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Home , Canagliflozin

6/17/2019

1. Oral Secretagogues (e.g. ) 2. 3. Alpha glucosidase inhibitors New medicines for 4. 5. GLP-1 receptor agonists 6. DPP-4 inhibitors 7. SGLT2 inhibitors 8. 9. 10. (; colesevelam)

ADA/EASD algorithm Glycemic targets

6 classes of drugs: • Younger patients with short diabetes duration HbA1c < 7% reduces risk of microvascular & macrovascular Metformin complications (aim for 6% if it can be done safely) GLP1 receptor agonists/DPP 4 inhibitors Sulfonylureas (+other secretagogues) • Patients with history of severe & advanced SGLT2 inhibitors atherosclerosis should not aim for < 7% Insulin metformin Metformin Metformin More complex • Elderly with limited life expectancy <8% + another + 2 others insulin regimens • ~ 6 % In making therapeutic decision take into account efficacy, hypoglycemia risk, effect on weight, major side effects, cost, cardiovascular & renal benefits • Children ages 0-6 <8.5% ; 6-12 <8%; 13-19 <7.5% 6/17/2019

GLP1 receptor agonists and DPP4 inhibitors

GLP-1 receptor agonists GLP-1 receptor agonists : adverse events (Byetta) 5 & 10mcg Inject twice daily. Reduce dose 5 mcg stage 3 CKD. Do not use for GFR < 30 * Placebo Exenatide (n= 483) (963) Exenatide LAR 2mg powder - Resuspend in diluent and inject SC (Bydureon) resuspend weekly Nausea 18 % 44 % 0.6, 1.2 and 1.8 mg Usual dose 1.2 mg daily. No dose Vomiting 4 13 (Victoza) change in renal failure Diarrhea 6 13 30 mg Weekly. No dose change renal failure Feeling jittery 4 9 (Tanzeum) Dizziness 6 9 0.75, 1.5 mg Usually does 0.75 mg weekly. No dose Headache 6 9 (Trulicity) change renal failure. Dyspepsia 3 6 10, 20 mcg 20 mcg daily. No dose change eGFR (Adlyxin) >30* 0.25, 0.5, 1 mg 0.5 mg weekly. No dose change renal (Ozempic) failure

* Exenatide and lixisenatide renal excreted. Others metabolized by proteolysis 6/17/2019

Caution using GLP-1 receptor agonists in patients Differences between the GLP1 receptor agonists with renal impairment • GI symptoms less with weekly treatment FDA: 16 cases of renal kidney impairment and 62 cases of • Weight loss greater with semaglutide compared to acute kidney injury in patients taking exenatide liraglutide, albiglutide, dulaglutide, exenatide • ~ 6% of patients on exenatide and 2.4% on lixisenatide - preexisting kidney disease develop antibodies that attenuate glycemic response. - one or more risk factors for kidney disease. - nausea, vomiting, and diarrhea - possible that these side effects caused volume depletion and renal injury.

DPP 4 inhibitors DPP4 inhibitors: adverse events (Januvia) 25, 50, 100 mg 100 mg daily usual dose. Use 50 mg for GFR 30-50; 25 mg for < 30 Saxagliptin (Onglyza) 2.5, 5 mg 5 mg daily usual dose. Use 2.5 mg • Nasopharyngitis; upper respiratory infections if GFR< 50 or if taking strong CYP/3A4 inhibitors (Tradjenta) 5 mg 5 mg daily. No dose changerenal • Allergic reactions – angioedema, anaphylaxis, failure (Nesina) 6.25,12.5,25 mg 25 mg daily usual dose. Use 12.5 exfoliative dermatologic reactions mg for GFR 30-60; 6.25 mg for < 30 • Joint pains that resolve with a month of stopping the drug 6/17/2019

Postmarketing study with – 16, 492 T2D randomized to Saxagliptin or Placebo. Mean followup Differences between the DPP4 Inhibitors 2.1 years • Linagliptin- no dose adjustment for renal or disease 289, 3.5% on Saxagliptin vs 228, 2.8% on placebo admitted to hospital for heart failure (P=0.007) • Sitagliptin/saxagliptin/alogliptin adjust dose if renal disease

Scirica et al Circ. 130:1579 (2014) • Adjust saxagliptin dose if a strong CYP3A4/5 inhibitor is prescribed

Alogliptin 106 admission for heart failure (3.1%) vs Placebo 89 (2.9%) NS (5380 patients, median followup 18 months)

