American Diabetes Association requires the following...Second Sentence: ›Ongoing patient self-management education and support are critical to preventing acute complications and

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In compliance with the accrediting board policies, the

American Diabetes Association requires the following

disclosure to the participants:

Discuss the American Diabetes Association Anti-

hyperglycemic therapy recommendations for T2DM

Understand the importance of co-morbidities when

choosing therapy

Review the recent CV risk reduction findings in regard to

anti-hyperglycemic therapies

Discuss how to keep the patient centered in your choice of anti-hyperglycemic medication

Second Sentence:

› Ongoing patient self-management

education and support are critical to

preventing acute complications and

reducing the risk of long-term

complications.

Standards of Medical Care in Diabetes -2018 Diabetes Care 2018;41(Suppl.1):S1-S2.

Antihyperglycemic therapy in type 2 diabetes: general recommendations. *If patient does not tolerate or has contraindications to metformin, consider agents from another class in Table 8.1. #GLP-1 receptor agonists and

DPP-4 inhibitors should not be prescribed in combination.

American Diabetes Association Dia Care 2018;41:S73-S85

©2018 by American Diabetes Association

Combination injectable therapy for type 2 diabetes.

American Diabetes Association Dia Care 2018;41:S73-S85

©2018 by American Diabetes Association

Medication Centric

Inattentive to Diabetes Life Cycle

Less focused on Co-morbid conditions

Promotes Polypharmacy

What are Patients Thinking?

Cost

Side Effects

Hassle Factors

Future Implications

What are Physicians Thinking?

Efficacy

Side Effect Profile

Tolerability

Coverage

Economics

Safety

Efficacy

Co-Morbid

Conditions

Patient

Co-Morbid

Conditions

Patient

Cardiovascular Risk – Underlying CVD,

Stroke, MI, PVD

Renal Risk – Diabetic nephropathy, declining

renal Fx

GI Tolerability – Underlying GI conditions

Obesity -

Endocrine – Thyroid, PCOS, others

Obesity: 1999-2004 (NHANES) Type 2 patients

27% overweight and 61% were obese

Dyslipidemia: 99% eligible for lipid lowering therapy

1999-2004 (NHANES) 46% had elevated lipids

HTN: 67% of T2DM patients were being treated or

had HTN

Chronic Kidney Disease: ~40% of patients with

diabetes

Cardiovascular Disease:

Depression, Sleep Disorders, Cancers

(NHANES) 1999-2004

14% of patients with

T2DM had no co-morbidity

http://outpatient.aace.com/type-2-diabetes/management-of-common-comorbidities-of-diabetes

SafetyPatient

Can I take this medication with the other

medications that I am already taking?

Will this medication affect other health

problems that I am having?

I see the ads on TV. They scare me.

EconomicsPatient

Will my insurance cover this new medicine?

Can I afford to take this with all of my other

medications?

If I get a coupon or co-pay card, how long will

it last?

Is the benefit that I will get be worth the

money that I am spending?

EfficacyPatient

Will it work?

Will it be worth it?

HTN

Hyperlipidemia

Obesity

Social – elderly, frail, falls risk

CVD – stroke, MI, CAD, PVD, CHF

CKD

GI – GERD, Gall Bladder, NASH, Pancreatitis, IBS,

Crohn’s, Ulcerative Colitis

Endocrine – obesity, PCOS, Thyroid, Adrenal

Choosing Medications While

Giving Consideration to

Co-Morbid Conditions

HTN – SGLT-2 Inhibitors

› Volume Contraction and possible hypotension need to be considered.

› Canagliflozin noted with SBP reductions of 3.3 and 5.0 mm/Hg at 26 weeks1

› Empagliflozin: Mean Arterial Pressure reductions of 2.3 and

2.1 mm/Hg at 24 weeks2

› Dapagliflozin: reduced mean seated SBP -10.4 vs -7.3

mm/Hg and mean 24 hr ambulatory SBP -9.6 vs -6.7 mm/Hg at 12 weeks

1. https://www.google.com/search?q=Invokana+PI&oq=Invokana+PI&aqs=chrome.0.69i59j0j69i60j0l3.2423j0j7&sourceid=chrome&ie=UTF-8 (Accessed

1/13/2018)

2. Chilton R, et.al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes

Obesity Metabolism 2015;17(12):1180-1193.

