Evidence-Based New

Therapies in Diabetes

Subbulaxmi Trikudanathan, MD, MRCP, MMSC

Clinical Associate Professor

University of Washington Medical Center

WAFP Meeting- July 2020

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Disclosures and Financial conflicts

• Research support from Sanofi, vTv

therapeutics, Tolerion Inc. and Insulet

corporation

Learning objectives

• Interpret the evidence from cardiovascular outcome trials

with sodium glucose co-transporter -2 (SGLT-2 )

inhibitors and Glucagon like peptide (GLP-1) receptor

agonists.

• Implement treatment plans for ASCVD and heart failure

patients with T2 Diabetes using SGLT-2 inhibitors and

GLP-1 receptor agonists.

• Identify strategies for facilitating effective patient focused

collaborative care

• Cardiovascular disease is a major cause of

death and disability in people with diabetes.

• About 2/3 rd of deaths in diabetes are

attributable to CVD

• Every 10 years of diabetes is associated with

86% increase in risk of death from CVD

Diabetes Care, Volume 41, May 2018

Diabetes and Cardiovascular Disease (CVD)

• CVD occurs 10-15 years earlier in patients with diabetes

compared with those without diabetes

• 1% ↑ in A1c is associated with 10-30%

increase in CVD risk

• Heart failure is frequently forgotten complication of T2

diabetes – 2.4 to 5-fold increased risk

Wang CL et al Circulation 2016;133:2459-2502

Economic burden of diabetes

• Total estimated cost of diagnosed

diabetes in 2017 - $ 327 billion

• Direct medical costs- $ 237 billion

• Lost productivity - $90 billion

• Antidiabetic agents and insulin- $ 30.9

billion

Diabetes Care, Volume 41, May 2018

Economic burden of diabetes

• Estimated $37.3 billion in cardiovascular-

related spending is associated with

diabetes

Diabetes Care, Volume 41, May 2018

Value in Health 21(2018):881-890

• Obese

• HTN, Hyperlipidemia

• H/o CAD s/p PTCA

• Recent hospitalization for

heart failure with EF - 32%

• Background retinopathy

• No prior foot ulcers

• Microalbuminuria

• OSA on CPAP

On maximal dose of

• Metformin

• ARB

• Beta blockers

• MRA

• Statin

• Aspirin

Pt :SC60 yr male with T2 Diabetes with A1c of 7.5

Established ASCVD with HF

What next?

• Add sulfonylurea

• Add pioglitazone

• Add SGLT2 inhibitors

• Add DPP- IV inhibitors

• Add GLP-1 receptor agonists

Indicators of High Risk or Established ASCVD, CKD or HF

Consider Independently of Baseline A1c or Individualized A1c Target

SGLT2 inhibitors

Glucose regulation in a non diabetic

individual

Chao EC, Discovery medicine 2011

SGLT2 inhibitorsDosage Renal adjustment

Canagliflozin

(Invokana)

100mg -300 once daily >60ml/min –No dose adjustment

45-60ml/min –max 100mg

SGLT-2 inhibitors and CVOT’s

NEJM Sept 17,2015

32%RR 35%RR

38%RR

Empa Reg Cardiac Outcomes

Zinman B et al NEJM ,2015

RR-35%

Meta-analysis of SGLT-2 inhibitors on hospitalizations

for HF and CV death in the presence of ASCVD

Zelniker T et al Lancet 2019;393:31-39

Zelniker T et al Lancet 2019;393:31-39

Meta-analysis of SGLT-2 inhibitors – HF and CV death stratified by history of HF

4744 pts treated with dapagliflozin 10mg vs placebo followed over 18 months

Patients with HFrEF

• NYHA class II-IV

• EF≤40%

• With/without T2D

• eGFR≥ 30ml/min

• Stable std of care HF treatment

Primary Outcome

Composite of

• CV death

• Hospitalization for HF

• Urgent HF visit

McMurray JJ et al NEJM 2019;381:1995-2008

Mechanisms of CV protection by SGLT-2 inhibitors

• Reduction in preload – secondary to natriuresis

and osmotic diuresis

• Reduction in afterload from reduction to BP and

improvement in vascular function

• Change in substrate composition – increase in

ketones

• Beta hydroxybutyrate “super fuel” –taken up by

both kidney and heart in a very efficient way and

it is not insulin dependent

• Obese

• HTN, