Recent Advances in Diabetes 2017 - Blank Titleimcourseonline.com/files/2 Tuesday/4 Enrico... · Study SAVOR EXAMINE TECOS CAROLINA CARMELINA DPP4-i saxagliptin alogliptin sitagliptin

Recent Advances in Diabetes

2017

Enrico Cagliero, MD

MGH Diabetes Center

Harvard Medical School

Conflict of Interest Disclosure

Enrico Cagliero, MD

has no significant relationships with industry to report

Recent Advances in Diabetes

Rationale

Current guidelines

Cases

Therapies

CVD reduction

Goals of Treatment

Avoid acute complications of diabetes

Prevent micro and macrovascular

complications

Minimize hypoglycemia

Minimize weight gain

Increase quality of life

Individualize A1c goals !

Type 2 diabetes is a progressive disease Secondary Failure of Metformin Monotherapy

Diabetes Care 2010; 33:501-506

Standards of Medical Care in

Diabetes - 2017

Pharmacologic Approaches to

Glycemic Management

Diabetes Care 2017;40 (Suppl. 1):S64-S74

Antihyperglycemic therapy in type 2 diabetes: general recommendations

Diabetes Care 2017;40 (supplement1):S64-S74

Diabetes Care 2017;40 (supplement1):S64-S74

Combination injectable therapy for type 2 diabetes

Start with monotherapy with Metformin unless A1c > 9% (consider starting with dual therapy), or A1c > 10% (consider injectable therapy)

If monotherapy not effective after 3 months, proceed to dual therapy

If dual therapy not effective after 3 months, proceed to triple therapy

If triple therapy not effective after 3 months, proceed to basal insulin or GLP-1 analogs

Summary

How to choose among the new

therapies?

Why do we need more oral agents and not start

insulin therapy sooner?

Insulin associated with more hypoglycemia

Weight gain

Insulin still “refused” by many patients

Worse adherence to insulin injections

Some agents seem to provide CVD protection in

patient with pre-existing CVD disease

Novel Therapies for Type 2 Diabetes

GLP-1 Agonists

DPP-IV Inhibitors

Bile acid sequestrant

Bromocriptine

Sodium Glucose Co-Transporter 2 Inhibitors

Case 1

56 year old patient with type 2 diabetes referred by PCP

Presented with polyuria and polydipsia 2 years ago, random glucose ~ 400 mg/dl (22 mmol/l), HbA1c 11%

PMH: type 2 diabetes, HTN, hyperlipidemia

Patient started on Glipizide 20 mg qd, then titrated to 20 mg bid

Case 1

Patient started on insulin, NPH 30 units qHS,

titrated up to 78 units qHS

A1c down to 7.6

Lispro insulin then added at biggest meal of the

day

With insulin therapy A1c down to 7.2, weight up

by 22 pounds (10 kg)

What is the next step?

240

250

260

270

280

4

5

6

7

8

9

10

A1c

lb

1 2 3 4 5 6 7 8 9

Start NPH at bedtime

Exenatide added

years

Case 1

Lispro added at dinner

Case 1

Patient was switched from basal insulin plus

prandial to basal and Exenatide

Total insulin daily dose decreased from 95 units

to 75 units

Weight down 36 pounds (16 kg) on Exenatide

and kept off for > 9 years

A1c has remained < 7% for > 9 years

Incretin Hormones

Peptide hormones released by cells in the GI tract in response to nutrient stimulus

Most potent is Glucagon-Like Peptide 1 (GLP-1)

GLP-1 stimulates insulin secretion, suppresses glucagon secretion, delays GI tract motility and decrease appetite

In patients with type 2 diabetes GLP-1 levels are decreased

GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV)

Strategies To Prolong GLP-1 Action

GLP-1

(active) GLP-1

(inactive)

DPP-4

1. GLP-1 Agonists • Exenatide (Byetta®)

• Liraglutide (Victoza®)

• Exenatide ER (Bydureon®)

• Albiglutide (Tanzeum®)

• Dulaglutide (Trulicity®)

• Lixisenatide (Adlyxin®)

2. DPP-4 Inhibitors • Sitagliptin (Januvia®)

• Saxagliptin (Onglyza®)

• Linagliptin (Tradjenta®)

• Alogliptin (Nesina®)

Effects of Exenatide versus Aspart Insulin in Type 2 Diabetes

Nauck et al, Diabetologia 50:259-267, 2007

5 kg

Glucagon-Like Peptide 1 Receptor Agonist or Bolus Insulin with

Optimized Basal Insulin in Type 2 diabetes

Diabetes Care 2014;37:2763-2773

Comparison of adding weekly GLP-1 agonist

versus 3 daily Lispro injections

Diabetes Care 2014;37:2317-25

Exenatide once weekly versus twice daily

for the treatment of type 2 diabetes

Drucker et al. Lancet 372;1240-1250, 2008

Glucose Variability in Type 2 Diabetes

Basal + Oral Basal + GLP-1 Premixed Basal + Bolus

Hypoglycemia

(% of time)

0.6 0.1 1.9 2.5

Hyperglycemia

(% of time)

16.4 14.5 20.2 20.4

% of patients

with at least 1

hypoglycemic

event

21 18 35 57

Diabetes Care 2017;40:194-200

Risk of pancreatitis in patients treated with incretin-based therapies

Diabetologia 2014; 57:1320-24

GI adverse events of Liraglutide

Liraglutide Placebo Difference

Nausea 40 15 25%

Diarrhea 21 9 12

Constipation 20 9 11

Vomiting 16 4 12

Dyspepsia 9 3 6

Abdominal Pain 5 3 2

N Engl J Med 2015;373:11-22

GLP-1 Receptor Agonists

Exenatide (Byetta®)

Twice/day sc. Injections

Start with 5 mcg bid within 60 minutes of a meal and after 1 month increase the

dose to 10 mcg bid if eGFR > 30 ml/min

Liraglutide (Victoza®)

Once day sc injection, “use with caution in renal impairment”

Start with 0.6 mg qd for 1 week, then increase to 1.2 mg qd; may go to 1.8 mg qd

Exenatide ER (Bydureon®)

Once per week injection 2 mg, do not use if eGFR < 30 ml/min

Albiglutide (Tanzeum®)

Once per week injection, 30 mg, can increase to 50 mg if eGFR> 15 ml/min

Lixisenatide (Adlyxin®)

Once per day, start at 10 mcg per day and increase to 20 mcg/day after 2 weeks

Dulaglutide (Trulicity®)

Once per week, start 0.75 mg, can increase to 1.5 mg. No renal dose adjustement

needed

Case 2

78 year old patient with 12 years history of type 2 diabetes

Very physically active, competitive snowboarder

PMH: type 2 diabetes, HTN, hyperlipidemia, hypothyroidism, benign prostatic hypertrophy

Patient on Metformin 1000 mg bid, Aspirin 81 mg qd, Atorvastatin 10 mg qd, Levo-thryoxine 100 mcg qd, Lisinopril 20 mg qd

Normal renal function, A1c 8.3


Case 2

Years

Sitagliptin added

Case 2

A1c levels came back to goal and remained at

goal for > 2 years

DPP-4 Inhibitors well tolerated with minimal side

effects

Low risk of hypoglycemia, important in elderly

patients

No weight gain

Efficacy of sitagliptin in patients with type 2

diabetes

J Diabetes 2013; 5:68-79

Diabetes Medications for Adults With Type 2 Diabetes: An Update

Agency for Healthcare Research and Quality (US); 2016 Apr.Report No.: 16-EHC013-EF

http://effectivehealthcare.ahrq.gov/index.cfm/

Agency for Healthcare Research and Quality (US); 2016 Apr.Report No.: 16-EHC013-EF

Diabetes Medications for Adults With Type 2 Diabetes: An Update

http://effectivehealthcare.ahrq.gov/index.cfm/

Saxagliptin and Cardiovascular Outcomes in

Patients with Type 2 Diabetes Mellitus

N Engl J Med 2013;369:1317-26

Diabetes Care 2016 May; 39(5): 735-737

FDA warning: saxagliptin and alogliptin may increase the risk of heart failure,

particularly in patients who already have heart or kidney disease

DPP-4 Inhibitors and Heart Failure

Risk of pancreatitis in patients treated with incretin-based therapies

Diabetes Care 2017; 40:164-70

DPP-IV Inhibitors

Sitagliptin (Januvia®) 2006

100 mg po qd (reduce dose in renal insufficiency)

Saxagliptin (Onglyza®) 2009

2.5 or 5 mg po qd (reduce dose in renal insufficiency)

Linagliptin (Tradjenta®) 2011

2.5 mg po qd (no renal adjustment)

Alogliptin (Nesina®) 2013

25 mg po qd (reduce dose in renal insufficiency)

DPP-4 Inhibitors

Less powerful than sulfonylureas

Minimal risk of hypoglycemia

Less weight gain than sulfonylureas

Easy to use and tolerate

Neutral effects on cardiovascular disease

Risk of heart failure?

