Oral Hypoglycemics Roland Halil, BScPharm, ACPR, PharmD Clinical Pharmacist, Bruyere Academic Family Health Team Assistant Professor, Dept of Family Medicine, U of Ottawa July 2015

Objectives List the classes of oral antihyperglycemic agents and understand their place in therapy. Determine the relative efficacy, toxicity, cost and convenience of these agents before choosing therapy Rationalize prescribing of oral hypoglycemics Describe the current approach to pharmacologic management of type 2 diabetes.

Diagnosis of IFG, IGT Category FPG 2-hour after OGTT And/or IFG 6.1-6.9 N/A IFG (isolated) AND < 7.8 IGT (Isolated) < 6.1 7.8-11.0 IFG and IGT If 5.7-6.0 FPG + risk factor for diabetes/IGT order a 2hPG in a 75-OGTT. If 6.1-6.9 and no risk factor then IFG. Can J Diabetes 2003;27(2);S11

Diabetes: complications MACROvascular MICROvascular Stroke Diabetic eye disease (retinopathy & cataracts) Heart disease & hypertension Nephropathy Peripheral vascular disease Neuropathy Foot problems Foot problems

Kumamoto Study – HbA1c & Complications Intensive vs. conventional insulin therapy (N=110) Median A1c - 7.1% vs. 9.4% Retinopathy 16 Nephropathy 16 14 14 12 12 Rate per patient-years Rate per patient-years 10 10 8 8 6 6 7% 7% 4 4 2 2 5 6 7 8 9 10 11 5 6 7 8 9 10 11 HbA1c (%) HbA1c (%)

Prevention of Diabetes in IGT Lifestyle modification (see Finnish Diabetes Trial) Moderate weight loss (5%) (esp. abd fat) Regular physical activity > 150 minutes per week 58% RRR for type 2 Diabetes at four years Pharmacotherapy Multiple effective trials Eg. LIFE trial - Losartan  onset of new DM2 ***Based on the Finnish Diabetes Prevention Study and the Diabetes Prevention Program. Can J Diabetes 2003;27(2);S12

Pharmacological Prevention Studies Study Drug Duration (years) RRR (%) DPP Metformin 850mg BID 2.8 31 STOP-NIDDM Acarbose 100mg TID 3.3 30 DREAM Rosiglitazone 8mg daily 3.0 55 XENDOS Orlistat 120mg TID 4.0 37 DPP Diabetes Prevention Program Metformin was more effective in younger more obese subjects and less effective among older, thinner people. STOP-NIDDM - Study to Prevent Non-Insulin Dependent Diabetes Mellitus TRIPOD Troglitazone in Prevention of Diabetes This glitazone was withdrawn from the market and was never availabe in Canada XENDOS Xenical in the prevention of diabetes in obese swedish subjects Prouded an average weight loss of 5.8 kg DREAM Published Sept 2006. Included patients with IFG or IGT or both.

Non-Pharmacologic Tx Mainstay of therapy! Nutrition therapy ↓ A1c 1-2% CDA recommends counseling by a dietician for all type 2 diabetics www.cvtoolbox.com diet for Type 2 diabetes Can J Diabetes 2003;27(2);S27

Comparison of antihyperglycemics Pharmacotherapy Comparison of antihyperglycemics

Drug Classes Sensitizers Secretagogues Other

Drug Classes Sensitizers Secretagogues Other Metformin Glitazones Rosiglitazone (AVANDIA) Pioglitazone (ACTOS) Secretagogues Sulfonylureas Eg. Glyburide, Gliclazide Meglitinides Eg Repaglinide (GLUCONORM) Other Alpha glucosidase inhibitors (Acarbose) SGLT2 inhibitors (Canagliflozin)(Dapagliflozin ) DPP4 inhibitors (Gliptins) Incretin (GLP1) Analogues Sitagliptin, Linagliptin * Liraglutide (VICTOZA) (sc inj) Saxagliptin, Alogliptin * Exenatide (BYETTA) (sc inj)

