chronic care management: focus on diabetes · 3. discuss the role of diabetes in the promotion of...

CHRONIC CARE MANAGEMENT:

FOCUS ON DIABETES

FRIDAY/8:45-10:45AM

ACPE UAN: 0107-9999-20-026-L01-P 0.2 CEU/2.0 hr

Activity Type: Application-Based

Learning Objectives for Pharmacists:

Upon completion of this CPE course participants should be able to:

1. Evaluate the cardiovascular evidence available for commonly used diabetes medications.

2. Apply data from recent cardiovascular outcome trials to individualize and optimize a medication plan for

patients with diabetes.

3. Discuss the role of diabetes in the promotion of kidney disease.

4. Review the evidence to support the use of SGLT-2 inhibitors and GLP-1 receptor agonists in decreasing

progression of kidney disease in patients with type 2 diabetes.

5. Identify the possible benefits and limitations of technology aids that may aid adherence in patients with

diabetes.

Speakers: Emily Beckett, PharmD, BCPS

Emily Beckett is an Ambulatory Care Clinical Pharmacist with the Broadlawns Family Medicine

Residency Program and holds an Adjunct Clinical Faculty appointment with University of Iowa. She

received her Doctor of Pharmacy degree from the University of Iowa College of Pharmacy and

completed an ASHP-accredited PGY1 residency at Mercy Medical Center Des Moines. She

obtained her BCPS certification in 2013. She assists in the Family Medicine Anticoagulation clinic,

as well as provides diabetes education and management to family medicine patients. She assists

on-site medical residents with research projects and precepts University of Iowa pharmacy

students. Her professional interests include anticoagulation, diabetes and chronic disease

management, quality metric measurement, as well as professional education and nutrition. In her

free time, she enjoys biking, traveling, and spending time with her husband and three children.

Emily Knezevich, PharmD, BCPS, CDE, FCCP

Emily Knezevich is an Associate Professor of Pharmacy Practice at Creighton

University’s School of Pharmacy and Health Professions. She is a Board Certified

Pharmacotherapy Specialist and Certified Diabetes Educator who, along with her

teaching and scholarly requirements, maintains a clinical practice site at the CHI

Health - Dundee clinic in Omaha, Nebraska. Here, Dr. Knezevich is part of the Diabetes

Education team, serves as a drug information resource and provides medication

therapy management services for patients within the clinical practice. Her research

interests include pharmacotherapeutic management of endocrine disorders and identifying methods to

improve access to diabetes care in rural Nebraska and Iowa.

Jamie Pitlick, PharmD, BCPS, BC-ADM

Jamie Pitlick graduated from Drake University College of Pharmacy and Health Sciences on

2008 with a doctorate in pharmacy and a concentration in diabetes. After graduation she

continued her training with a PGY1 in Pharmacy Practice at St. Louis of Pharmacy/Mercy

Family Medicine in St. Louis, MO. She was then hired by St. Louis College of Pharmacy as an

Assistant Professor practicing in an internal medicine outpatient clinic. The focus of her

teaching and patient care for the 9 years in St. Louis was the management of chronic

diseases. In 2017, she transitioned back to Drake University as an Associate Professor and is

practicing at MercyOne Des Moines Endocrinology Care with a focus on teaching pharmacy students how to

care for patients with diabetes.

Speaker Disclosure: Emily Knezevich reports she is on the speaker’s bureau for Valeritas. The other speakers

report no actual or potential conflicts of interest in relation to this CPE activity. Off-label use of medications will

not be discussed during this presentation.

#RxExpo20

Chronic Care Management: Diabetes

Focus on Cardiovascular Evidence and Application

Emily Beckett, PharmD, BCPSClinical Pharmacist, Broadlawns Family Medicine Residency Program

Adjunct Faculty, University of Iowa February 2020

#RxExpo20

Disclosure

• Emily Beckett reports no actual or potential conflicts of interest associated with this presentation

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Learning Objectives

• Upon successful completion of this course, participants should be able to:

• Evaluate the cardiovascular evidence available for commonly used diabetes medications.

• Apply data from recent cardiovascular outcome trials to individualize and optimize a medication plan for patients with diabetes.

#RxExpo20

Informal Poll

• I understand and keep up with cardiovascular data for current diabetes medications

• Mostly Agree – I’m feeling pretty good…• Kind of – I try….• There is too much and it is difficult to keep up!

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Informal Poll

• I feel comfortable recommending appropriate diabetes medications for my patients with or at risk for heart disease

• Mostly Agree• Umm, kind of… with my hand half raised….• Mostly Disagree – this is why I’m attending this presentation!

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Diabetes and Cardiovascular Disease

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First, Do No Harm…

Home P. Diabetologia 2019;62:357-369.

Prior to 2000:

• Only 2 major cardiovascular (CV) outcomes trials studying diabetes medications

2006-7:

• Thiazolidinediones (TZDs) found to raise risk for CV adverse effects

• Myocardial infarction (MI) signal was discovered that pre- and post-marketing data did NOT detect

2008: FDA mandates diabetes meds mustbe reviewed in CV

outcomes trials (CVOTs)

• Pre-marketing: Must achieve a hazard ratio of less than 1.8 (upper 95% CI) for composite endpoint of first MI, stroke or CV death

• If upper limit of 95% CI falls between 1.3 and 1.8 – need a post-marketing trial with ULN < 1.3 for FDA approval

#RxExpo20

FDA Premarketing Requirements for CVOTs

Diabetes Care 2011; 34(Suppl 2): S101–S106.

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CVOT Timeline

Cefalu WT et al. Diabetes Care 2018;41:14‐31.

#RxExpo20

Dictionary Please!• MACE =

• Major Cardiovascular Events• Cardiovascular mortality• Myocardial infarction• Stroke• Can include hospitalization for acute coronary

syndrome, urgent revascularization procedures, and possibly other endpoints.

Home P. Diabetologia 2019;62:357‐369. FDA Center for Drug Evaluation and Research. Guidance for Industry Diabetes Mellitus: Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008.

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What do the

Guidelines Say?

American Diabetes Association. Diabetes Care 2020;43 (Supplement 1):S103.