Risk of pancreatitis?

Case 3

57 year old woman with type 2 diabetes referred by PCP

Diagnosed with diabetes in 2010, A1c was 8.2, started on Metformin at the time. Now A1c 8.1

PMH: type 2 diabetes, HTN, hyperlipidemia, obesity, hypothyroidism, OSA, GERD

Medications: Metformin 1000 mg bid, aspirin 81 mg qd, Levothyroxine 100 mcg qd, Losartan 100 mg qd, Nifedipine ER 60 mg qd, Omeprazole 40mg qd, Simvastatin 20 mg qd


Case 3

Years

Case 3

Significant improvement in A1c (at goal for 1

year)

Weight loss of 8 pounds

Developed 1 episode of UTI (? drug related?)

CVD benefit?

Sodium-Glucose Co-Transporter 2 Inhibition

Effects of Canaglifozin in Patients with Type 2 Diabetes

Diabetes, Obesity and

Metabolism 15:372-382,

2013

Lancet Diabetes Endocrinol 2014;2:691-700

Comparison of Empagliflozin and Glimepiride as add-on to Metformin in patients with

type 2 diabetes: a 104 week randomized, active controlled, double-blind, phase 3 trial

Glimepiride

Empagliflozin

Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea

as add-on therapy to metformin in patients with type 2 diabetes: 4-year data

Diabetes, Obesity and Metabolism 2015;17:581-90

SGLT2-associated “euglycemic” DKA

DKA occurred in 12 of 17,596

patients in canagliflozin program <1

per 1000 patient-years

Most were insulin-treated or, in

retrospect, had LADA

Other triggers are carbohydrate

restriction, insulin cessation,

illness, alcohol

Hyperglycemia may be absent

A predicatable occurrence in type 1

DM

Peters AL. Diabetes Care 2015; Erondu. Diabetes Care 2015; Rosenstock J. Diabetes Care 2016; Ogawa W. JDI 2016

SGLT2

↓Blood glucose

↑ ↑ Glycosuria

↓Insulin/glucagon

ratiofavorable to

ketogenesis

Trigger plus ↑ ↑ Glycosuria

Euglycemic DKA

Adverse Events in the EMPA-REG

OUTCOME Trial

Placebo Empagliflozin 10 mg Empagliflozin 25 mg

UTI male 9 11 10%

UTI female 41 36 37

Gen. Infection male 2 5 5

Gen Infection female 3 9 11

N Engl J Med 2015;373:2117-28

SGLT-2 Inhibitors

Canagliflozin (Invokana®) 2013

100 mg qd, if eGFR> 60 mg/min can increase to 300

mg qd

Dapagliflozin (Farxiga®) 2014

5 or 10 mg qd, do not use if eGFR< 60 mg/min

Empagliflozin (Jardiance®) 2014

10 to 25 mg qd, do not use if eGFR < 45 mg/min

Side effects: •Polyuria •UTI •Genital infections •Hypovolemia •DKA

FDA Guidance—2008 Goal: to demonstrate

cardiovascular safety

Approach

Blinded central adjudication of

CVD events

Inclusion of high-risk subjects:

advanced CVD, elderly, CKD

Minimum exposure of 2 years in

large CVOT

Approximately 15,000 pt-yrs

Adapted from Inzucchi, SI Yale 2016 and Darren McGuire, UTSW Medical Ctr, 2015

Glucose Lowering Medications and Cardiovascular Disease

Study SAVOR EXAMINE TECOS CAROLINA CARMELINA

DPP4-i saxagliptin alogliptin sitagliptin linagliptin linagliptin

Comparator placebo placebo placebo sulfonylurea placebo

N 16,500 5,400 14,000 6,000 8,300

Results 2013 2013 2015 2017 2017

Study LEADER ELIXA SUSTAIN 6 EXSCEL REWIND

GLP1-RA liraglutide lixisenatide semaglutide exenatide LR dulaglutide

Comparator placebo placebo placebo placebo placebo

N 16,500 14,000 6,000 5,400 8,300

Results 2016 2015 2016 2018 2019

Study EMPA-REG CANVAS DECLARE NCT01986881

SGLT-2-i empaglifozin canagliflozin dapagliflozin ertugliflozin

Comparator placebo placebo placebo placebo

N 7300 4300 22,200 3900

Results 2015 2017 2019 2020

Large CV Outcomes Trials in Diabetes post-2008

✓

✓ ✓ ✓

Slide courtesy of Silvio Inzucchi, Yale

Summary of early CVD Outcomes Trials

All cardiovascular disease outcomes trials have enrolled people

at high risk of CVD outcomes

Most trials of new diabetes drugs have shown neither benefit nor

harm

Most have had a small difference in glycemic control between

the intervention and control group

On the order of 0.5% A1C

It seems likely that differences in glycemic control of this

magnitude, in this population, have no impact on cardiovascular

disease risk

EMPA-REG CVD Outcomes

Zinman B et al. N Engl J Med 2015;373:2117-2128

CVD benefit apparent at 3 months… A1C difference ~0.5

Primary outcome (CVD death, non-fatal MI, stroke) HR 0.86 (0.74-0.99)

CVD Death HR 0.62 (0.49-0.77)

All-cause Death HR 0.68 (0.57-0.82)




N 16,500 5,400 14,000 6,000 8,300

Results 2013 2013 2015 2017 2017




N 16,500 14,000 6,000 5,400 8,300

Results 2016 2015 2016 2018 2019




N 7300 4300 22,200 3900

Results 2015 2017 2019 2020


✓

✓ ✓ ✓

✓


LEADER Outcomes

Marso SP et al. N Engl J Med 2016.

Benefit apparent at 1 year

Primary outcome (CVD death, non-fatal MI, stroke) HR 0.87 (0.78-0.97)

CVD Death HR 0.78 (0.66-0.93)





N 16,500 5,400 14,000 6,000 8,300

Results 2013 2013 2015 2017 2017




N 16,500 14,000 6,000 5,400 8,300

Results 2016 2015 2016 2018 2019




N 7300 4300 22,200 3900

Results 2015 2017 2019 2020


✓

✓ ✓ ✓

✓


✓

SUSTAIN-6 Outcomes Primary outcome (CVD death, non-fatal MI, stroke) HR 0.74 (0.58-0.95)

CVD Death HR 0.98 (0.65-1.48)


Weight and glycemic control improved most with highest dose semaglutide, with treatment difference of 4.3 kg and HbA1c of 1.0%

***Increased risk of retinopathy complications in semaglutide group, though numbers were small.




N 16,500 5,400 14,000 6,000 8,300

Results 2013 2013 2015 2017 2017




N 16,500 14,000 6,000 5,400 8,300

Results 2016 2015 2016 2018 2019




N 7300 4300 22,200 3900

Results 2015 2017 2019 2020


✓

✓ ✓ ✓

✓


✓ ✓

•In patients with long standing type 2 diabetes and

established cardiovascualr disease, Empagliflozin or

Liraglutide should be considered as they have been

shown to reduce cardiovascular and all cause mortality

when added to standard care

•FDA approved new indication for Empagliflozin for

reduction of CVD death

Standards of Medical Care in Diabetes – 2017

American Diabetes Association

New Drugs for Type 2 Diabetes

FDA Approved over the last year

Basaglar

Degludec (Tresiba)

Degludec/Aspart (Ryzodeq)

Lixisenatide (Adlyxin)

Glargine/Lixisenatide (Soliqua)

Degludec/Liraglutide(Xulthopy)

Xultophy Dosing:

• Recommended starting dose is

16 units of degludec (and 0.58

mg of liraglutide)

• Maximum daily dosage 50 units

of degludec and 1.8 mg

liraglutide

New combination treatment of basal insulin and

GLP-1 analog

Take Home Messages

GLP-1 Analogs: As effective as prandial insulin but with less hypoglycemia and weight loss

Good post-prandial efficacy

About 25% of patients can not tolerate for GI side effects

Decrease CVD mortality and morbidity

DPP-4 Inhibitors: Less powerful than other oral agents

Easy to use, also in patients with CKD

Minimal risk for hypoglycemia

Consider for elderly, simple regimens, patients unable to tolerate

Metformin

SGLT-2 Inhibitors: Consider as second line agents

Decrease CVD mortality and morbidity

Monitor for risk of DKA

Documents

Recent Advances in Diabetes 2017 - Blank Titleimcourseonline.com/files/2 Tuesday/4 Enrico... · Study SAVOR EXAMINE TECOS CAROLINA CARMELINA DPP4-i saxagliptin alogliptin sitagliptin