Weber, MA et.al Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade. Blood Pressure 2016;25(2):93-

103.

Hyperlipidemia:› SGLT-2 Class Medications: Can cause a slight

elevation in LDL Cholesterol (canagliflozin 4.5 to 8%)1(dapagliflozin 2.9%)2 (empagliflozin 4.6, 6.5%)3

› TZD Class Medications: Pioglitazone can cause a reduction in triglycerides (-9.9% to -12.3%), HDL Cholesterol (-18.1 to -20.3%), LDL Chol increased

(+5.2% to +9.6%)4

1. https://www.google.com/search?q=Invokana+PI&oq=Invokana+PI&aqs=chrome.0.69i59j0j69i60j0l3.2423j0j7&sourceid=chrome&ie=UTF-8 (Accessed

1/13/2018)

2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202293s000lbl.pdf (Accessed 1/13/2018)

3. http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jardiance/jardiance.pdf (Accessed 1/13/2018)

4. Spanheimer R et.al. Long-term lipid effects of pioglitazone by baseline anti-hyperglycemia medication therapy and statun use from the PROactive experience

(PROactive 14). Am J Cardiol 2009;104(2): 234-239.

https://www.google.com/search?q=Invokana+PI&oq=Invokana+PI&aqs=chrome.0.69i59j0j69i60j0l3.2423j0j7&sourceid=chrome&ie=UTF-8

https://www.google.com/search?q=Invokana+PI&oq=Invokana+PI&aqs=chrome.0.69i59j0j69i60j0l3.2423j0j7&sourceid=chrome&ie=UTF-8

https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202293s000lbl.pdf

http://docs.boehringer-ingelheim.com/Prescribing Information/PIs/Jardiance/jardiance.pdf

Obesity:› Gain:

SU Class can cause weight gain

TZD Class can cause fluid retention and weight gain

Glinide Class can cause weight gain

Insulins

› Neutral:

DPP-4i Class

Biguanides – metformin

› Lose:

SGLT-2 Class

GLP-1 Class

Social – elderly, frail, falls risk, isolated

› Anything that is a hypoglycemia risk

SU’s

Insulins

Glinides

› Volume Depletion

SGLT-2’s

Economics –

Everything past metformin and SU’s tend to get

expensive

Try to simplify, limit or combine medications

Insured:

› Follow formulary as much as possible

› Use Coupon programs when you can

› Sample Access: try to limit to extreme or emergency situations

Cardiovascular Risk

Pre-2008 2008 The Present

CVD – TZD’s

› Pioglitazone – PROactive Trial

› 5238 Patients with evidence of macrovascular Dse.

› 34.5 month avg. time of observation

› Primary Endpoint: All-cause mortality, non-fatal MI, stroke, ACS, revascularization coronary or leg and

amputation

HR 0.90; CI 0.80-1.02, p=0.095

› Secondary Endpoint: All-cause mortality, non-fatal MI

and stroke

HR 0.84; CI 0.72-0.98, p = 0.027

Dormandy, JA, et.al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective

pioglitazone Clinical Trial In macrovascular Events): a randomized controlled trial. The Lancet 2005;366: 1279-1289.

CVD – TZD’s

› Rosiglitazone – RECORD Trial1

4447 Patients – HR for CV Death 0.84;CI 0.59-1.18, MI 1.14;

CI 0.80-1.63, Stroke 0.72; CI 0.49-1.06

Heart Failure Admission or death HR 2.10; CI 1.35-3.27.

Increased risk of long bone Fx, mainly women

› Nissen Meta-analysis2

42 trials, avg. age 56 y

Odds ratio for MI 1.43

Odds ratio of death 1.64

1. Home,PD, et.al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a

multicenter, randomized, open-label trial. The Lancet 2009;373:2125-2135.

2. Nissen, SE, et al. Effect of Rositglitaone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med 2007;356:

2457-2471.