Cases of pancreatitis during clinical trials with GLP-1 receptor agonists No cases of pancreatitis reported during clinical

Experimental drug Comparator group trials with sitagliptin and saxagliptin. FDA adverse (placebo; other reporting mechanism 2009 – 88 cases of acute meds; insulin) pancreatitis in patients on sitagliptin

Exenatide 8 2 In one study with linagliptin, 8 cases of Liraglutide 13 1 pancreatitis in 4687 patients exposed to drug Albiglutide 6 2 (4311 patient yrs) & no cases in 1183 patients on Dulaglutide 5 1 placebo (433 patient yrs). Lixisenatide 21 14 Semaglutide 7 3 With alogliptin there were 11 cases in 5902 patients exposed to drug (0.2%) and 5 cases in 5183 on comparator drugs (<0.1%) 1.4-2.2 vs 0.6-0.9 cases of pancreatitis per 1000 patient years FDA reporting mechanism 30 cases of acute pancreatitis with exenatide 6/17/2019

SGLT2 inhibitors Canagliflozin (Invokana) 100 mg, 300 mg 100 mg daily usual dose. Can use (2013) 300 for additional glucose lowering (Farxiga) 5, 10 mg 10 mg daily usual dose. Use 5 mg if liver disease (Jardiance) 10,25 mg 10 mg daily usual dose. Can use 25 for additional glucose lowering SGLT2 inhibitors (Steglatro) 5, 15 mg 5 mg daily usual dose. Can use 15 for additional glucose lowering

SGLT 2 inhibitors lower threshold for glycosuria to 70 to 90 mg/dl 6/17/2019

100 mg canagliflozin lowers fasting and postprandial glucose SGLT2 inhibitors – adverse effects

Genital mycotic infections; urinary tract infections ~ 8-9 %

Case reports of pyelonephritis and septicemia

Necrotizing fasciitis of the perineum

Hypotension

Amputation (canagliflozin)

Bladder cancer and breast cancer (dapagliflozin) in clinical trials

Diabetic ketoacidosis if used in patients or patients labeled as having type 2 diabetes but who are very insulin deficient and ketosis prone

Differences between the SGLT2 inhibitors

• Inducers of glucuronosyl transferase enzymes (e.g. rifampin, , , ) increase metabolism of canagliflozin

• Dapagliflozin- higher rates of breast cancer and bladder cancer in clinical trials

• Canaglifozin & empagliflozin – do not use if eGFR < 45 Insulins

• Dapagliflozin & ertugliflozin- do no use if eGFR < 60 6/17/2019

Effective Insulin Preparations Onset of Action Peak Action Duration 4 T study - 708 T2D on metformin and/or lispro, 5–15 minutes 1–1.5 hours 3–4 hours aspart, glulisine add

Human regular 30–60 minutes 2 hours 6–8 hours

5-15 minutes 1 hour 3 hours Inhaled

Human NPH 2–4 hours 6–7 hours 10–20 hours

Twice daily 0.5 -1 hour Flat ~24 hours Novolog Mix 70/30 premeals

Insulin detemir 0.5 - 1 hour Flat 17 hours

Insulin degludec 0.5-1.5 hours Flat > 42 hours Used predetermined insulin titration algorithm

Fiasp – insulin aspart formulated with niacinamide ~ 10 minutes faster onset of action; and lower postprandial peak at 1 hour Holman et al N Engl J Med 357:1716 (2008)

At 1 year:

Novolog Mix and Novolog equal glucose lowering; detemir less (p<0.001)

-but greater wt.gain & hypoglycemia Clinical approach 6/17/2019

Decisions based on: ADA/EASD algorithm Efficacy – DPP4 and SGLT2 inhibitors moderate; others high

6 classes of drugs: Hypoglycemia risk – oral secretagogues and insulin have high risk

Metformin Effect on weight – metformin, DPP4 neutral; GLP1 receptor agonists, SGLT2 GLP1 receptor agonists/DPP 4 inhibitors inhibitors promote weight loss; oral secretagogues, insulin, Sulfonylureas (+other secretagogues) pioglitazone cause weight gain Pioglitazone SGLT2 inhibitors Major side effects - metformin: lactic acidosis Insulin pioglitazone: fractures; fluid retention, possib. bladder CA GLP1 receptor agonists: nausea, vomiting, possibly pancreatitis metformin Metformin Metformin More complex DPP4 inhibitors: may cause pancreatitis, joint pains + another + 2 others insulin regimens SGLT inhibitors: UTI; genital mycotic infections;