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ASCVD and HF Footnotes

1. Proven CV benefits means it has label indication of reducing CV events.

1. Use a GLP-1 receptor agonist with known CVD benefits. Liraglutide is FDA approved to reduce the risk of MACE in adults with type 2 diabetes and established CVD; liraglutide and dulaglutide showed superiority for MACE outcomes in large CVOTs; semaglutide showed superiority for MACE outcomes in a safety CVOT. These results were primarily in patients with known ASCVD although there was consistent benefit in the dulaglutidetrial in patients with and without established ASCVD.

2. Be aware SGLT2i vary by region and individual agent with regard to indicated level of eGFR for initiation and continued use

3. Empagliflozin, canagliflozin and dapagliflozin have shown reduction in HF and reduction in CKD progression in CVOTs

4. Degludec and U100 glargine have demonstrated CVD safety

5. Low dose may be better tolerated though less well studied for CVD effects

American Diabetes Association. Diabetes Care 2020;43 (Supplement 1):S103.

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#RxExpo20Garber AJ et al. Endocrine Practice 2019;25:69‐100

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Which Diabetes Meds have CV Benefit?“Older” Agents• Metformin

• Improves CV outcomes compared to sulfonylureas (SU)• UKPDS showed metformin:

• Decreased MI, coronary deaths and all-cause mortality in newly diagnosed patients with T2DM with LOW CV risk

• 10-year follow-up: metformin-treated patients CONTINUED to show a reduction in MI and death from any cause

• Bottom line: Continue to recommend metformin first-line for all patients

UK Prospective Diabetes Study group. Lancet 1998;352:837‐865.Holman RR et al. N Engl J Med 2008;359:1577‐1589.

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Which Diabetes Meds have CV Benefit?“Older” Agents• Sulfonylureas (SUs)

• 3 recent trials FAILED to demonstrate an INCREASE in CVD mortality/morbidity in patients using SUs

• ADVANCE trial showed severe hypoglycemia was associated with significant increase in major macrovascular events and death from CV cause

• Recent study showed SU monotherapy versus metformin monotherapy was associated with severe hypoglycemia, INCREASED risk of MI and all-cause mortality

• Bottom line: Results are mixed• Consider alternative agents with stronger evidence for CV benefit in appropriate

patients• If using SUs – avoid hypoglycemia

UK Prospective Diabetes Study group. Lancet 1998;352:837‐853.Patel A et al. N Engl J Med 2008;358:2560‐2572.

Action to Control Cardiovascular Risk in Diabetes study group. N Engl J Med;2008;358:2545‐59.Douros A et al. BMJ 2018;362:k2693.

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Which Diabetes Meds have CV Benefit?“Older” Agents• Pioglitizone

• PROactive study showed no significant CV benefit in primary endpoint• Secondary endpoint showed CV benefit in patients with MACROvascular disease

• IRIS study showed:• Significant benefit in preventing stroke in patients with previous stroke• More frequent weight gain, edema, bone fractures

• Recent meta-analysis in patients with CV disease showed reduction of recurrent major CV events (RR 0.74; 95% CI: 0.60-0.92)

• Bottom line: Pioglitizone likely has CV benefit, at least in certain patients• Consider alternative agents with stronger evidence for CV benefit in appropriate

patients• If using, monitor for weight gain, edema, heart failure exacerbations, etc.

Dormandy JA et al. Lancet 2005;366:1279‐1289.Wilcox R et al. Stroke 2007;38:865‐873.

Kernan WN et al. N Engl J Med 2016:374:1321‐1331.De Jong M et al. Cardiovasc Diabetol 2017;12:134.

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Which Diabetes Meds have CV Benefit?“Newer” Agents: DPP4 Inhibitors• Proposed CV benefits

• Increased ischemia tolerance• Improved endothelial function• Decreased inflammatory

response• Decreased platelet

aggregation?

• 5 current DPP4 inhibitor CVOTs• 4 medications studied:

• Sitagliptan (Januvia)• Saxagliptan (Onglyza)• Alogliptan (Nesina)• Linagliptan (Tradjenta)

Zhang Z et al. Cardiovasc Diabetol 2017;16:31.Nauck MA et al. Circulation 2017:136:849-870.

#RxExpo20

DPP4i CVOTsInclusionCriteria

Primary Outcome CV Death MI StrokeHF

hospitalizationAll‐causemortality

Alogliptan(EXAMINE)N=53801.5yr follow‐up

T2DM + history of ACS

3‐point MACE0.96 (ULN ≤1.16)

0.85 (0.66‐1.10)

1.08(0.88‐1.33)

0.91 (0.55‐1.50)

1.19(0.90‐1.58)

0.88 (0.71‐1.09)

Saxagliptin(SAVOR‐TIMI)N=164922.1yr follow‐up

T2DM + preexisting

CVD/risk factors

3‐point MACE1.00 (0.89‐1.12)

1.03 (0.87‐1.22)

0.95 (0.80‐1.12)

1.11 (0.88‐1.39)

1.27 (1.07‐1.51)

1.11(0.96‐1.27)

Sitagliptan(TECOS)N=146713.0yr follow‐up

T2DM + preexisting CVD

4‐point MACE0.98 (0.89‐1.08)

1.03 (0.89‐1.19)

0.95(0.81‐1.11)

0.97(0.79‐1.19)

1.00 (0.83‐1.20)

1.01 (0.90‐1.14)

Linagliptan(CARMELINA)N=69912.2yr follow‐up

T2DM + high risk for CVD

3‐point MACE1.02 (0.89‐1.17)

0.96 (0.81‐1.14)

1.12(0.90‐1.40)

0.91(0.67‐1.23)

0.90(0.74‐1.08)

0.98 (0.84‐1.13)

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Which Diabetes Meds have CV Benefit?“Newer” Agents• DPP4 inhibitors

• Bottom line:• No INCREASED risk for CV events, mortality, or all-cause mortality• However, NO signal for CV benefit, either• Saxagliptin shows a statistically significant 27% increase in risk of heart failure

hospitalization• ADA recommends avoiding saxagliptin in patients with heart failure

• Post-hoc analysis of alogliptin study showed increased risk of heart failure hospitalization in patients WITHOUT history of heart failure

• Not noted in patients with pre-existing heart failure

• Sitagliptin and linagliptin appear to be heart failure neutral

Scirica BM et al. N Engl J Med 2013; 369:1317-1326.Zannad F et al. Lancet 2015; 385:2067-2076.

