New medicines for type 2 diabetes 4. Thiazolidinediones 5. GLP-1 - - PowerPoint PPT Presentation

6/17/2019

New medicines for type 2 diabetes

1. Oral Secretagogues (e.g. sulfonylureas) 2. Metformin 3. Alpha glucosidase inhibitors 4. Thiazolidinediones 5. GLP-1 receptor agonists 6. DPP-4 inhibitors 7. SGLT2 inhibitors 8. Insulin 9. Pramlintide

• 10. (Bromocriptine; colesevelam)

ADA/EASD algorithm

6 classes of drugs: Metformin GLP1 receptor agonists/DPP 4 inhibitors Sulfonylureas (+other secretagogues) Pioglitazone SGLT2 inhibitors Insulin metformin Metformin + another Metformin + 2 others More complex insulin regimens In making therapeutic decision take into account efficacy, hypoglycemia risk, effect on weight, major side effects, cost, cardiovascular & renal benefits

Glycemic targets

• Younger patients with short diabetes duration HbA1c <

7% reduces risk of microvascular & macrovascular complications (aim for 6% if it can be done safely)

• Patients with history of severe hypoglycemia & advanced

atherosclerosis should not aim for < 7%

• Elderly with limited life expectancy <8%
• Pregnancy ~ 6 %
• 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 Exenatide (Byetta) 5 & 10mcg Inject twice daily. Reduce dose 5 mcg stage 3 CKD. Do not use for GFR < 30 * Exenatide LAR (Bydureon) 2mg powder - resuspend Resuspend in diluent and inject SC weekly Liraglutide (Victoza) 0.6, 1.2 and 1.8 mg Usual dose 1.2 mg daily. No dose change in renal failure Albiglutide (Tanzeum) 30 mg

• Weekly. No dose change renal failure

Dulaglutide (Trulicity) 0.75, 1.5 mg Usually does 0.75 mg weekly. No dose change renal failure. Lixisenatide (Adlyxin) 10, 20 mcg 20 mcg daily. No dose change eGFR >30* Semaglutide (Ozempic) 0.25, 0.5, 1 mg 0.5 mg weekly. No dose change renal failure

* Exenatide and lixisenatide renal excreted. Others metabolized by proteolysis

GLP-1 receptor agonists : adverse events

Placebo Exenatide (n= 483) (963) Nausea 18 % 44 % Vomiting 4 13 Diarrhea 6 13 Feeling jittery 4 9 Dizziness 6 9 Headache 6 9 Dyspepsia 3 6

6/17/2019

Caution using GLP-1 receptor agonists in patients with renal impairment

FDA: 16 cases of renal kidney impairment and 62 cases of acute kidney injury in patients taking exenatide

• preexisting kidney disease
• ne or more risk factors for kidney disease.
• nausea, vomiting, and diarrhea - possible that these side

effects caused volume depletion and renal injury. Differences between the GLP1 receptor agonists

• GI symptoms less with weekly treatment
• Weight loss greater with semaglutide compared to

liraglutide, albiglutide, dulaglutide, exenatide

• ~ 6% of patients on exenatide and 2.4% on lixisenatide

develop antibodies that attenuate glycemic response.

DPP 4 inhibitors Sitagliptin (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 if GFR< 50 or if taking strong CYP/3A4 inhibitors Linagliptin (Tradjenta) 5 mg 5 mg daily. No dose change renal failure Alogliptin (Nesina) 6.25,12.5,25 mg 25 mg daily usual dose. Use 12.5 mg for GFR 30-60; 6.25 mg for < 30

DPP4 inhibitors: adverse events

• Nasopharyngitis; upper respiratory infections
• Allergic reactions – angioedema, anaphylaxis,

exfoliative dermatologic reactions

• Joint pains that resolve with a month of stopping

the drug

6/17/2019

Postmarketing study with Saxagliptin – 16, 492 T2D randomized to Saxagliptin or Placebo. Mean followup 2.1 years 289, 3.5% on Saxagliptin vs 228, 2.8% on placebo admitted to hospital for heart failure (P=0.007)

Scirica et al Circ. 130:1579 (2014) Alogliptin 106 admission for heart failure (3.1%) vs Placebo 89 (2.9%) NS (5380 patients, median followup 18 months)

Differences between the DPP4 Inhibitors

• Linagliptin- no dose adjustment for renal or liver disease
• Sitagliptin/saxagliptin/alogliptin adjust dose if renal disease
• Adjust saxagliptin dose if a strong CYP3A4/5 inhibitor is

prescribed Cases of pancreatitis during clinical trials with GLP-1 receptor agonists