Cost – all except metformin and oral secretagogues are expensive In making therapeutic decision take into account efficacy, hypoglycemia risk, effect on weight, major side effects, cost, cardiovascular & renal benefits CVS benefit – Metformin, GLP1 receptor agonists, SGLT2 inhibitors

Renal benefit – SGLT2 inhibitors , possibly pioglitazone

Randomized controlled study of gastric banding vs lifestyle weight loss in 60 obese patients (BMI 30 to 40) with DM < 2 years

Weight loss

Dixon et al. JAMA 299: 316 (2008) 6/17/2019

Effect of exenatide therapy for 30 wks on glycemic control and Exenatide promotes weight loss when added to weight loss in metformin treated type 2 patients diet and exercise in obese nondiabetic subjects

0

0.2 0 -1 0.1 -0.5 0 -2 -0.1 -1 Total (73) -0.2 -3 Placebo Nausea (18) -0.3 -1.5 5 mcg No Nausea (55) -0.4 10 mcg Kg -4 -0.5 -2 -0.6 -5 -0.7 -2.5 -0.8 -6 -0.9 -3 Exenatide Placebo

Weight loss (kg) Rosenstock et al. Diabetes Care 33: 1173 (2010) % HbA1c lowering * Liraglutide 3 mg daily approved for weight loss DeFronzo et al. Diabetes 28:1092; 2005

Weight loss

Metformin Neutralor <1 kg *

GLP1 receptor agonists 1.5 to 4 kg **

SGLT2 inhibitors 2 to 5 kg

* Metformin ameliorates wt gain with sulfonylureas, thiazolidinediones, insulin Cardiovascular benefit and augments wt. loss with GLP1 receptor agonists

**Semaglutide > liraglutide, exenatide> lixisenatide, dulaglutide > albiglutide

Madsbad Diab Obes Metab 2016, 18:317 6/17/2019

2008 – FDA required manufacturers to perform a long term cardiovascular outcome trial for safety • Metformin (UKPDS) • Pioglitazone • GLP1 receptor agonists • Trials were designed to rule out unacceptable CV risk • SGLT2 inhibitors • Performed in patients with established CVD or high risk for CVD • Primary outcome = 3 point major adverse cardiovascular events (MACE) – CV death, nonfatal MI, nonfatal stroke ( + admission for unstable angina = 4 point MACE) • Designed to minimize glycemic differences between Rx and placebo arms – so Rx intensification in placebo arm. In most trials, Rx arm had better HbA1c • High proportion of patients on antihypertensives, lipid lowering and antiplatelet Rx

Metformin as the first line therapy for overweight type 2 DM 5238 DM with with CVS disease (MI, CAD, PVD or stroke). Addition of pioglitazone or placebo to preexisting meds. Primary endpoint - all cause mortality, MI, stroke, RR (95% CI) amputation or revascularization, ACS, cardiac intervention M v Int RR p 0.2 1 5 0.25 Any diabetes related endpoint p=0.0034 Metformin 0.68 0.0023 Pioglitazone Placebo Intensive 0.93 0.46 0.20 Diabetes related deaths p=0.11 Metformin 0.58 0.017 0.15 Intensive 0.80 0.19 All cause mortality p=0.021 HR 0.90 Metformin 0.64 0.011 0.10 P 0.095 Intensive 0.92 0.49 CI 0.80-1.02 Myocardial infarction p=0.12 0.05 Metformin 0.61 0.01 Intensive 0.79 0.11 Kaplan-MeierRate Event 0.0 N at risk: 5238 5018 4786 4619 4433 4268 693 (228) favors favors 0 6 12 18 24 30 36 metformin or Intensive = insulin or sulfonylurea ( 951) conventional Metformin (342) intensive Time From Randomization (mo) Conventional (411) UKPDS 1998, Lancet 12: 352 Adapted from Dormandy JA, et al. Lancet 2005;366:1279–89; proactive-results.com 6/17/2019

Incidence of heart failure : Control vs DM; PROactive Secondary Endpoint: Significant Difference vs placebo in Time placebo vs pioglitazone; insulin vs insulin + to Death, MI, or Stroke 12 0.15 % Pioglitazone 10 Placebo 8 0.10 6

