia type 2; SBP: systolic blood pressure. 1. CDA. Can J Diabetes. 2013;37(suppl 1):S61-8; 2. Saxenda Product Monograph. Novo Nordisk Canada Inc. Disadvantages Nausea and vomiting Administration by injection Use in renal impairment limited: Exenatide: caution for GFR ml/min, contraindicated GFR <30 ml/min Liraglutide: caution for GFR ml/min; not recommended GFR <30 ml/min Rare reported cases of pancreatitis (causality unproven) Parafollicular cell hyperplasia in rats and mice Contraindicated with personal/family history of medullary thyroid cancer or in patients with MEN2 26

27 Summary of Incretin Actions on Different Target Tissues: GLP-1 Heart Brain Neuroprotection Appetite Gastric Emptying Stomach Liver (indirect effect) Cardioprotection Cardiac Output _ GLP-1 GI Tract Insulin Secretion Glucose Production Adapted from Drucker DJ, Cell Metab. 2006;3: Muscle (indirect effect) + Glucose Uptake β-cell Neogenesis* β-cell Apoptosis* Glucagon Secretion * pre-clinical data

28 Primary and Exploratory Outcomes. Marso SP et al. N Engl J Med 2016;375:

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30 SGLT2 Inhibitors (canagliflozin, dapagliflozin, empagliflozin) Advantages A1C lowering 0.5% to 1.0% as add-on to MET Significant weight loss Reduction in SBP Rare hypoglycemia Efficacy independent of insulin secretion or action CV superiority (EMPA in patients with established CVD) Disadvantages Urinary and genital tract infections Osmotic diuresis and volume related adverse effects Caution or not recommended with loop diuretics Small increase in LDL-C Not for use in patients with moderate or severe renal impairment Rare DKA (may be euglycemic) Newer agents with unknown longterm safety DKA: Diabetic ketoacidosis; EMPA: empagliflozin; LDL-C:low-density lipoprotein cholesterol; MET: metformin; SBP: systolic blood pressure. 1. Tahrani et al. Lancet Diabetes Endocrinol. 2013;1:140-51; 2. Zinman et al. N Engl J Med Sep 17. [Epub ahead of print]. 30

31 Equivalent of 476 kcal? or Equivalent physical activity for a 200-lb. person 9 cookies Walking (3 km/hr) for 1.9 hours 43 sugar packs

32 Mechanism of action: SGLT2 inhibitors Glomerulus Collecting tubule S1 Proximal tubule Distal tubule Filtration of glucose X SGLT2 SGLT1 S3 Glucose reabsorption Loop of Henle Inhibition by canagliflozin Reduction in A1c and weight No Glycosuria glycosuria g/day = calories/day SGLT=Sodium/GLucose co-transporter Abdul-Ghani MA, DeFronzo, RA. Endocr Pract. 2008;14(6): Bays H. Curr Med Res Opin. 2009;25(3): Product monograph, INVOKANA (canagliflozin), Janssen Inc., 2014 Product monograph, FORXIGA (dapagliflozin), Astra Zenaca, 2014

33 SGLT2 Inhibitors : Dosage and administration Canagliflozin Starting dose 100 mg Dapagliflozin Starting dose 5 mg Empagliflozin Starting dose 10 mg Dose could be increase if well tolerated to 300 mg and require additional glycemic control. Dose could be increased if well tolerated to 10 mg. Dose could be increase if well tolerated to 25 mg and require additional glycemic control. Monographie d INVOKANA. Janssen Inc., novembre Monographie de FORXIGA. AstraZeneca, décembre Monographie de JARDIANCE, Boehringer Ingelheim (Canada) Ltée, juillet 2015

34 EMPA-REG Outcome: Primary Composite Endpoint CV Death, MI, or Stroke Patients With Event (%) PBO EMPA HR p value CV death, MI, stroke (%) CV deaths (%) <0.001 Nonfatal MI (%) Nonfatal stroke (%) Hosp. heart failure (%) All-Cause mortality (%) <0.001 Placebo HR 0.86 (95% CI 0.74, 0.99) p<0.001 for noninferiority p=0.04 for superiority Empagliflozin No. of patients Empagliflozin Placebo Months EMPA-REG Outcome: n=7020 patients (mean age 63 years) with type 2 diabetes and established CVD. Median duration of follow-up: 3.1 years. Mean diff in A1C: 0.4% at wk 94. Mean diff in SBP 4 mm Hg. CI: confidence interval; CV: cardiovascular; EMPA: empagliflozin; HR: hazard ratio; MI: myocardial infarction; PBO: placebo. 1. Zinman B et al. N Engl J Med. 2015;373:

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37 Multifactorial Intervention on CV Outcomes N = 160 with type 2 diabetes and microalbuminuria 60 Primary composite outcome* (%) % RRR P = 0.01 NNT=5 Conventional 20 Intensive Follow-up (months) *CV death, MI, stroke, CABG/PCI, amputation, PAD surgery Adjusted for duration of diabetes, age, sex, smoking, CV disease Gæde P, et al. N Engl J Med 2003; 348:

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