2020 Symposia Series 2 › symposia › slides › live... · 2020-06-04 · 3 • Describe evidence supporting use of SGLT2 inhibitors in the setting of existing cardiovascular disease

2020 Symposia Series 22020 Symposia Series 2

Improving Glycemic and Cardiorenal Outcomes in T2DM: The Expanding Role

of SGLT2 Inhibitors

3

• Describe evidence supporting use of SGLT2 inhibitors in the setting of

existing cardiovascular disease (CVD), heart failure (HF), or renal disease

• Integrate SGLT2 inhibitors into the treatment plans of patients with type 2

diabetes (T2DM) according to evidence-based guidelines and patient-

specific factors

• Implement patient-centered management for patients with T2DM within the

context of current guidelines

Learning Objectives

SGLT2 = sodium-glucose cotransporter 2.

4

• CVD is the leading cause of death among patients with diabetes

‒ Risk highest for individuals with prior history of CVD and with increasingly

poorer glycemic control

• ~1/3 of patients with T2DM have comorbid CVD

‒ 68.4% of patients with T2DM are hypertensive

‒ 43.5% have high LDL-C

• Mitigating CVD risk is important to improving long-term outcomes for

patients with T2DM

• Updated guidance from the ADA recommends using treatments that convey

both glycemic and CVD benefits

CVD and T2DM

LDL-C = low-density lipoprotein cholesterol.

Centers for Disease Control and Prevention. www.cdc.gov/diabetes/library/features/diabetes-stat-report.html. Accessed June 1, 2020;

Einarson TR, et al. Cardiovasc Diabetol. 2018;17:83; Raghavan S, et al. J Am Heart Assoc. 2019;8:e011295.

5

Case Study: Diane, a 57-Year-Old With 6-Year History of T2DM

• New patient presenting for annual physical

• Stent placement 2 years ago after hospitalization for ACS

• Physical exam

‒ Height 5 ft 6 in

‒ Weight: 165 lb

‒ BMI: 26.6 kg/m2

‒ BP: 144/92 mm Hg on ACE inhibitor

‒ No overt retinopathy or neuropathy

ACE = angiotensin-converting enzyme; ACS = acute coronary syndrome.

6

Case Study (cont’d): Diane’s History and Laboratory Values

• Lab Results

‒ FPG: 136 mg/dL

‒ PPG: 196 mg/dL

‒ A1C: 7.8%

‒ LDL-C: 81 mg/dL on statin

‒ Mild renal impairment

• eGFR: 59 mL/min/1.732

‒ Albuminuria present

• A/C ratio = 360 mcg/mg on

spot test

A1C = glycated hemoglobin; A/C = albumin/creatinine; eGFR = estimated glomerular filtration rate; FPG = fasting plasma glucose; PPG = postprandial

glucose.

• Current Medications

‒ Metformin 1500 mg/day

‒ Ramipril 10 mg/day

‒ Atorvastatin 80 mg/day

‒ Aspirin 81 mg/day

• Family/Social History

‒ Full-time office manager

‒ Engages in group

exercise 3 days per week

‒ Enjoys traveling, visiting

grandchildren

7

HF or CKD predominates

PREFERABLY: SGLT2i with evidence of reducing HF and/or

CKD progression in CVOTs if eGFR is adequate

OR

If SGLT2i not tolerated or contraindicated or inadequate eGFR,

add GLP-1 RA with proven CVD benefit

Choose agent with CV safety; Avoid TZD in setting of HF

ASCVD predominates

PREFERABLY:

GLP-1 RA with

proven CVD

benefit

SGLT2i with

proven CVD

benefit if eGFR

is adequate

If further intensification required or patient unable to tolerate

GLP-1 RA and/or SGLT2i, choose agents with CV safety

For all patients: lifestyle modification

For most patients: metformin

Indicators of high-risk or established ASCVD, HF, or CKD

ADA 2020: Use Agents That Address Patient-Specific Comorbidities

EITHER/OR

CKD = chronic kidney disease; CVOT = cardiovascular outcome trial.

Adapted from: American Diabetes Association. Diabetes Care. 2020;43:S1-S212.