CVD –

These events should include cardiovascular mortality, myocardial infarction, and stroke, and can include

hospitalization for acute coronary syndrome, urgent

revascularization procedures, and possibly other endpoints.

https://www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf

CVD –

What is 3 pt. MACE:

Cardivascular Death

Non-fatal MI

Non-fatal Stroke

https://www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf

Study EXAMINE1 CARMELINA2 SAVOR3 TECOS4

DPP-4i Alogliptin linagliptin saxagliptin sitagliptin

N 5380 7003 16492 14671

Duration 40 months,

median 18 months2013-2018 2.1 years 3.0

Resulted 2013 Ant. 2018 2013 2015

Primary

Endpoint

MACE MACE MACE MACE

HR 0.95; CI upper

limit 1.16

TBD 1.00; CI 0.89-

1.12

0.98; CI 0.88-

1.09

Results Non-inferior

p<0.001

TBD Non-inferiority

p<0.001

Non-inferior

P<0.001

1. White,W, et al. Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med 2013; 369:327-335.

2. https://clinicaltrials.gov/ct2/show/NCT01897532 (Accessed 2/2/2018)

3. Green, JB. et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2015; 373:232-242.

https://clinicaltrials.gov/ct2/show/NCT01897532

Study CANVAS1 DECLARE2 EMPA-Reg3

SGLT-2 Canagliflozin Dapagliflozin Empagliflozin

N 10142 17276 7020

Duration 188.2 weeks 3.1 years

Resulted2017

Mid-2018

(anticipated)