Experimental drug Comparator group (placebo; other meds; insulin)

Exenatide 8 2 Liraglutide 13 1 Albiglutide 6 2 Dulaglutide 5 1 Lixisenatide 21 14 Semaglutide 7 3 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

No cases of pancreatitis reported during clinical trials with sitagliptin and saxagliptin. FDA adverse reporting mechanism 2009 – 88 cases of acute pancreatitis in patients on sitagliptin In one study with linagliptin, 8 cases of pancreatitis in 4687 patients exposed to drug (4311 patient yrs) & no cases in 1183 patients on placebo (433 patient yrs). With alogliptin there were 11 cases in 5902 patients exposed to drug (0.2%) and 5 cases in 5183 on comparator drugs (<0.1%)

6/17/2019

SGLT2 inhibitors

SGLT2 inhibitors Canagliflozin (Invokana) (2013) 100 mg, 300 mg 100 mg daily usual dose. Can use 300 for additional glucose lowering Dapagliflozin (Farxiga) 5, 10 mg 10 mg daily usual dose. Use 5 mg if liver disease Empagliflozin (Jardiance) 10,25 mg 10 mg daily usual dose. Can use 25 for additional glucose lowering Ertugliflozin (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 Type 1 diabetes 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,

phenytoin, phenobarbital, ritonavir) increase metabolism of canagliflozin

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

clinical trials

• Canaglifozin & empagliflozin – do not use if eGFR < 45
• Dapagliflozin & ertugliflozin- do no use if eGFR < 60

Insulins

6/17/2019

Insulin Preparations Onset of Action Peak Action Effective Duration Insulins lispro, aspart, glulisine 5–15 minutes 1–1.5 hours 3–4 hours Human regular 30–60 minutes 2 hours 6–8 hours Inhaled regular insulin 5-15 minutes 1 hour 3 hours Human NPH 2–4 hours 6–7 hours 10–20 hours Insulin glargine 0.5 - 1 hour Flat ~24 hours Insulin detemir 0.5 - 1 hour Flat 17 hours Insulin degludec 0.5-1.5 hours Flat > 42 hours

Fiasp – insulin aspart formulated with niacinamide ~ 10 minutes faster onset

• f action; and lower postprandial peak at 1 hour

4 T study - 708 T2D on metformin and/or sulfonylurea Twice daily Novolog Mix 70/30 Insulin aspart premeals Insulin detemir add Used predetermined insulin titration algorithm

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

ADA/EASD algorithm

6 classes of drugs: Metformin GLP1 receptor agonists/DPP 4 inhibitors Sulfonylureas (+other secretagogues) Pioglitazone SGLT2 inhibitors Insulin metformin Metformin + another Metformin + 2 others More complex insulin regimens In making therapeutic decision take into account efficacy, hypoglycemia risk, effect on weight, major side effects, cost, cardiovascular & renal benefits Decisions based on: Efficacy – DPP4 and SGLT2 inhibitors moderate; others high Hypoglycemia risk – oral secretagogues and insulin have high risk Effect on weight – metformin, DPP4 neutral; GLP1 receptor agonists, SGLT2 inhibitors promote weight loss; oral secretagogues, insulin, pioglitazone cause weight gain Major side effects - metformin: lactic acidosis pioglitazone: fractures; fluid retention, possib. bladder CA GLP1 receptor agonists: nausea, vomiting, possibly pancreatitis DPP4 inhibitors: may cause pancreatitis, joint pains SGLT inhibitors: UTI; genital mycotic infections; dehydration Cost – all except metformin and oral secretagogues are expensive CVS benefit – Metformin, GLP1 receptor agonists, SGLT2 inhibitors Renal benefit – SGLT2 inhibitors , possibly pioglitazone

Weight loss

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

Dixon et al. JAMA 299: 316 (2008)

6/17/2019

• 0.9
• 0.8
• 0.7
• 0.6
• 0.5
• 0.4
• 0.3
• 0.2
• 0.1

0.1 0.2

• 3
• 2.5
• 2
• 1.5
• 1
• 0.5

Placebo 5 mcg 10 mcg

% HbA1c lowering

Effect of exenatide therapy for 30 wks on glycemic control and weight loss in metformin treated type 2 patients

DeFronzo et al. Diabetes 28:1092; 2005

Weight loss (kg)

Exenatide promotes weight loss when added to diet and exercise in obese nondiabetic subjects

• 6
• 5
• 4
• 3
• 2
• 1

Exenatide Placebo

Total (73)