If A1C above target

If A1C above target

8

HF or CKD predominates

PREFERABLY: SGLT2i with evidence of reducing HF and/or

CKD progression in CVOTs if eGFR is adequate

OR

If SGLT2i not tolerated or contraindicated or inadequate eGFR,

add GLP-1 RA with proven CVD benefit

Choose agent with CV safety; Avoid TZD in setting of HF

ASCVD predominates

PREFERABLY:

GLP-1 RA with

proven CVD

benefit

SGLT2i with

proven CVD

benefit if eGFR

is adequate

If further intensification required or patient unable to tolerate

GLP-1 RA and/or SGLT2i, choose agents with CV safety

For all patients: lifestyle modification

For most patients: metformin

Indicators of high-risk or established ASCVD, HF, or CKD

ADA 2020: Use Agents That Address Patient-Specific Comorbidities

EITHER/OR

CKD = chronic kidney disease; CVOT = cardiovascular outcome trial.

Adapted from: American Diabetes Association. Diabetes Care. 2020;43:S1-S212.

If A1C above target

If A1C above target

9

Baseline Characteristics of SGLT2 Inhibitor CVOTs

*DAPA-HF enrolled patients with HF with and without T2DM; ~42% of included patients had diabetes at baseline.

Cannon CP, et al. Am Heart J. 2018;206:11-23; McMurray JJV, et al. N Engl J Med. 2019;381:1995-2008; Neal B, et al. N Engl J Med.

2017;377:644-657; Wiviott SD, et al. N Engl J Med. 2019;380:347-357; Zinman B, et al. N Engl J Med. 2015;373:2117-2128.

Characteristics

EMPA-REG

Empagliflozin

CANVAS &

CANVAS-R

Canagliflozin

CREDENCE

Canagliflozin

DECLARE-TIMI 58

Dapagliflozin

DAPA-HF*

Dapagliflozin

VERTIS-CV

Ertugliflozin

N 7020 10,142 4401 17,160 4744 9463

Established

ASCVD, %100 72 50 41 — 100

Renal

impairment, %

11

Nephropathy

18

Nephropathy

100

Albuminuric

CKD

7

eGFR <60

40.6

eGFR <60

22

CKD

Baseline eGFR,

mL/min/1.732 74 77 56 85 66 76

Baseline HF, % 11 14 15 10 100 23

10

Outcomes of SGLT2 Inhibitor CVOTs

10

*DAPA-HF enrolled patients with HF with and without T2DM; ~42% of included patients had diabetes at baseline.

MACE = major adverse cardiovascular event (composite of CV death, MI, or stroke).

Cannon CP, et al. Am Heart J. 2018;206:11-23; McMurray JJV, et al. N Engl J Med. 2019;381:1995-2008; Neal B, et al. N Engl J Med.

2017;377:644-657; Percovic V, et al. Lancet Diabetes Endocrinol. 2018;6:691-704; Percovic V, et al. N Engl J Med. 2019;380:2295-2306; Radholm

K, et al. Circulation. 2018;138:458-468; Wiviott SD, et al. N Engl J Med. 2019;380:347-357; Zinman B, et al. N Engl J Med. 2015;373:2117-2128;

Zoler ML. www.medscape.com/viewarticle/929647. Accessed June 1, 2020.

Characteristics

EMPA-REG

Empagliflozin

CANVAS &

CANVAS-R

Canagliflozin

CREDENCE

Canagliflozin

DECLARE-TIMI 58

Dapagliflozin

DAPA-HF*

Dapagliflozin

VERTIS-CV

Ertugliflozin

Primary outcome MACE MACE Renal compositeMACE +

compositeHHF or CV death

MACE + CV

death or HHF

Est. ASCVD, % 100 72 50 41 — 100

MACE 0.86 (0.74-0.99) 0.86 (0.75-0.97) 0.80 (0.67-0.95) 0.93 (0.84-1.03) NR Noninferior

CV death 0.62 (0.49-0.77) 0.87 (0.72-1.06) 0.78 (0.61-1.00) 0.98 (0.82-1.17) 0.82 (0.69-0.98) Noninferior

HHF 0.65 (0.50-0.85) 0.67 (0.52-0.87) 0.61 (0.47-0.80) 0.73 (0.61-0.88) 0.70 (0.59-0.83) Pending

CV death or HHF 0.66 (0.55-0.79) 0.78 (0.67-0.91) 0.69 (0.57-0.83) 0.83 (0.73-0.95) 0.75 (0.65-0.85) Noninferior

Fatal/non-fatal

stroke1.18 (0.89-1.56) 0.87 (0.69-1.09) NR 1.01 (0.84-1.21) Pending

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Outcomes in Observational Studies Are Consistent With CV Benefit

of Treatment With SGLT2 Inhibitors

HHF = hospitalization for heart failure; MI = myocardial infarction.

Due to the timing of data collection, the majority of patients in these studies received either dapagliflozin or canagliflozin; smaller percentages

received empagliflozin. EASEL also included a small percentage treated with SGLT2 inhibitors not currently approved in the US (ipragliflozin,

tofogliflozin, luseogliflozin).

Birkeland KI, et al. Lancet Diabetes Endocrinol. 2017;5:709-717; Kosiborod M, et al. Circulation. 2017;136:249-259; Kosiborod M, et al. J Am Coll

Cardiol. 2018;71:2628-2639; Patorno E, et al. BMJ. 2018;360:k119; Udell JA, et al. Circulation. 2018;137:1450-1459.

Characteristics CVD-REAL Patorno et al EASEL CVD REAL 2 CVD REAL Nordic

N 309,056 224,999 25,258 >400,00 91,930

Established

ASCVD, %13 16-18 100 27 25

All-cause death,

MI, stroke— —

0.67

(0.60-0.75)

0.51

(0.37-0.70)0.78 (0.69-0.87)

All-cause death0.49

(0.41-0.57)

0.66

(0.25-1.74)

0.57

(0.49-0.66)

0.51

(0.37-0.70)0.51 (0.45-0.58)

HHF0.61

(0.51-0.73)

0.70

(0.54-0.92)

0.57

(0.45-0.73)

0.64

(0.50-0.82)0.70 (0.61-0.81)

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• CREDENCE evaluated effect of canagliflozin on progression of renal disease in patients

with T2DM and CKD; outcomes showed reduced risk on:

‒ Primary endpoint (sustained creatinine doubling, ESRD, or CV or renal death): 0.70

(0.59-0.82)

‒ Other endpoints

• Sustained creatinine doubling, ESRD, or renal death: 0.66 (0.53-0.81)

• ESRD: 0.68 (0.54-0.86)

• Dialysis, transplant, or renal death: 0.72 (0.54-0.97)

‒ Patients with baseline eGFR <45 had renal, but not glycemic, benefit with canagliflozin

Improvements in Renal Outcomes With SGLT2 Inhibitors

All data presented as hazard ratio (95% confidence interval). ESRD = end-stage renal disease.

Herrington WG, et al. Clin Kidney J. 2018:749-761; McMurray JJV, et al. N Engl J Med. 2019;381:1995-2008; Neal B, et al. N Engl J Med.

2017;377:644-657; Percovic V, et al. N Engl J Med. 2019;380:2295-2306; Wanner C, et al. N Engl J Med. 2016;375:323-334; Wiviott SD, et al.

N Engl J Med. 2019;380:347-357.

13

• Data from EMPA-REG, DECLARE-TIMI 58, and DAPA-HF suggest renal

benefit with empagliflozin and dapagliflozin in CVOTs

• Renal-specific trials ongoing

‒ EMPA-Kidney (NCT03594110)

‒ Dapa-CKD (NCT03036150)

Improvements in Renal Outcomes With SGLT2 Inhibitors (cont’d)

Herrington WG, et al. Clin Kidney J. 2018:749-761; McMurray JJV, et al. N Engl J Med. 2019;381:1995-2008; Neal B, et al. N Engl J Med.

2017;377:644-657; Percovic V, et al. N Engl J Med. 2019;380:2295-2306; Wanner C, et al. N Engl J Med. 2016;375:323-334; Wiviott SD, et al. N

Engl J Med. 2019;380:347-357.

14

Current Indications for SGLT2 Inhibitors in T2DM

Canagliflozin [prescribing information]. Janssen Pharmaceuticals; 2020; Dapagliflozin [prescribing information]. Bristol Myers Squibb; 2020;

Empagliflozin [prescribing information]. Boehringer Ingelheim; 2020; Ertugliflozin [prescribing information]. Merck & Co, Inc; 2020.