Drug Classes Sensitizers Sensitizers – reduce insulin resistance Metformin Glitazones Rosiglitazone (AVANDIA) Pioglitazone (ACTOS) Sensitizers – reduce insulin resistance Increase glucose uptake & utilization in muscle and adipose tissue Reduce hepatic glucose output

Drug Classes Secretagogues ↑Basal & prandial insulin secretion, ↓hepatic gluconeogenesis Doesn’t correct impaired 1st phase insulin secretion; primarily affects 2nd phase Beta-cell sensitizer – primes glucose mediated insulin secretion (1st phase) Secretagogues Sulfonylureas Eg. Glyburide, Gliclazide Meglitinides Eg Repaglinide (GLUCONORM)

Drug Classes: Other Alpha glucosidase inhibitors (Acarbose) Competitive inhibitor of pancreatic α-amylase and intestinal brush border α-glucosidases, resulting in delayed hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose; Dose-dependent reduction in postprandial serum insulin and glucose peaks; inhibits the metabolism of sucrose to glucose and fructose SGLT2 inhibitors (Canagliflozin, Dapagliflozin) Inhibits sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, reducing reabsorption of filtered glucose from the tubular lumen and lowering the renal threshold for glucose (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations. DPP4 inhibitors (Gliptins) – (Sitagliptin, Lingliptin, Saxagliptin, Alogliptin) Prolongs the action of endogenous incretin hormones by blocking their breakdown by the enzyme, dipeptidyl peptidase-4 (DPP-4). This leads to more insulin release after eating. Incretin (GLP1) Analogues – (Liraglutide (Victoza®), Exenatide (Byetta®)) sc injection mimic endogenous incretin hormones

Rational Prescribing FOUR steps to Rational Prescribing: EFFICACY TOXICITY COST CONVENIENCE

EFFICACY – Ask… HARD Outcomes SURROGATE Outcomes Any mortality benefit? Any morbidity benefit? Then, SURROGATE Outcomes Clinically relevant?

EFFICACY HARD Outcomes SURROGATE Outcomes Mortality benefit Morbidity Metformin – UKPDS-34 trial Morbidity Reduction in microvascular complications (nephropathy, retinopathy, neuropathy) SURROGATE Outcomes Hgb-A1c reduction Blood glucose level reduction Fasting or Prandial Insulin Sparing Effects

Effect of Metformin on Event Rates in the UKPDS Diabetes-related endpoint 32% p=0.002 All-cause mortality  36% p=0.011  MI / CVA Diabetes-related death  42% p=0.017 But.. When added early to sulfonylurea  risk of DM-related death (?statistical anomaly?)

EFFICACY A) Surrogate Outcome - Hgb-A1c ~ 1% to 2% ~ 0.5% to 0.8% Metformin (1% - 2%) Sulfonylureas (1% - 2%) Repaglinide (1% - 1.5%) Glitazones (TZDs) (0.4% - 1.5%) Canagliflozin  (0.8 – 1%) ~ 0.5% to 0.8% Acarbose DPP4 inhibitors (‘Gliptins) Nateglinide Dapagliflozin Nathan DM, et al. Diabetes Care 2008 (Dec);31:1-11.

EFFICACY B) Surrogate Outcome - Insulin Sparing Effect METFORMIN ACARBOSE TZD’s (GLITAZONE’s) DPP4 inh (‘gliptins) Incretin Analogues (Liraglutide, Exenatide) SGLT2 inh (Canagliflozin, Dapagliflozin) = Weight neutral or weight negative = Reduction of hyperinsulinemia

TOXICITY – Ask… Serious / Fatal Side Effects Bothersome / Common s.e. Age? Newer agents = Less Safety Data Older agents = More Safety Data

TOXICITY – Serious / Fatal Glitazones CHF Fractures M.I. (rosiglitazone) Bladder Cancer (pioglitazone) Secretatgogues (Sulfonylureas & Meglitinides) Severe Hypoglycemia