4 HR 0.84 0.05 P 0.027 2 95% CI 0.72-0.98

Kaplan-MeierRate Event 0 0.0 Control DM DM DM DM DM N at risk: 5238 5012 4991 4877 4752 4651 786 (256) +placebo + pio +INS +INS +Rosi * ** 0 6 12 18 24 30 36 Time From Randomization (mo) * PROactive study Lancet 366:1279, 2005 ** Drug insert -- Rosiglitazone Adapted from Dormandy JA, et al. Lancet 2005;366:1279–89; proactive-results.com Composite secondary endpoint: all cause mortality, non-fatal MI (excluding silent MI), or stroke

Major adverse cardiac event (CV Notes Liraglutide and cardiovascular outcomes (Rx 4668; placebo 4672; death, non fatal MI, non fatal stroke median followup 3.8 yrs. Primary outcome - cardiovascular death; nonfatal MI; non fatal stroke Empagliflozin study Hazard ratio 0.86 No decrease in non (n= 7,020) 95% CI 0.74-0.99, p= 0.04 fatal MI, stroke. 50% had MI; 75 % CAD; Decrease CV death. 25 stroke; 20% PVD Decrease heart failure. Decrease albuminuria Primary outcome driven Canagliflozin study Hazard ratio 0.86 No decrease in non by decrease in CV death. (n = 10,142) 95% CI 0.75-0.97, p=0.02 fatal MI, stroke. Trend in lower non fatal 72% had CAD, CVD, Decrease heart failure. MI & non fatal stroke PVD Increase amputation. Decrease albuminuria

Rx group lower systolic Dapagliflozin study Hazard ratio 0.93 Decrease heart failure. BP (1.2mmHg), (n =10,186) 95% CI 0.84-1.03, p=0.17 Lower progression of HbA1c (0.4%), 40.6% had CAD, CVD, renal disease Weight (2.3 kg) PVD

Marso et al N Engl J Med 2016, 375:311 N Engl J Med 373: 2117 (2015); N Engl J Med 377:644 (2017); N Engl J Med 2019;380:347 6/17/2019

Summary

Major adverse cardiac event (CV death, non fatal MI, non fatal stroke)

DPP4 inhibitors (saxagliptin, No benefit alogliptin, sitagliptin Liraglutide Benefit Lixisenatide No benefit Semaglutide Benefit Exenatide LAR Probably beneficial but high drop out rate Renal benefits Empagliflozin Benefit Canaglilflozin Benefit but possible risk of amputation Dapagliflozin No benefit

Cefalu et al 2018 Diab Care 2018, 41:14

Empagliflozin reduces albuminuria Benefit lost when empagliflozin was discontinued

Cherney et al Lancet Diab Endocrinol 2017 5:610 6/17/2019

Canagliflozin in diabetic nephropathy (Credence trial, n=4401; primary outcome – ESRD, doubling of serum creatinine, death from renal or cardiovascular cause) Explanation of benefit of empagliflozin on albuminuria

Improved glucose Improved BP Reduced weight Improved intrarenal hemodynamics – supported by observation that benefit lost when drug stopped. Animal data that drug may reduce glomerulosclerosis and tubulointersitial fibrosis.

eGFR 30 - <90 and urine albumin >300 -5000 mcg/g creat; 60 % had stage 3 CKD; all on ACE or ARB; median FU 2.62 yrs

CV benefits of SGLT2 inhibitors are principally seen in patients with known atherosclerotic disease Secondary outcomes

HR Doubling serum Creatinine HR 0.60[0.48-076] MACE With atherosclerotic 0.86 (0.8-0.93) p <0.01 disease ESRD HR 0.68 [0.54-0.86] Multiple risk factors 1.0 (0.87-1.16) P 0.002 CVD Cardiovascular death HR 0.78 [0.61-1.00] p = 0.05 Heart failure and With atherosclerotic 0.76 (0.69-0.84) Heart failure hospitalization HR 0.61 [0.47-0.80] p<0.001 cardiovascular death disease ESRD, doubling serum HR 0.66 [0.53-0.81] p<0.001 Multiple risk factors 0.84 (0.69-1.01) creatinine, renal death MACE 3 HR 0.80 [0.67-0.95] p=0.01 Empagliflozin, canagliflozin and dapagliflozin trial data

No increased risk of amputation HbA1c 0.31 % lower; systolic BP lower 3.3 mm Hg, weight 0.8 kg Zelniker et al. Lancet 2019; 393:31 6/17/2019