Agent FDA Indication in T2DM

Empagliflozin • Adjunct to diet and exercise to improve glycemic control

• Reduce risk of CV death in adults with T2DM and established CVD

Canagliflozin • Adjunct to diet and exercise to improve glycemic control

• Reduce risk of MACE in adults with T2DM and established CVD

• Reduce risk of ESRD, doubling of serum creatinine, CV death, and HHF in

adults with T2DM and diabetic nephropathy with albuminuria

Dapagliflozin • Adjunct to diet and exercise to improve glycemic control in patients with T2DM

• Reduce risk of HHF in adults with T2DM and established CVD or multiple CV

risk factors

Ertugliflozin • Adjunct to diet and exercise to improve glycemic control

15

• Current recommendations:

Achieving/maintaining appropriate weight

Regular physical activity

Smoking cessation, if applicable

Reducing stress

Lifestyle Modifications: Cornerstone of Treatment for T2DM

American Diabetes Association. Diabetes Care. 2020;43:S1-S212; Garber AJ, et al. Endocr Pract. 2019;25:69-100.

16

Use of SGLT2 Inhibitors to Reduce CV Risk Is a “Paradigm Shift”

• Demonstrated reductions in risk for CV death, MI, stroke, HF

hospitalization, progression of renal disease, and associated mortality

• Choose agents based on evidence and established indications

• SGLT2 inhibitors may be considered as first-line oral option

• Recommended in guidelines from ADA/EASD, ACE/AACE, and ESC

ACE/AACE = American College of Endocrinology/American Association of Clinical Endocrinologists; ESC = European Society of Cardiology.

American Diabetes Association. Diabetes Care. 2020;43:S1-S212; Cosentino F, et al. Eur Heart J. 2020;41:255-323; Garber AJ, et al. Endocr Pract.

2019;25:69-100.

17

Approach to Individualization of A1C Targets for Treatment

Readily available Limited

High motivation/adherence Low motivation/adherence

Absent Few/mild Severe

Absent Few/mild Severe

Long Short

Newly diagnosed Long-standing

Low High

A1C

7.0%More Stringent Less Stringent

Usually not

modifiable

Potentially

modifiable

Patient/Disease Features

Risk of hypoglycemia/drug adverse effects

Disease duration

Life expectancy

Relevant comorbidities

Established vascular complications

Patient attitude and expected treatment efforts

Resources and support system

American Diabetes Association. Diabetes Care. 2020;43:S1-S212.

18

Factors to Consider When Choosing Treatment

• Treatment efficacy

• Hypoglycemia risk

• Impact on weight

• Potential side effects

• Renal effects

American Diabetes Association. Diabetes Care. 2020;43:S1-S212

• Cost

• Route of administration

• Patient CV history and risk

• Comorbidities

• Patient preferences

19

• Moderate renal impairment and reduced eGFR diminish efficacy, and may increase AEs

‒ Evaluate renal function prior to and periodically during treatment

• May cause acute kidney injury; discontinue and promptly treat if occurs

‒ Hypovolemia, CKD, NSAIDs, ACE inhibitors, ARBs, diuretics, HF increase risk

Using SGLT2 Inhibitors for Patients With Renal Impairment

AE = adverse event; ARB = angiotensin-receptor blocker; NSAID = nonsteroidal anti-inflammatory drug.

Canagliflozin [prescribing information]. Janssen Pharmaceuticals; 2020; Dapagliflozin [prescribing information]. Bristol Myers Squibb; 2020;

Empagliflozin [prescribing information]. Boehringer Ingelheim; 2020; Ertugliflozin [prescribing information]. Merck & Co, Inc; 2020.