Nausea (18) No Nausea (55)

Rosenstock et al. Diabetes Care 33: 1173 (2010)

Kg * Liraglutide 3 mg daily approved for weight loss

Weight loss Metformin Neutral or <1 kg * GLP1 receptor agonists 1.5 to 4 kg ** SGLT2 inhibitors 2 to 5 kg

* Metformin ameliorates wt gain with sulfonylureas, thiazolidinediones, insulin and augments wt. loss with GLP1 receptor agonists **Semaglutide > liraglutide, exenatide> lixisenatide, dulaglutide > albiglutide

Madsbad Diab Obes Metab 2016, 18:317

Cardiovascular benefit

6/17/2019

2008 – FDA required manufacturers to perform a long term cardiovascular

• utcome trial for safety
• Trials were designed to rule out unacceptable CV risk
• 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 (UKPDS)
• Pioglitazone
• GLP1 receptor agonists
• SGLT2 inhibitors

M v Int RR p Any diabetes related endpoint Metformin Intensive p=0.0034 0.68 0.93 0.0023 0.46 Diabetes related deaths Metformin Intensive p=0.11 0.58 0.80 0.017 0.19 All cause mortality Metformin Intensive p=0.021 0.64 0.92 0.011 0.49 Myocardial infarction Metformin Intensive p=0.12 0.61 0.79 0.01 0.11

favors metformin or intensive favors conventional

RR (95% CI)

Metformin as the first line therapy for overweight type 2 DM

Intensive = insulin or sulfonylurea ( 951) Metformin (342) Conventional (411) 0.2 1 5

UKPDS 1998, Lancet 12: 352

5238 DM with with CVS disease (MI, CAD, PVD or stroke). Addition of pioglitazone

• r placebo to preexisting meds. Primary endpoint - all cause mortality, MI, stroke,

amputation or revascularization, ACS, cardiac intervention

Kaplan-Meier Event Rate Time From Randomization (mo)

5238 5018 4786 4619 4433 4268 693 (228) 0.25 0.20 0.15 0.10 0.05 0.0 Placebo Pioglitazone

HR 0.90 P 0.095 CI 0.80-1.02 6 12 18 24 30 36

Adapted from Dormandy JA, et al. Lancet 2005;366:1279–89; proactive-results.com

N at risk:

6/17/2019

PROactive Secondary Endpoint: Significant Difference vs placebo in Time to Death, MI, or Stroke

Kaplan-Meier Event Rate Time From Randomization (mo)

5238 5012 4991 4877 4752 4651 786 (256) 0.10 0.05 0.15 0.0 Placebo Pioglitazone

6 12 18 24 30 36

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

N at risk:

HR 0.84 P 0.027 95% CI 0.72-0.98

2 4 6 8 10 12

Control DM DM DM DM DM +placebo + pio +INS +INS +Rosi * **

* PROactive study Lancet 366:1279, 2005

** Drug insert -- Rosiglitazone

Incidence of heart failure : Control vs DM; placebo vs pioglitazone; insulin vs insulin + rosiglitazone %

Liraglutide and cardiovascular outcomes (Rx 4668; placebo 4672; median followup 3.8 yrs. Primary outcome - cardiovascular death; nonfatal MI; non fatal stroke Primary outcome driven by decrease in CV death. Trend in lower non fatal MI & non fatal stroke Rx group lower systolic BP (1.2mmHg), HbA1c (0.4%), Weight (2.3 kg)

Marso et al N Engl J Med 2016, 375:311

Major adverse cardiac event (CV death, non fatal MI, non fatal stroke Notes Empagliflozin study (n= 7,020) 50% had MI; 75 % CAD; 25 stroke; 20% PVD Hazard ratio 0.86 95% CI 0.74-0.99, p= 0.04 No decrease in non fatal MI, stroke. Decrease CV death. Decrease heart failure. Decrease albuminuria Canagliflozin study (n = 10,142) 72% had CAD, CVD, PVD Hazard ratio 0.86 95% CI 0.75-0.97, p=0.02 No decrease in non fatal MI, stroke. Decrease heart failure. Increase amputation. Decrease albuminuria Dapagliflozin study (n =10,186) 40.6% had CAD, CVD, PVD Hazard ratio 0.93 95% CI 0.84-1.03, p=0.17 Decrease heart failure. Lower progression of renal disease

N Engl J Med 373: 2117 (2015); N Engl J Med 377:644 (2017); N Engl J Med 2019;380:347

6/17/2019

Major adverse cardiac event (CV death, non fatal MI, non fatal stroke) DPP4 inhibitors (saxagliptin, alogliptin, sitagliptin No benefit Liraglutide Benefit Lixisenatide No benefit Semaglutide Benefit Exenatide LAR Probably beneficial but high drop

• ut rate

Empagliflozin Benefit Canaglilflozin Benefit but possible risk of amputation Dapagliflozin No benefit

Cefalu et al 2018 Diab Care 2018, 41:14

Summary

Renal benefits

Empagliflozin reduces albuminuria

Cherney et al Lancet Diab Endocrinol 2017 5:610

Benefit lost when empagliflozin was discontinued

6/17/2019

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

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

Doubling serum Creatinine HR 0.60[0.48-076] p <0.01 ESRD HR 0.68 [0.54-0.86] P 0.002 Cardiovascular death HR 0.78 [0.61-1.00] p = 0.05 Heart failure hospitalization HR 0.61 [0.47-0.80] p<0.001 ESRD, doubling serum creatinine, renal death HR 0.66 [0.53-0.81] p<0.001 MACE 3 HR 0.80 [0.67-0.95] p=0.01

Secondary outcomes No increased risk of amputation HbA1c 0.31 % lower; systolic BP lower 3.3 mm Hg, weight 0.8 kg CV benefits of SGLT2 inhibitors are principally seen in patients with known atherosclerotic disease

HR MACE With atherosclerotic disease 0.86 (0.8-0.93) Multiple risk factors CVD 1.0 (0.87-1.16) Heart failure and cardiovascular death With atherosclerotic disease 0.76 (0.69-0.84) Multiple risk factors 0.84 (0.69-1.01)

Empagliflozin, canagliflozin and dapagliflozin trial data

Zelniker et al. Lancet 2019; 393:31

6/17/2019

Summary

Metformin is first line Second agent Consider GLP1 receptor agonist if goal is wt. loss and/or patient has CAD Consider SGLT2 inhibitor if patient has diabetic kidney disease and/or heart failure Avoid SGLT2 inhibitor in patients with significant PVD

Case 1

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). Peripheral neuropathy; nephropathy with urine albumin 3.1 g/g creatinine . Normal creatinine. HbA1c 8.1 % Started metformin + 40 insulin glargine; 15 to 20 insulin aspart premeals. HbA1c ~ 6.7%. Weight loss ~ 4 lbs. 2015 – GLP1 receptor agonist and insulin discontinued over few months. HbA1c 5.9% on exenatide, metformin and glimepiride. 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 A cautionary case: SGLT2 inhibitor use in type 1 diabetes 23 year old Caucasian woman with T1D since age 8 – on injections HbA1c around 8 % Started on Canagliflozin Sept 2014 Glucose levels dropped and so insulin doses were gradually decreased Insulin glargine dose reduced 30 to 10 to 8 to 2; also significant decrease in bolus insulin doses Admitted to hospital with nausea, vomiting, dehydration and ketoacidosis Glycosuria and ketosis can be prolonged even after discontinuing the SGLT2 inhibitor

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

BG Na Creat AG (4-14) BOHB (<0.27) Urine glucose At admission 343 123 1.61 17 Stop empagliflozin; insulin glargine 30 units Day 2- 4 72-120 129-130 12-16 No insulin 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

Traits Genetic loci Cluster 1 Low insulin increased proinsulin MTNR1B, HHEX, TCF7L2, SLC30A8, HNF1A, and HNF1B Insulin production and processing Cluster 2 Low insulin Low proinsulin ARAP1 SPRY2 Insulin production and processing Cluster 3 Waist circumference, BMI, % body fat FTO MC4R Obesity mediated insulin resistance Cluster 4 Insulin resistance Low adiponectin Low HDL Increased triglycerides PPARG, ANKRD55, ARL15, GRB14, IRS1, LYPLAL1 Lipodystrophy like insulin resistance Cluster 5 Low triglycerides GCKR, TM6SF2, PNPLA3 Liver lipid metabolism. Association with NAFLD

Udler et al Plos Med 2018 Sept 15 e1002654

Costs for 1 month supply (standard doses; Walgreens, Costco) Metformin (4 ); glipizide (5); repaglinide (50) Pioglitazone (12) Acarbose (48) DPP4 inhibitors ( ~ 330 ) SGLT2 inhibitors ( ~ 370) GLP1 receptor agonists (~500) Analog insulins ( ~ 400) Old insulins ( ~ 150) Make your own toolkit Metformin Oral secretagogues – glipizide, glimepiride, nateglinide, 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