Case 1 Summary UCSF 2013 – 66 yr old Caucasian man with DM 10 yrs. BMI 39.5 (290lb). On metformin for 5yrs. Stopped and on insulin. 50 units of glargine; 20 to 30 units insulin aspart premeals (total insulin ~ 125 units daily). Metformin is first line Peripheral neuropathy; nephropathy with urine albumin 3.1 g/g creatinine . Normal creatinine. HbA1c 8.1 % Second agent Started metformin + 40 insulin glargine; 15 to 20 insulin aspart premeals. Consider GLP1 receptor agonist if goal is wt. loss and/or patient has CAD HbA1c ~ 6.7%. Weight loss ~ 4 lbs.

Consider SGLT2 inhibitor if patient has diabetic kidney disease 2015 – GLP1 receptor agonist and insulin discontinued over few months. and/or heart failure HbA1c 5.9% on exenatide, metformin and .

Avoid SGLT2 inhibitor in patients with significant PVD 2019 – weight gain ~ 8 lbs after stopping smoking [BMI 40]. No exercise, dietary indiscretion, HbA1c 7.7%. Urine albumin 1.6 g/g creatinine.

Start empagliflozin. Stay on metformin and liraglutide, Stop glimepiride

Glycosuria and ketosis can be prolonged even after discontinuing A cautionary case: SGLT2 inhibitor use in type 1 diabetes the SGLT2 inhibitor

66 yr old man with DM, CAD, heart failure, stroke, dementia, admitted for surgery 23 year old Caucasian woman with T1D since age 8 – on injections for squamous cell carcinoma right forearm DM for many yrs. Metformin Rx. Started insulin 6/18 because HbA1c > 14%. HbA1c around 8 % Empagliflozin 25 mg 10/18. At time of admission, insulin glargine 53 units + Empagliflozin 25 mg. HbA1c 6.6 % Started on Canagliflozin Sept 2014 FH 4/6 sibs with DM – 3 on insulin, father DM on insulin, granddaughter Rx T1D

BG Na Creat AG (4-14) BOHB Urine Glucose levels dropped and so insulin doses were gradually decreased (<0.27) glucose At 343 123 1.61 17 Stop Insulin glargine dose reduced 30 to 10 to 8 to 2; also significant decrease admission empagliflozin; insulin glargine in bolus insulin doses 30 units Day 2- 4 72-120 129-130 12-16 No insulin Admitted to hospital with nausea, vomiting, dehydration and ketoacidosis Day 5 69 131 0.75 18 7.28 mmol/l >=500 Start insulin

Day 7 90 134 0.8 18 7.66 >=500

Day 8 ~ 180 134 13 3.39 >=500

Kelmenson et al; Pujara & Ioachimescu; 2017 J Invest Med. Case Reports 6/17/2019

Type 2 diabetes is a heterogeneous disease – clustering of genetic loci by multi-trait associations Costs for 1 month supply (standard doses; Walgreens, Costco) Traits Genetic loci Cluster 1 Low insulin MTNR1B, HHEX, Insulin production increased proinsulin TCF7L2, SLC30A8, and processing Metformin (4 ); (5); (50) HNF1A, and HNF1B Pioglitazone (12) Cluster 2 Low insulin ARAP1 Insulin production (48) Low proinsulin SPRY2 and processing DPP4 inhibitors ( ~ 330 ) Cluster 3 Waist circumference, FTO Obesity mediated SGLT2 inhibitors ( ~ 370) BMI, % body fat MC4R insulin resistance GLP1 receptor agonists (~500) Analog insulins ( ~ 400) Cluster 4 Insulin resistance PPARG, ANKRD55, Lipodystrophy like Low adiponectin ARL15, GRB14, IRS1, insulin resistance Old insulins ( ~ 150) Low HDL LYPLAL1 Increased triglycerides Cluster 5 Low triglycerides GCKR, TM6SF2, Liver lipid PNPLA3 metabolism. Association with NAFLD

Udler et al Plos Med 2018 Sept 15 e1002654

Make your own toolkit

Metformin

Oral secretagogues – glipizide, glimepiride, , repaglinide

DPP4 inhibitors – sitagliptin, linagliptin

GLP-1 receptor agonists – exenatide, liraglutide, semaglutide

Insulins – glargine U100, aspart, lispro, some premixed; NPH, Regular

SGLT2 inhibitor – empagliflozin, canagliflozin