SGLT2 InhibitoreGFR (mL/min/1.732)

≥60 <60 but ≥45 <45 but ≥30 <30

Canagliflozin All doses 100 mg only Not recommended Contraindicated

Dapagliflozin All doses All doses Not recommended Contraindicated

Empagliflozin All doses All dosesDo not initiate,

discontinue if persistsContraindicated

Ertugliflozin All dosesDo not initiate,

discontinue if persists

Do not initiate,

discontinue if persistsContraindicated

20

Evaluate Patients’ Renal Status Before Initiating SGLT2

Inhibitor Therapy

• Monitor renal function periodically during treatment, and adjust/discontinue

if necessary

• Use baseline renal status in choosing an SGLT2 inhibitor, recommended

use varies

• Be aware of risk for acute kidney injury in patients at higher risk, and

discontinue SGLT2 inhibitor promptly if occurs

21

Normal Physiology of Renal Glucose Homeostasis

GlomerulusDistal tubule

Glucosefiltration

Minimalglucose

excretion

Collectingduct

90%

10%Glucose

reabsorption

Proximal tubule

S1

S3SGLT1

Loop of Henle

Han S. Diabetes. 2008;57:1723-1729; Lee YJ, et al. Kidney Int Suppl. 2007;106:S27-S35; Wright EM. Am J Physiol Renal Physiol. 2001;280:

F10-F18.

SGLT2

22

SGLT2 Inhibition Reduces Renal Glucose Absorption

SGLT2

Proximal tubule

S1

GlomerulusDistal tubule

Glucosefiltration

S3

Collectingduct

90%

10%Glucose

reabsorption

Loop of Henle

SGLT1

SGLT2 inhibitor

Increasedglucose

excretion –70-80 g/day

(–280-320 Kcal/day)

Han S. Diabetes. 2008;57:1723-1729; Lee YJ, et al. Kidney Int Suppl. 2007;106:S27-S35; Wright EM. Am J Physiol Renal Physiol. 2001;280:

F10-F18.

23

Potential Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors

Zelniker TA, Braunwald E. J Am Coll Cardiol. 2020;75:422-434.

CV and Renal

Protection

Decrease arterial

stiffness

Reduce

glucotoxicity

Increase

hematocrit and

hemoglobin

Increase

weight loss

Reduce

plasma

volume

Decrease

systolic blood

pressure

Decrease adiposity

and inflammation

Improve cardiac

fuel energetics

24

• Alleviate glucotoxicity, improving β-cell function and insulin sensitivity

• Lower A1C as monotherapy (≤1.0%) or in combination with other T2DM

therapies

• Reduce both fasting and postprandial glucose levels

• Reduce glucose independent of insulin response

• Have a low risk of hypoglycemia, even when combined with basal insulin

or sulfonylureas

Glycemic Efficacy of SGLT2 Inhibitors

Abdul-Ghani M, et al. Diabetes Care. 2016;39:717-725; Anderson JE, et al. Diabetes Ther. 2017;8:33-53; Consoli A, et al. Expert Opin Drug Saf.

2018;17:293-302; DeFronzo RA, et al. Nat Rev Nephrol. 2017;13:11-26.

25

SGLT2 Inhibitors Provide Additional A1C Reductions When Added

to Other Diabetes Medications*

*As a class; where they appear, ranges include different doses and agents.

Frías JP, et al. Lancet Diabetes Endocrinol. 2016;1004-1016; Jabbour SA, et al. Diabetes Care. 2014;37:740-750; Nauck MA. Drug Des Devel Ther.

2014;8:1335-1380; Vivian EM. Drugs Context. 2014;3:212264.

Therapy A1C Reduction With Added SGLT2 Inhibitor

Metformin –0.4% to –0.7%

Glimepiride –0.5% to –0.68%

Pioglitazone –0.4% to –0.55%

DPP-4 inhibitor –0.5% to –0.79%

GLP-1 RA –0.4%

Basal insulin –0.4% to –0.89%

26

• Body weight reductions

• Modest reduction in systolic and diastolic BP

• Small increase in LDL-C, greater increase in HDL-C, decrease in triglycerides

• Albuminuria: reductions of 30% to 40%

• Renal health: meta-analysis

‒ Among patients with renal impairment, initial decrease in eGFR, increase in

serum creatinine levels followed by return to baseline

‒ Among those without impairment, no significant change in either parameter

Benefits Beyond Glycemic Reductions

Baker WL, et al. J Am Heart Assoc. 2017;6:e005686; DeFronzo RA, et al. Nat Rev Nephrol. 2017;13:11-26; Grossman A, Grossman E. Cardiovasc

Diabetol. 2017;16:3; Kelly MS, et al. Postgrad Med. 2019;131:31-42; Seidu S, et al. Prim Care Diabetes. 2018;12:265-283; Takenaka T. Diab Vasc

Dis Res. 2018;15:154-157; Zelniker TA, et al. Lancet. 2019;393:31-39.