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Which Diabetes Meds have CV Benefit?“Newer” Agents: GLP-1 receptor agonists (GLP-1 RAs)

• Proposed CV benefits• Blood pressure reduction

• Reduced myocardial work, reduced filling pressures, pre- and afterload reduction

• Decreased body weight/waist circumference from early satiety and delayed gastric emptying

• Decreased cholesterol• Even LDL reduction!

• Anti-inflammatory action• Increased nitric oxide regulation,

decreasing arterial stiffness, decreased CRP and BNP

• Less risk of hypoglycemia• Decreased platelet aggregation?

• 8 current GLP-1 RA CVOTs• 7 medications studied:

• Lixisenatide (Adlyxin)• Liraglutide (Victoza)• Semaglutide SQ (Ozempic) and oral (Rybelsus)• Exenatide (Byetta, Bydureon)• Dulaglutide (Trulicity)• Albiglutide (Tanzeum – not available in US)

Zhang Z et al. Cardiovasc Diabetol 2017;16:31.Nauck MA et al. Circulation 2017:136:849‐870.

Deedwania P et al. Amer J of Cardvasc Drugs 2019; 19:249‐257.Das SR, et al. J Am Coll Cardiol 2018;72:3200–3223.

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GLP-1 RA CVOTs

InclusionCriteria



Lixisenatide(ELIXA)N=60682.1yr follow‐up

T2DM + history of ACS

4‐point MACE1.02 (0.89‐1.17)

0.98 (0.78‐1.22)

1.03(0.87‐1.22)

1.12 (0.79‐1.58)

0.96 (0.75‐1.23)

0.94 (0.78‐1.13)

Liraglutide(LEADER)N=93403.8yr follow‐up

T2DM + preexisting

CVD/CKD/HF OR w/ CV risk factors

3‐point MACE0.87 (0.78‐0.97)

0.78 (0.66‐0.93)

0.86 (0.73‐1.00)

0.86 (0.71‐1.06)

0.87 (0.73‐1.05)

0.85(0.74‐0.97)

Exenatide ER(EXSCEL)N=147523.2yr follow‐up

T2DM + with or without

CVD

3‐point MACE0.91 (0.83‐1.00)

0.88 (0.76‐1.02)

0.97(0.85‐1.10)

0.85(0.70‐1.03)

0.94 (0.78‐1.13)

0.86 (0.77‐0.97)

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GLP-1 RA CVOTs

InclusionCriteria



Semaglutide SQ(SUSTAIN)N=32972.1yr follow‐up

T2DM + preexisting

CVD/CKD/HF OR w/ CV risk factors

3‐point MACE0.74 (0.58‐0.95)

0.98 (0.65‐1.48)

0.74 (0.51‐1.08)

0.61(0.38‐0.99)

1.11 (0.77‐1.61)

1.05 (0.74‐1.50)

Dulaglutide(REWIND)N=99015.4yr follow‐up

T2DM + preexisting

CVD/risk factors

3‐point MACE0.88 (0.79‐0.99)

0.91 (0.78‐1.06)

0.96 (0.79‐1.15)

0.76 (0.62‐0.94)

0.93 (0.77‐1.12)

0.90(0.80‐1.01)

Semaglutide PO(PIONEER 6)N=31831.3yr follow‐up

T2DM + preexistingCVD/CKD OR

w/ CV risk factors

3‐point MACE0.79 (0.57‐1.11)

0.49 (0.27‐0.92)

1.18(0.73‐1.90)

0.74(0.35‐1.57)

0.86(0.48‐1.55)

0.51 (0.31‐0.84)

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GLP-1 RA Summary

Variable BEST (lowest) upper CI

WORST (highest) upper CI

MACE Semaglutide SQ0.74 (0.58-0.95)Liraglutide 0.87 (0.78-0.97)

Lixisenatide1.02 (0.89-1.17)

CV Death Semaglutide PO0.49 (0.27-0.92)Liraglutide 0.78 (0.66-0.93)

Semaglutide SQ0.98 (0.65-1.48)

MI Liraglutide 0.86 (0.73-1.00)

Semaglutide PO1.18 (0.73-1.90)

Stroke Dulaglutide0.76 (0.62-0.94)

Lixisenatide1.12 (0.79-1.58)Semaglutide PO0.74 (0.35-1.57)

HF hospitalization

Liraglutide 0.87 (0.73-1.05)


All-cause mortality

Semaglutide PO0.51 (0.31-0.84)


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GLP-1 RA Summary

Non

infe

rior

Non

infe

rior

but

NO

T S

uper

ior

Non

infe

rior

AN

D S

UP

ER

IOR

Liraglutide

Dulaglutide

Lixisenatide

Exenatide ER

Semaglutide PO

Semaglutide SQ

Primary Outcome

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GLP-1 RA Bottom Line

• GLP-1 receptor agonists – Bottom line:

• Lixisenatide: noninferior but NOT superior• CV neutral, no beneficial effect on any CV

outcome• Liraglutide: noninferior and SUPERIOR

• Driven by reduction in CV and all-cause death; trend toward numerical benefit in MI, stroke and HF hospitalization

• FDA indication: To reduce risk of MACE in patients with T2DM and established CVD

• Exenatide ER: noninferiorbut NOT superior

• Only driven by decrease in all-cause death; NO difference in CV death, MI, stroke, etc

• Semaglutide SQ: noninferior (not powered for superiority)

• Significant decrease in non-fatal stroke; trend toward decrease in non-fatal MI

• NO trend for CV death or all-cause mortality• Increased retinopathy risk

• Dulaglutide: non-inferior and SUPERIOR• Only driven by decrease in non-fatal stroke;

NO difference in CV death, MI, or all-cause death

• Trend towards increase in hospital admission for unstable angina and fatal MI

• Semaglutide PO: noninferior and NOT superior

• Significant decrease in CV death and all-cause mortality; trend toward INCREASE in non-fatal MI

• NO trend for stroke or HF hospitalization


GLP‐1 RA Superior? Comments

Lixisenatide NO • CV neutral, no beneficial effect on any CV outcome

Liraglutide YES • Driven by reduction in CV and all‐cause death; trend toward numerical benefit in MI, stroke and HF hospitalization

• FDA indication: To reduce risk of MACE in patients with T2DM and established CVD

Exenatide ER NO • Only driven by decrease in all‐cause death; NO difference in CV death, MI, stroke, etc

Semaglutide SQ ?? (not powered for superiority)

• Significant decrease in non‐fatal stroke; trend toward decrease in non‐fatal MI• NO trend for CV death or all‐cause mortality• Increased retinopathy risk

Dulaglutide YES • Only driven by decrease in non‐fatal stroke; NO difference in CV death, MI, or all‐cause death

• Trend towards increase in hospital admission for unstable angina and fatal MI

Semaglutide PO NO • Significant decrease in CV death and all‐cause mortality; trend toward INCREASE in non‐fatal MI

• NO trend for stroke or HF hospitalization

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GLP-1 RA Considerations

• Contraindications• Severe renal impairment/ESRD (exenatide, lixisenatide)• Personal or family history of medullary thyroid cancer• Medullary Endocrine Neoplasia Type 2 (MEN2)

• Cautions• Pancreatitis• Hypoglycemia if using with insulin or SU• Gastroparesis, gastric surgery• Semaglutide – increased risk of retinopathy

Das SR, et al. J Am Coll Cardiol 2018;72:3200–3223.

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GLP-1 RA Considerations for Initiation

• If A1c well-controlled or frequent hypoglycemia:• Reduce SU by 50% or basal insulin by 20%

• Discontinue DPP4i before starting

• Start low, go slow to mitigate nausea and other GI side effects• Aim for doses in CVOTs

• Encourage appropriate, guideline-recommended eye exams annually


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Which Diabetes Meds have CV Benefit?“Newer” Agents - SGLT-2 inhibitors

• Proposed CV benefits• Diuresis and naturesis

• Pre-/afterload reduction• Reductions in SBP (up to 6mmHg)• Weight loss

• Reduction in albuminuria• Reduced HF risk

• Shift to more efficient ketone-based metabolism• Blockade of sodium/hydrogen cotransporter

• Kidney and heart tissue protection

• Less risk of hypoglycemia

• 4 current true SGLT-2i CVOTs (others for HF and CKD)

• 4 medications studied:• Canagliflozin (Invokana)• Empagliflozin (Jardiance)• Dapagliflozin (Farxiga)• Ertugliflozin (Steglatro)

Zhang Z et al. Cardiovasc Diabetol 2017;16:31.Nauck MA et al. Circulation 2017:136:849-870.

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InclusionCriteria

PrimaryOutcome(s)

CV Death MI StrokeHF


Empagliflozin(EMPA‐REG)N=70203.1yr follow‐up

T2DM + preexisting CVD

3‐point MACE0.86 (0.74‐0.99)

0.62 (0.49‐0.77)

0.87 (0.70‐1.09)

1.18(0.89‐1.56)

0.65 (0.50‐0.85)

0.68 (0.57‐0.82)

Canagliflozin(CANVAS)N=101422.4yr follow‐up

T2DM + preexisting

CVD/risk factors

3‐point MACE0.86 (0.75‐0.97)

0.87 (0.72‐1.06)

0.85 (0.69‐1.05)

0.90 (0.71‐1.15)

0.67 (0.52‐0.87)

0.87(0.74‐1.01)

Dapagliflozin(DECLARE)N=171604.2yr follow‐up

T2DM + preexisting

CVD/risk factors

3‐point MACE0.93 (0.84‐1.03)

CV Death or HF hosp0.83 (0.73‐0.95)

0.98 (0.82‐1.17)

0.89 (0.77‐1.01)

1.01 (0.84‐1.21)

0.73 (0.61‐0.88)

0.93 (0.82‐1.04)

SGLT2i CVOT Data

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SGLT2i real world data


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Which Diabetes Meds have CV Benefit?“Newer” Agents• SGLT-2 inhibitors

• Bottom line:• Empagliflozin: Non-inferior and SUPERIOR

• Driven by CV death (MI favored empagliflozin, stroke favored placebo)• Also demonstrated benefit in all-cause mortality and HF hospitalization• FDA indication: To reduce risk of CV death in patients with T2DM and CV disease

• Canagliflozin: Non-inferior and SUPERIOR• Unique statistics – all secondary results deemed ‘exploratory’

• Did see benefits in HF hospitalization (?); trend towards benefit for MI, stroke, CV death and all-cause mortality

• Amputation risk increased• FDA indication: To reduce risk of MACE in patients with T2DM and CV disease

• Dapagliflozin: Non-inferior for MACE but SUPERIOR for CV death/heart failure hospitalization

• No difference in CV death, all-cause death, MI or stroke


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SGLT2i Considerations• Contraindications

• Severe renal impairment, ESRD, dialysis

• Cautions• Watch for intravascular volume contraction

• AKI, hypotension• Hypoglycemia if using with insulin or SU• Increased risk of mycotic genital infections and UTIs• Euglycemic ketoacidosis in vulnerable patients• History of prior amputation, severe PVD, neuropathy or foot ulcers

• Especially with canagliflozin and ertugliflozin• Increased bone fracture risk (canagliflozin)• Osteoporosis (canagliflozin)


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SGLT2i Considerations for Initiation

• If A1c well-controlled or frequent hypoglycemia:• Reduce SU by 50% or basal insulin by 20%

• Avoid hypovolemia• May need to reduce thiazide/loop diuretic dose• Educate patients on AKI, hypotension symptoms

• Educate patients on ketoacidosis symptoms• Even if euglycemic

• Encourage routine foot examinations• Monitor kidney function• Educate regarding potential genital mycotic infections