TOXICITY – Serious / Fatal SGLT2 inhibitors (Canagliflozin) (Dapagliflozin) ?DKA “March 2013 to June 6, 2014, 20 cases of acidosis — diabetic ketoacidosis, ketoacidosis or ketosis — were recorded in the FDA Adverse Event Reporting System in patients treated with SGLT2 inhibitors. All patients required emergency room visits or hospitalization to treat the ketoacidosis.” http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm Unknown – too new Incretin Analogues – (Liraglutide, Exenatide (sc inj)) & DPP4 inhibitors (‘gliptins) ?Heart failure http://www.medscape.com/viewarticle/839315 ?Pancreatitis http://www.ncbi.nlm.nih.gov/pubmed/24352344 Unknown - too new

TOXICITY – Serious / Fatal Metformin ?Risk of Lactic Acidosis 0.03 cases / 1000 pt-yrs ~ 50% fatal When implicated: Metformin plasma levels are usually >5 μg/mL Cases - primarily diabetics w/ significant renal insufficiency, both intrinsic renal disease and renal hypoperfusion, w/ multiple medical/surgical problems and multiple medications.

Metformin Dosing Dosing recommendations with renal insufficiency: (CONTROVERSIAL) CrCl 60ml/min→ 1700 mg/day (Rxfiles) 2.5g/day (Roland) CrCl 30ml/min→ 850mg/day (Rxfiles) CrCl < 30ml/min→ Contraindicated (Rxfiles) 1g/day (>20mL/min) (Roland) If NO other risk factors, else D/C. Take home: assess OTHER RISK FACTORS for L.A.

Risk Factors - Lactic Acidosis Severe renal impairment (caution if CrCl < 30ml/min) and Hepatic disease alcoholism CHF COPD CRF Pneumonia Ongoing acidosis Lactic, keto etc.

TOXICITY - Bothersome 1) METFORMIN GI upset / diarrhea – Start low, go slow! Initial dose 250mg QDaily to BID B12 / folate deficiency / anemia (6 - 8/100) Reduced absorption – so, supplement Anorexia – usually transient Metallic taste

TOXICITY - Bothersome 2) Sulfonylureas: Sulfa skin reactions Rash / photosensitivity ~1% Weight gain (2-3kg) Mild Hypoglycemia: Most with glyburide. Least w/ glimepiride & gliclazide Requires consistent food intake Major episodes 1-2% (esp. in elderly)

TOXICITY - Bothersome 3) Glitazones: 4) Meglitinides: 5) Acarbose: Edema 4) Meglitinides: Hypoglycemia 5) Acarbose: GI upset / diarrhea / bloating Gliptins: GI upset, edema, ?infection Incretin analogues N/V/D, ?infection 8) SGLT2 inhibitors HyperK+, ARF, GU infection

Cost – Ask… Patient cost vs societal cost Rx cost? ODB coverage? Covered under other plans?

Cost From Rxfiles May 2013 Cost per 100 days therapy (in Sask.) (N.B. June 2015 costs ~ same) Cost per 100 days therapy (in Sask.) Alternatively, check ODB e-formulary N.B. Not true pt costs Comparative costs http://www.rxfiles.ca/rxfiles/uploads/documents/members/cht-diabetes.pdf

Convenience PO vs IV? QD vs QID?

Convenience Gliptin’s - QD Glitazones - QD SGLT2 inh - QD Sulfonylureas – QD to BID Metformin - QD to TID Meglitinides – QD to TID with meals Acarbose – QD to TID

Did I say, never? I meant NEVER! 1st line – METFORMIN 2nd line - SULFONYLUREA or INSULIN Meglitinide – if poor CrCL or irregular eating 3rd line – any other hypoglycemic if patients absolutely REFUSE insulin NEVER USE GLITAZONEs! Did I say, never? I meant NEVER!

Individualization of Drug Therapy www.rxfiles.ca Patient Factor Consider→ Possibly preferred drugs Renal Failure Repaglinide, Acarbose, ‘Gliptins Also: insulin Hepatic Disease Insulin, repaglinide, acarbose, Caution: glyburide, metformin, glitazones Hyoglycemia Metformin, Acarbose, (DPP4 inh),(SGLT2 inh) Also, repaglinide, gliclazide Obese Metformin, Acarbose Irregular Mealtimes Repaglinide (may be preferred over SU) PPBG >10mmol/L and FBG minimally ↑’d Repaglinide or Acarbose Rapid insulin if PPBG very high

Questions?