2015

Primary EndpointMACE

MACE MACE

HR0.86;CI 0.75-0.97

TBD 0.86; CI 0.74-.099

ResultsNon-inferior

p<0.001

Superior p=0.02

TBD Superiority

p=0.04

1. Neal,B et.al. Canagliflozin and Cardiovasculary and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644-657.


3. Zinman, B et.al. Empagliflozin, Cardiovascular Outcomesn and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128.

Study CANVAS1 DECLARE2 EMPA-Reg3

SGLT-2 Canagliflozin Dapagliflozin Empagliflozin

N 10142 17276 7020

Duration 188.2 weeks 3.1 years

Resulted 2017Mid-2018

(anticipated)2015

Primary Endpoint MACE MACE MACE

HR 0.86;CI 0.75-0.97 TBD 0.86; CI 0.74-.099

ResultsNon-inferior

p<0.001

Superior p=0.02

TBDSuperiority

p=0.04



3. Zinman, B et.al. Empagliflozin, Cardiovascular Outcomesn and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128.

Study ELIXA1 EXSCEL2 LEADER3 REWIND4 SUSTAIN-65

GLP-1RA Lixisenatide Exenatide LR Liraglutide Dulaglutide semaglutide

N 6068 5400 9340 8300 2735

Duration 25 month

median3.2 years 3.8 years Up to 6.5

years104 weeks

Resulted 2015 2017 2016 2019 2016

Primary

Endpoint

MACE + hosp

for unstable

angina

MACE Time to

event MACE

Time to

event

MACE

Time to event

MACE

HR 1.02; CI 0.89-

1.17

0.91;CI 0.83-

1.000.87; CI

0.78-0.97

TBD 0.74; CI

0.58-0.95


P<0.001

Non-inferior

P<0.001

Non-inferior

P<0.001

Superior P<0.01

TBD Non-inferior

p<0.001

1. Pfeffer,MA et.al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med 2015;373:2247-2257.

2. Holman,RR et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2017;377:1228-1239.

3. Marso, SP et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375:311-322.

4. ClinicalTrial.gov: https://clinicaltrials.gov/ct2/show/NCT01394952 (Accessed Jan 31st, 2018)

5. Marso SP et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375:1834-1844.




Study ELIXA1 EXSCEL2 LEADER3 REWIND4 SUSTAIN-65

GLP-1RA Lixisenatide Exenatide LR Liraglutide Dulaglutide semaglutide

N 6068 5400 9340 8300 2735

Duration 25 month

median3.2 years 3.8 years Up to 6.5

years104 weeks

Resulted 2015 2017 2016 2019 2016

Primary

Endpoint

MACE + hosp

for unstable

angina

MACE Time to

event MACE

Time to

event

MACE

Time to event

MACE

HR 1.02; CI 0.89-

1.17

0.91;CI 0.83-

1.000.87; CI

0.78-0.97

TBD 0.74; CI

0.58-0.95


P<0.001

Non-inferior

P<0.001

Non-inferior

P<0.001

Superior P<0.01

TBD Non-inferior

p<0.001

1. Pfeffer,MA et.al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med 2015;373:2247-2257.

2. Holman,RR et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2017;377:1228-1239.

3. Marso, SP et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375:311-322.

4. ClinicalTrial.gov: https://clinicaltrials.gov/ct2/show/NCT01394952 (Accessed Jan 31st, 2018)

5. Marso SP et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375:1834-1844.

CVD – CV Risk Reduction› Canagliflozin

› Empagliflozin

› Liraglutide

CV Risk: PVD and SGLT-2i

› Lower Extremity Amputation1

CANVAS Trial – higher risk of amputations at

toes, feet or legs with canagliflozin (6.3 vs. 3.4

participants with amputations/ 1000 pt. yrs.) (HR

1.97)

Highest absolute risk was with patients who had

a previous amputation or PVD.



CV Risk: PVD and SGLT-2i

› Reasonable Recommendations:

Diabetes Foot Exam

Check Pulses and document

Hx of PVD – if questions, check Art. Duplex

Hx of Amputations

Interval Changes in Foot Health

CKD Improve:

› ACE/ARB medication to improve renal function

› HTN Control

› BGM/A1c Control

Cautions:

› Metformin

› DPP-4’s (linagliptin ok here as it is gut cleared)

› SGLT-2i

› GLP-1RA

CKD – Stage Process 1-5 based on GFR

› Stage 1: 120-90 ml/min/1.73m2

› Stage 2: 89-60 ml/min/1.73m2

› Stage 3a: 59-45 ml/min/1.73m2

› Stage 3b: 44-30 ml/min/1.73m2

› Stage 4: 29-15 ml/min/1.73m2

› Stage 5: <15 ml/min/1.73m2

Cautions:

› Metformin

Cautions:

› Metformin

CKD – Safe Dosing for Metformin

› Stage 3a: 59-45 ml/min/1.73m2

› Stage 3b: 44-30 ml/min/1.73m2

CKD – Safe Dosing for Metformin

› Stage 2: per package

› Stage 3a: 500 mg am and 1 gm pm

› Stage 3b: 500 mg BID

› Stage 4: Withdraw medication/Contraindicated

› Stage 5: Contraindicated.

Metformin should be withdrawn in patients like

to experience acute kidney injury in the context

of severe pathologies

Lalau,JD, et.al. Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B,

or 4. Diabetes Care 2018; https://doi.org/10.2337/dc17-2231.


Crohn’s, Ulcerative Colitis, gastroparesis

https://doi.org/10.2337/dc17-2231



Metformin: GI Upset both upper and lower

TZD’s, GLP-1RA: Can be beneficial with NASH

DPP-4i: Small pancreatitis risk



GLP-1RA: Pancreatitis contraindication

› Hx of pancreatitis

› Consider high triglycerides

› Active alcoholism

› Do not use with gastroparesis

Endocrine – obesity, PCOS

Obesity:

› Cautions: Insulins, SU’s, glinides, TZD’s

› Beneficial: SGLT-2i, GLP-1RA

PCOS: TZD’s may be of benefit here

HTN

Hyperlipidemia

Obesity



CKD




Patient Cases:

› A –

› B –

› C –

SU’s Met -GITZD InsulinsGlin DPP-4iSGLT-

2i

GLP-

1RA

Case #1:

41 year old female patient with a Dx of T2DM for the past

7 years.


2i

GLP-

1RA

Case #2:

68 year old female patient with a Dx of T2DM for the past

19 years.


2i

GLP-

1RA

Case #3:

39 year old male patient with a Dx of T2DM for the past 4

years.

HTN

Hyperlipidemia

Obesity



CKD




The Standards of Medical Care in Diabetes can serve as

a guide for us as we choose therapy for patients with diabetes

Co-Morbid Conditions play a critical role in the health of our patients with diabetes and their choice of medications/therapy

Specifically, consideration of CV risk for patients with diabetes is important in deciding therapy with your

patient

Documents

American Diabetes Association requires the following...Second Sentence: ›Ongoing patient self-management education and support are critical to preventing acute complications and