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Comparing Classes

Fei et al. Cardiovasc Diabetol (2019) 18:112

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Comparing Classes

Fei et al. Cardiovasc Diabetol (2019) 18:112

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Considerations for Choosing Med Class

Goals when choosing GLP-1 RA first• Reducing MACE and stroke• Substantial weight loss• Once weekly SQ dosing• Therapy when eGFR consistently

<45mL/min/1.73m2

• Consider alternative agent if:• Persistent nausea• History of pancreatitis• History of gastroparesis• History of MEN2 or medullary thyroid

cancer• History of retinopathy (semaglutide)

Goals when choosing SGLT2i first• Reducing MACE and CV death• Preventing HF hospitalization• Reducing BP• Orally administered therapies• Consider alternative agent if:

• Significant CKD• History of genital infection, AKI• History of DKA• History of amputation, PAD• History of osteoporosis (canagliflozin)


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Application and Future Directions

• Things to keep in mind about the CVOTs discussed:• What if patient is not on baseline metformin prior to these meds?• What are the CV benefits if A1c is at goal?• What are the benefits (and risks) beyond 2-5 years?

• Is all CV disease diagnosed within 5 years of treatment?• Are all harms of medications apparent within 5 years of treatment?

• Current/Future CVOTs• Ertugliflozin CVOT (VERTIS CV)• Sotagliflozin CVOT (SCORED)• SGLT2 trials for patients with HF

• Dapagliflozin, empagliflozin, sotagliflozin

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Are CVOTs the End All, Be All?

• Apples vs. Oranges

• Nearly all CVOTs used placebo-comparator – but with both groups having “similar” glycemic control

• What medications were used in the placebo group to attain ‘similar’ glycemic control?

• Were these meds causing more CV events in the placebo group?

• Were groups really “similar”?• Treatment groups generally

had lower A1c, BP, more diuretic use – is that why the CV benefit?

• Most findings only pertain to patients with or at high risk of CV events

• May lack generalizability to larger population

Cefalu WT et al. Diabetes Care 2018;41:14‐31. Shimazawa R. J Pharm Policy and Prac 2019;12 (30)Kabadi, UM. WJMPR 2017;3(11):33‐35.

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Take Home Points

• Continue using metformin first-line for all appropriate patients• SGLT2 inhibitors and GLP-1 RAs appear to have the most

benefit for reducing major CV events• SGLT2i – CV mortality and heart failure hospitalization reduction

• Empagliflozin appears strongest• GLP1 RA – Stroke reduction

• Liraglutide and dulaglutide appear strongest

• Balance CV benefits of newer diabetes medications with known side effects

• Continue watching for new CVOT results/discussion and FDA indications!

#RxExpo20

Case• LA is a 67yo AA male presenting to you wondering if he needs a new diabetes med

• PMH = T2DM, HFrEF, hypertriglycemia, hypertension, IBS-C

• Meds:• Metformin 1g BID• Lantus 25 units QAM• Metoprolol succinate 100mg daily• Lisinopril 10mg daily• Bumetanide 1mg daily• Rosuvastatin 20mg daily• Fenofibrate 27mg daily

• Labs:• BMP WNL• A1c = 8.1%

• Vitals• BP = 141/92mmHg• HR = 66 bpm

• Pertinent physical exam:• Bilateral pitting edema

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Case

• Which of the following medications would be the best addition to get his A1c to goal and potentially provide benefit for his other co-morbidities?

A. Pioglitizone PO daily

B. Saxagliptin PO daily

C. Semaglutide SQ weekly

D. Empagliflozin PO daily

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Case

• Based on your choice, what side effect would be most important to monitor for?

A. Pedal edema

B. Retinopathy

C. Hypotension

D. Hypoglycemia

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Thank You!

• February 8 – National Iowa Day

• John Wayne’s dad was a pharmacist

“Tomorrow hopes we have learned something from yesterday”

-John Wayne

• Questions?

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Diabetes and Kidney Disease

Emily Knezevich, Pharm.D., CDE, BCPS, FCCP

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Disclosure

• Dr. Knezevich reports:• Speaker’s bureau member for Valeritas

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Learning Objectives


• Discuss the role of diabetes in the promotion of kidney disease• Review the evidence to support the use of SGLT-2 inhibitors and GLP-

1 receptor agonists in decreasing progression of kidney disease in patients with type 2 diabetes

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Case Study• EM is a 68yo Caucasian male with T2DM, HTN, HLD and COPD and OA limiting range of

motion in both knees. Calculated 10-yr ASCVD risk is 18%, eGFR is 58mL/min and A1c is 8.2%. UACR is 400mg/g. Today's BP is 142/76mm Hg. He reports difficultly adhering to low carb/low calorie diet but would like to lose a significant amount of weight to help improve his health and mobility.

• Medications:• Metformin 1g bid• Lisinopril 20mg daily• Chlorthalidone 12.5mg daily• Atorvastatin 80mg daily• Meloxicam 15mg daily• Anoro Elipta 62.5/25mcg: 1 puff daily

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Diabetic Kidney Disease - Defined

• “presence of albuminuria and/or reduced eGFR in the absence of signs or symptoms of other primary causes of kidney damage”

• Typically (but not always) associated with: • Long duration of diabetes• Retinopathy • Albuminuria without gross hematuria• Gradually progressive loss of eGFR

Akhtar et al. Adv Anat Pathol 2019; Epub ahead of print2020 ADA Standards

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Normal kidney morphology and structural changes in diabetes mellitus.

Radica Z. Alicic et al. CJASN 2017;12:2032-2045

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Radica Z. Alicic et al. CJASN 2017;12:2032-2045

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Prevalence of DKD in the US• Approximately 8.2 million people with DKD

• 4.6 million with albuminuria (> 30mg/g)• 1.9 million with macroalbuminuria (> 300mg/g)• 4.5 million with reduced eGFR (< 60mL/min/1.73m2)• 0.9 million with severely reduced eGFR (< 30mL/min/1.73m2)

• Diagnosis of DM increased from 6% 9.8% of US population in the past 20 years

• Prevalence DKD has not significantly changed (26.2% of those with DM)

• Albuminuria prevalence decreased (from 20.8% to 15.9%) while reduced eGFR increased (from 9.2% to 14.1%)

Afkarian M, et al. JAMA 2016;316:602‐610.

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CKD Staging

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DKD

Risks and Outcomes

Estimated risk of developing similar in both T1 and T2

25‐40% risk, may take 10‐20 years to manifest (could be present at dx of T2)

Diabetes is the leading cause of ESRD in the US

Dialysis/Kidney Transplant $$$ & Lower QOL

DKD increases risk for CVD

Increased risk of Death

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Financial Implications of Diabetes

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DKD as a predictor of

Mortality

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Risk Factors for DKD

Age

Duration of Diabetes

Ethnicity

Family history of CKD

Hyperglycemia Smoking

Hypertension Obesity

Hyperlipidemia Hyperuricemia

Recurrent Infections

NON‐MODIFIABLE MODIFIABLE

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Recommendations for patients with DKD

• Measure eGFR and albuminuria at least annually in those with diabetes

• After diagnosis of T1D, can wait 5 years until monitoring begins

• If urinary albumin > 30mg/g or eGFR < 60mL/min/1.73m2, monitor every 6 months

• Use ACE-I or ARB if UACR > 30mg/g

• Maintain dietary protein ~0.8g/kg/day (non-dialysis)

• Select pharmacotherapy that will prevent progression of renal disease

• Consider patient "high risk" when designing lipid lowering regimen

Diabetes Care 2020 Jan; 43 (Supplement 1): S135‐S151

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Medication Management

Type 2 Diabetes with Kidney Disease

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Medications that can be used safely in DKD• Metformin1

• Contraindicated if eGFR < 30 ml/min/1.73m2

• Use with caution when eGFR 30-45ml/min/1.72m2

• Do not initiate and consider using lower doses

• Sulfonylureas• Glipizide agent of choice, often dosed once daily due to reduced

elimination1

• Pioglitazone• May result greater decline in GFR, but has been shown to reduce

composite of all-cause mortality, MI and stroke) in those with CKD2

• May cause volume and bone loss

1. Knezevich E. Journal of Diabetes Nursing 20: 358–63 2. Schneider C. JASN January 2008, 19 (1) 182‐187;

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Medications that can be used safely in DKD• Meglitinides

• Repaglinide preferred due to lack of active metabolites1

• DPP-IV inhibitors• All have demonstrated safety at appropriate doses

• Linagliptin does not require dose adjustment• None have shown delay in progression of renal disease in CVOT’s done

prospectively• Saxagliptin post-hoc analysis of CVOT demonstrated reduced

progression/development2

• Insulin• Typically requires lowered dose• Evidence to support glargine 300 vs. NPH or U100 in reducing hypoglycemia

risk3

1. Knezevich E. Journal of Diabetes Nursing 20: 358–63 2. Scirica et al. N Engl J Med 2013; 369:1317‐13263. Betonico C et al. Clinical Therapeutics, Volume 41, Issue 10, 2008 ‐ 2020.e3

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Medications that may SLOW progression of renal disease

GLP‐1 Receptor Agonists

SGLT‐2 Inhibitors

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Mechanism for GLP-1 RA use in DKD

• Hemodynamic changes • Induction of natriuresis and diuresis

• Augment Tubuloglomerular feedback• Reduced renin and angiotensin levels

• Anti-inflammatory effects• May be responsible for albuminuria reduction• Reduction in inflammation, oxidative stress, weight, hyperglycemia and

blood pressure

Williams D et al. Diabetes Ther (2019). https://doi.org/10.1007/s13300‐019‐00747‐3

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Evidence for GLP-1 Agonists in DKD Study Drug Renal Outcome Results

ELIXA Lixisenatide • UACR

• 10% decrease in UACR with lixi(p=0.004)

• Similar median UACR at BL (< 30mg/g)

• Little clinical significance

SUSTAIN‐6 Semaglutide • Onset/worsening of nephropathy• HR 0.64 (0.46‐0.88) in

semaglutide group

LEADER Liraglutide• Composite microvascular outcome• Composite nephropathy

• HR 0.84 (0.73‐0.97) for composite microvascular

• Findings driven down by reduction in nephropathy events (HR 0.78 (0.67‐0.92)


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Evidence for GLP-1 Agonists in DKD

Study Drug Renal Outcome Key Findings

REWIND Dulaglutide • Renal composite outcome• HR 0.85 (0.77‐0.93 for decrease in renal

outcome

AWARD‐7 (non‐CVOT)

Dulaglutide vs. insulin glargine

• eGFR and UACR

• eGFR higher after 1 year with dulaglutide1.5mg (34ml/min/1.73m2) vs. glargine (31.3ml/min/1.73m2) p=0.005

• UACR reduction not significantly different between meds

EXCEL Exenatide • Renal composite• HR 0.85 for renal composite for exenatide

vs. PBO


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Limitations with GLP-1 data

• All CVOT results were from secondary outcomes

• Many different outcomes analyzed makes interpretation difficult• Projected use of MARE (major adverse renal event) in the future to

standardize

• Most patients in CVOT’s did not have advanced kidney disease• Very few had eGFR’s < 45mL/min/1.73m2 or UACR > 300mg/g• Studies of efficacy and safety of GLP-1 RA’s in those with reduced

eGFR include very few patients

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Mechanism for SGLT-2i’s use in DKD

• Hemodynamic and tubular factors• Reduction in hyperfiltration

• Reduction in inflammatory markers and renal fibrosis• Increased activity of SGLT-2 receptor in response to hyperglycemia

promotes production of pro-inflammatory cytokines

• Address risk factors for renal disease• Lower blood pressure• Reduce weight


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SGLT-2 inhibitors effect on GFR

Cherney et al. Circulation. 2014;129:587‐597.

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Synergism of ACE/ARB + SGLT‐2 inhibition

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SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis

• Study Design• Systematic Review & Meta-analysis

• EMPA-REG OUTCOME• CANVAS Program• DECLARE-TIMI 58• CREDENCE

• Participants • Baseline renal function & use of RAS

blockade varied greatly

Neunen et al. Lancet Diabetes & Endocrinology, The, 2019‐11‐01, Volume 7, Issue 11, Pages 845‐854.