27

• Body weight: glucose loss → calorie loss → weight loss

• Modest, dose-dependent weight loss: 1.5 to 2 kg (placebo-adjusted)

• Weight loss maintained in 4 years of follow-up

• Amount of weight loss due to glucosuria mitigated by compensatory

mechanisms

• Majority of weight loss is from subcutaneous and visceral fat tissue, not

lean tissue

‒ Reductions in waist circumference

Body Weight Loss With SGLT2 Inhibitors

Bolinder J, et al. J Endocrinol Metab. 2012;97:1020-1031; Cefalu WT, et al. Lancet. 2013;382;941-950; Neeland IJ, et al. Diab Vasc Dis Res. 2016;

13:119-126; Pereira MJ, Eriksson JW. Drugs. 2019;79:219-230.

28

SGLT2 Inhibitors in Context With Other T2DM Medications

*Potential for moderate weight loss; **Can occur in various stress settings.

DPP-4i = DPP-4 inhibitor; MET = metformin; SU = sulfonylurea.

American Diabetes Association. Diabetes Care. 2020;43:S1-S212; Davidson JA. Mayo Clin Proc. 2010;85:S27-S37; Garber AJ, et al. Endocr Pract.

2019;25:69-100; Nathan DM. N Engl J Med. 2002;347:1342-1349.

Effect MET SGLT2i GLP-1 RA DPP-4i TZD SU Basal Insulin

Typical A1C

reduction, %

1.0 to 2.0 ≤1.0 0.6 to 1.5 0.5 to 0.8 0.5 to 1.0 1.0 to 2.0 1.5 to 2.5

Efficacy High Intermediate High Intermediate High High Highest

Hypoglycemia No No No No No Yes Yes

Weight ∆ Neutral* Loss Loss Neutral Gain Gain Gain

Bone Neutral Neutral Neutral Neutral Moderate

fracture risk

Neutral Neutral

Ketoacidosis Neutral Potential** Neutral Neutral Neutral Neutral Neutral

29

SGLT2 Inhibitors: Glycemic and Nonglycemic Effects Contribute

to Cardiorenal Benefits

Zelniker TA, Braunwald E. J Am Coll Cardiol. 2020;75:422-434.

Mechanism

Glucose lowering ✓

Body weight reduction ✓ ✓ ✓

Blood pressure reduction ✓ ✓ ✓

Natriuresis ✓ ✓

Anti-inflammation ✓ ✓ ✓

Antifibrotic ✓ ✓

Extracellular matrix turnover reduction ✓ ✓

Intrarenal hypoxia amelioration ✓

Tubuloglomerular feedback restoration ✓

Natriuretic protein reduction ✓ ✓

Energy demand reduction ✓ ✓

Liver fat reduction ✓

HF ASCVD CKD

30

Avogaro A, et al. Diabetes Metab Res Rev. 2018;34:e2981; Cinti F, et al. Drug Des Devel Ther. 2017;11:2905-2919; Consoli A, et al. Expert Opin

Drug Saf. 2018;17:293-302; DeFronzo RA, et al. Nat Rev Nephrol. 2017;13:11-26; Lega IC, et al. Diabetes Obes Metab. 2019;21:2394-2404; McGill

JB, Subramanian S. Am J Cardiol. 2019;124:S45-S52; Mosley JF, et al. P T. 2015;40:451-462; Patel S, et al. Diabetes Ther. 2020;11:1347-1367;

Russo GT, et al. Int J Endocrinol. 2016;1615735; Simes BC, MacGregor GG. Diabetes Metab Syndr Obes 2019;12:2125-2136;

Potential AEs of SGLT2 Inhibitors and Their Management

Issue Notes Management

Genital mycotic

infections (GMI)

7% to 8% of women; 1% to 2% of men Standard antifungal

treatment

Urinary tract infection Triggered by glycosuria Standard treatment

Polyuria 2% to 3% of patients; typically transient Educate patients

Increase in LDL-C Usually offset by increase in HDL-C Monitor

Hypoglycemia Rare with monotherapy, more common

in combination with insulin or SU

Educate patients regarding

rarity with SGLT2 inhibitors

31

• SGLT2 inhibitors have a loop diuretic effect

• Due to increased diuresis, treatment may result in dehydration, initial transient

decrease in eGFR, hypotension, fainting, or falls

‒ Assess and correct volume status in at-risk patients

‒ Risk factors: older age, renal impairment, low systolic BP, on treatment with

diuretics, ACE inhibitors, or ARBs

‒ Dehydration is also a factor in risk for amputation, diabetic ketoacidosis

• In patients with preexisting HF, consult with cardiologist to adjust all medications

• In patients with eGFR <45 mL/min/1.732, consult with nephrologist to ensure

treatment will not worsen any other aspects of renal function

Fluid Management for Patients Using SGLT2 Inhibitors

American Diabetes Association. Diabetes Care. 2020;43:S1-S212; Canagliflozin [prescribing information]. Janssen Pharmaceuticals; 2020;

Dapagliflozin [prescribing information]. Bristol Myers Squibb; 2020; Empagliflozin [prescribing information]. Boehringer Ingelheim; 2020; Ertugliflozin

[prescribing information]. Merck & Co, Inc; 2020; Garber AJ, et al. Endocr Pract. 2019;25:69-100.

32

Fracture and Amputation Risk With Canagliflozin

• CANVAS and other data suggest increased fracture risk with canagliflozin; data from CANVAS also

showed increased risk for amputation (especially toes)

• Only canagliflozin has boxed warning for amputation and warning for fractures

• No clear pathogenetic mechanism for either identified

• No increase in fracture or amputation was seen with other SGLT2 inhibitors

• Population-based cohort (N = 73,173) found no increased fracture risk with SGLT2 inhibitors as a

class versus use of DPP-4 inhibitors

Abrahami D, et al. Diabetes Care. 2019;42:e150-e152; Canagliflozin [prescribing information]. Janssen Pharmaceuticals; 2020; Dapagliflozin

[prescribing information]. Bristol Myers Squibb; 2020; DeFronzo RA, et al. Nat Rev Nephrol. 2017;13:11-26; Empagliflozin [prescribing information].

Boehringer Ingelheim; 2020; Ertugliflozin [prescribing information]. Merck & Co, Inc; 2020; Erythropoulou-Kaltsidou M, et al. Diabetes Ther. 2020;11:7-

14; Neal B, et al. N Engl J Med. 2017;377:644-657; Patel S, et al. Diabetes Ther. 2020;11:1347-1367; Ye Y, et al. Front Pharmacol. 2019;9:1517.

Outcome CANVAS: Canagliflozin vs Placebo, HR (95% CI)

Amputation (toes, feet, or legs) 1.97 (1.41-2.75)

All fractures 1.26 (1.04-1.52)

33

• Mechanism not clear; seen only with canagliflozin

• Avoid or discontinue SGLT2 inhibitor in patient with lower limb complications

• Closely monitor patients with risk factors for amputation

‒ Peripheral vascular disease

‒ Neuropathy

‒ Avoid in patients with previous amputations and diabetic foot ulcers

• Educate patients on foot care and include foot exams at office visits

• Avoid volume depletion: adequate hydration important

• Monitor patients for signs and symptoms of infection (including osteomyelitis),

new pain or tenderness, sores or ulcers involving the lower limbs

Clinical Considerations: Amputation Risk With Canagliflozin

Canagliflozin [prescribing information]. Janssen Pharmaceuticals; 2020; Dapagliflozin [prescribing information]. Bristol Myers Squibb; 2020;

Empagliflozin [prescribing information]. Boehringer Ingelheim; 2020; Ertugliflozin [prescribing information]. Merck & Co, Inc; 2020.