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SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis

Neunen et al. Lancet Diabetes & Endocrinology, The, 2019‐11‐01, Volume 7, Issue 11, Pages 845‐854

Zelniker TA, et al. Lancet. 2019;393:31‐39.

• Standardized composite of renal outcomes

• composite of chronic dialysis, kidney transplantation, or death due to kidney disease

• End‐stage renal disease

• Renal or CV death

Endpoints

• Baseline eGFR < 45mL/min: 30% reduction

• Baseline eGFR 45‐60mL/min: 45% reduction

• Baseline eGFR 60‐90mL/min: 40% reduction

• Baseline eGFR >90mL/min: 63% reduction

Composite Renal Outcome

Overall, 42% decrease in worsening renal function, end‐stage renal disease, death due to kidney disease (CI 0.51‐0.66)

• DKA: composite 2.2x increased risk

• Incidence: <1 per 1000 patient‐years

• Increased risk of fracture and amputation only seen in canagliflozin

From previous meta‐analysis not including CREDENCE:

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Effect of SGLT-2i on composite of dialysis, transplantation, or death due to kidney disease

#RxExpo20Neunen et al. Lancet Diabetes & Endocrinology, The, 2019‐11‐01, Volume 7, Issue 11, Pages 845‐854.

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Summary of effects on Major kidney outcomes

Neunen et al. Lancet Diabetes & Endocrinology, The, 2019‐11‐01, Volume 7, Issue 11, Pages 845‐854.

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CREDENCE: Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation

Perkovic V et al. N Engl J Med. 2019;380(24):2295‐2306.

•Randomized, double‐blind, placebo‐controlled, multicenter trial

Study design

•4401 patients 30+ years old, A1c 6.5%‐12%*

•Chronic kidney disease: eGFR > 30 ‐ <90 mL/min/1.73m2 AND albuminuria (UACR >300 ‐ ≤ 5000mg/g)

•60% of patients eGFR 30‐60mL/min/1.73m2

•Stable dose of ACE/ARB 4 weeks prior

Participants

•Composite of:

•End‐stage renal disease

•Doubling of SCr for >30 days

•Death from renal or CV disease

Primary Endpoints

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CREDENCE: Trial Design

Perkovic V, et al. N Engl J Med. 2019;380(24):2295‐2306.Jardine MJ, et al. Am J Nephrol 2017;46(6):462‐472.

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CREDENCEResults

Perkovic V,, et al. N Engl J Med. 2019;380(24):2295‐2306.

Efficacy Canagliflozin Placebo Hazard Ratio P‐value

Primary CompositeOutcome

245/2202 340/2199 0.70 (0.59‐0.82) 0.00001

Doubling of SCr 118/2202 188/2199 0.60 (0.48‐0.76) <0.001

End‐stage kidney disease

116/2202 165/2199 0.68 (0.54‐0.86) 0.002

Safety

Amputation* 70/2200 63/2197 1.11 (0.79‐1.56) NA

Fracture 67/2200 68/2197 0.98 (0.70‐1.37) NA

DKA 11/2200 1/2197 10.80 (1.39‐83.65) NA

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CREDENCE: Subgroup analysis


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Primary Composite Outcome

22Patients

ESKD, Doubling of serum creatinine, or renal death

28 Patients

ESKD

43 Patients

Hospitalization for heart failure CV death, MI, or stroke

46 patients 40 Patients

CREDENCE: Numbers Needed to Treat


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CREDENCE: Questions remain

Critique• Did not include patients with

very advanced kidney disease, non-albuminuric or microalbuminuric disease, or kidney disease caused by something besides type 2 diabetes

• Did not include 300mg Canagliflozin in trial

Perkovic V et al. N Engl J Med. 2019;380(24):2295‐2306.

Jardine MJ et al. Am J Nephrol 2017;46(6):462‐472.

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Standards of medical care in diabetes - 2020• 11.3 For patients with type 2 diabetes and diabetic kidney disease, consider use of a sodium–

glucose cotransporter 2 inhibitor in patients with an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 and urinary albumin >30 mg/g creatinine, particularly in those with urinary albumin >300 mg/g creatinine, to reduce risk of chronic kidney disease (CKD) progression, cardiovascular events, or both. A In patients with CKD who are at increased risk for cardiovascular events, use of a glucagon-like peptide 1 receptor agonist may reduce risk of progression of albuminuria, cardiovascular events, or both (Table 9.1). C

Diabetes Care 2020 Jan; 43(Supplement 1): S98‐S110

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Case Study• EM is a 68yo Caucasian male with T2DM, HTN, HLD and COPD and OA limiting range of

motion in both knees. Calculated 10-yr ASCVD risk is 18%, eGFR is 58mL/min and A1c is 8.2%. UACR is 400mg/g. Today's BP is 142/76mm Hg. He reports difficultly adhering to low carb/low calorie diet but would like to lose a significant amount of weight to help improve his health and mobility.

• Medications:• Metformin 1g bid• Lisinopril 20mg daily• Chlorthalidone 12.5mg daily• Atorvastatin 80mg daily• Meloxicam 15mg daily• Anoro Elipta 62.5/25mcg: 1 puff daily

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Case Study

• Taking maximum dose of metformin

• Needs additional therapy if adherence demonstrated

A1c is above target –patient's goal likely < 7%

• Patient does have CKD with eGFR < 60mL/min and UACR > 30mg/g

• ASCVD risk < 20% and no hx of CVD mentioned

Does patient have ASCVD, HF or CKD?

•Would benefit from BP reduction

• Would benefit from weight reduction

• Cost as a barrier was not mentionedOther considerations

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Diabetes Care 2020 Jan; 43(Supplement 1): S98-S110

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Take Home Points

Diabetes is a strong predictor for developing chronic kidney disease which significantly impacts healthcare costs & mortality

SGLT‐2 inhibitors provide renal protection independent of their glucose‐lowering abilities with canagliflozin being the only agent currently being FDA

labeled to do so

GLP‐1 RA's demonstrate reduction in progression of renal disease, but only studied as secondary outcomes

2020 ADA Standards of Care recommend use of SGLT‐2 inhibitors to prevent progression of kidney disease in addition to their benefit as glucose lowering agents

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Thank you for your Attention!

Emily Knezevich

[email protected]

402-280-3710

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Chronic Care Management: Focus on Diabetes: Utilizing Technology to

Improve AdherenceJamie Pitlick, Pharm.D., BCPS, BC-ADM

Associate Professor, Pharmacy Practice

Drake University College of Pharmacy and Health Sciences

MercyOne Des Moines Diabetes and Endocrinology Care

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Disclosure

• Jamie Pitlick reports no actual or potential conflicts of interest associated with this presentation

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Learning Objectives


• Identify the possible benefits and limitations of technology aids that may aid adherence in patients with diabetes.

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What is your comfort with continuous glucose monitoring?

a)Absolutely no comfortb)Ahh, it’s okayc)Got it downd)I’m an expert

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Adherence• Current state for patients with type 2 diabetes

• Oral medications: 33%• Insulins: 38%

• Traditional Strategies• Education on disease management• Simplification of dosing regimen• Counselling• Reminders

• Digital Solutions• Mobile text messaging• Two way communication

Krass et al, Diabet Med 2015; 32; 725‐737. Huang et al, BMC Medicine 2019; 17:127. Haider, et al, Diabetes Research and Clinical Practice 2019; 153: 184-190.

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Mobile Health Applications• Explosion of Applications

• Blood glucose levels could be recorded• Goal setting (37%)• Reminders (27.8%)• Alerts to glucose out of range (58%)

• Clinical decision making to alerts: 26.7%

• Mobile Diabetes Intervention Study• The act of using a diabetes application and interacting with the provider

through that application decreased A1c 0.62%

• Can these applications improve patient engagement?

Lum et al, JAMA 2019; 321; 1530‐1532. Quinn et al, JMIR Mhealth Uhealth 2018; 6:e31.

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Mobile Health Applications• Persuasive technology

• Using the theory of information, motivation, and behavioral skills model of self-care

• Combined with technology through a mixture of automated text messaging, and messages from a personal coach

• Improved glycemic control for Korean patients with prediabetes and diabetes

Kim et al, Patient Educ Couns. 2019; 102: 709 – 717.

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Self-Monitoring of Blood Glucose

• Meters

• Continuous Glucose Monitoring (CGM)

Monitoring of blood sugars alone does not lower blood glucose levels to be useful the information must be integrated into clinical and self-management plans

Diabetes Care 2020;43(Suppl. 1)

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CGM Reports

Freestyle Libre User Guide; Dexcom G6 User Guide. Lind et al, JAMA 2017; 317:379-387; Diabetes Care 2020;43(Suppl. 1)

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Comparison of CGMType Calibration Treatment

DecisionsWear time

Alarms Data View Insulin Pump Connection

Freestyle Libre

isCGM No Yes 14 days No Scanned to receiver or smartphone

No

Medtronic Guardian 3

rtCGM Yes No 7 days Yes (audible) Smartphone Yes

DexcomG6

rtCGM No Yes 10 days Yes (audible) Receiver, smartphone, other smart devices

Yes

Eversense rtCGM Yes Yes 90 days Yes (audible and vibration)

Smartphone No

Adapted from Kruger et al, The Diabetes EDUCATOR; 2019.

rtCGM: realtime CGM; isCGM: intermittently scanned CGM

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Continuous Subcutaneous Insulin Infusion Pumps (CSII)

Tandem.com; myomnipod.com; Medtronicdiabetes.com

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CSII Therapy

Improved controlReduced HbA1c Reduced risk of severe hypoglycemia

Additionally in childrenDecreased rates of DKADecreased rates of retinopathy and peripheral neuropathyTreatment satisfactionQuality of life

Diabetes Care 2020;43(Suppl. 1). Vallejo Mora et al, Diabetes Technol Ther 2017; 19: 402-409.

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Closed-loop CSII Technology

• Sensor-linked to pump technology• 1st phase: auto suspend of basal rate• 2nd phase: hybrid-closed loop system• 3rd phase: closed-loop system (not FDA approved)

• Hybrid-closed Loop System and Closed-Loop Systems• Time in range: ↑ 11 – 14%• A1c: ↓ 0.33 – 0.75%

Messer et al, Diabetes Care 2018; 41: 789-796. Brown et al, N Engl J Med. 2019; 381:1707-1717.

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Smart Insulin Pens• InPen combines

• Diabetes management app• Bluetooth®-enabled pen injector

• Use InPen like any other pen injector. • Tracks each dose and delivers the data to the app on

• Diabetes Management App• Displays active insulin• Last recorded blood glucose• Last insulin dose• Personalized reminders to take insulin• Calculates and recommends next dose• Tracks when insulin will expire• Senses if it has been stored outside of the recommended

temperature range

InPen User Guide.

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Take Home Points

• Technology is helpful to try to increase patient engagement in their treatment plan

• Some technologies have improved clinical outcomes

• Only as good as the patient using them

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Question #1

• True or False: Monitoring blood glucose levels will lower a patient’s A1c.

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Question #1

• True or False: Monitoring blood glucose levels will lower a patient’s A1c.

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Question #2

• Which of the following is a benefit of continuous glucose monitoring?

a. Increased treatment burdenb. Increased time in hypoglycemia rangec. Increased time in target glucose ranged. Increased standard deviation of blood glucose

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Question #2

• Which of the following is a benefit of continuous glucose monitoring?

a. Increased treatment burdenb. Increased time in hypoglycemia rangec. Increased time in target glucose ranged. Increased standard deviation of blood glucose

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Chronic Care Management: Focus on Diabetes: Utilizing Technology to

Improve AdherenceJamie Pitlick, Pharm.D., BCPS, BC-ADM

Associate Professor, Pharmacy Practice

Drake University College of Pharmacy and Health Sciences

MercyOne Des Moines Diabetes and Endocrinology Care

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chronic care management: focus on diabetes · 3. discuss the role of diabetes in the promotion of...

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