34

• Diabetic ketoacidosis risk

‒ Rare with T2DM: between 0.16 and 0.76 events/1000 patient-years

‒ Regardless of A1C level, assess patients with symptoms of malaise,

nausea/vomiting

‒ Avoid very-low carbohydrate diets, excess alcohol intake, dehydration

‒ Treat promptly—may require insulin and fluid/carbohydrate replacement

‒ Recommendation: stop SGLT2 inhibitor 24 to 48 hrs prior to planned surgeries

or metabolically stressful activities (eg, extreme sports)

• Risk of Fournier’s gangrene

‒ Assess patients presenting with pain, tenderness, erythema, swelling in genital

area; treat promptly

Additional Concerns: Warnings on all SGLT2 Inhibitors

American Diabetes Association. Diabetes Care. 2020;43:S1-S212; Garber AJ, et al. Endocr Pract. 2019;25:69-100; McGill JB, Subramanian S. Am

J Cardiol. 2019;124:S45-S52; Simes BC, MacGregor GG. Diabetes Metab Syndr Obes 2019;12:2125-2136.

35

SGLT2 Inhibitors Generally Are Well-Tolerated, but Rare

Serious Side Effects Can Occur

• GMIs are the most frequent side effect of treatment and respond to

antimycotic therapy

• Emphasize importance of adequate hydration due to potential for volume-

depletion side effects

• Consult with cardiologists and nephrologists to adjust BP and other

medications as needed

• Rare side effects include diabetic ketoacidosis, Fournier’s gangrene:

educate patients on signs and symptoms and treat promptly if occur

• Amputation and fracture risk cited in canagliflozin prescribing information,

but does not appear to be a class effect

36

• Individualize treatment based on goals and risks

‒ Partnership with patient, shared decisions

‒ Good communication and trust are essential

• Problem of nonadherence

‒ 20% to 30% of prescriptions for glucose-lowering drugs not filled

‒ ~50% of drugs not taken as prescribed

‒ Patients may feel fine and not perceive the need for treatment

‒ Patients may not understand consequences of nonadherence

Improving Outcomes With Patient-Centered Care

American Diabetes Association. Diabetes Care. 2020;43:S1-S212; Garber AJ, et al. Endocr Pract. 2019;25:69-100; Marden B. Martineau C.

www.pharmacytimes.com/publications/health-system-edition/2019/September2019/emphasize-medication-adherence-to-patients. Accessed June 1,

2020; Polonsky WH, Henry RR. Patient Prefer Adherence. 2016;10:1299-1307.

37

• Explore and address patient needs and preferences

• Motivational interviewing techniques to identify underlying issues

• Emphasize importance of adherence

• Simplify regimen as much as possible

‒ Oral vs injected; less frequent dosing; combined drugs in one tablet

• Educate patients about treatment options and possible side effects

Fostering Adherence

Dandona P, Chaudhuri A. Int J Clin Pract. 2017;71:e12937; Polonsky WH, Henry RR. Patient Prefer Adherence. 2016;10:1299-1307.

38

Reducing

cardiorenal riskWeight loss

Simplified

regimens

Manageable

side effects

Low

hypoglycemia

risk

Helping Patients Achieve Success

• Shared decision-making―educating patients while addressing concerns

about safety and efficacy―improves treatment adherence

• Greater adherence to therapy is associated with agents that meet other

personal or clinical goals, such as:

Battersby M, et al. Jt Comm J Qual Patient Saf. 2010;36:561-570; Dandona P, Chaudhuri A. Int J Clin Pract. 2017;71:e12937; Polonsky WH, et al.

Diabetes Obes Metab. 2011;13:144-149; Polonsky WH, Henry RR. Patient Prefer Adherence. 2016;10:1299-1307.

39

PCE Action Plan

✓ Consider SGLT2 inhibitors for patients with established HF, CKD, or ASCVD

✓ Use a patient-centered approach when collaborating on treatment goals and options

✓ Assess renal status prior to and periodically during treatment with SGLT2 inhibitors

✓ Consider SGLT2 inhibitors for patients who require glycemic control with weight loss and

cardiorenal protection

✓ Educate patients on side effect management and actions to minimize risk of volume

depletion and rare side effects

✓ Discuss patient priorities, ease of use, and formulary restrictions when selecting

antihyperglycemic regimens—watch for new agents and indications

PCE Promotes Practice Change

2020 Symposia Series 2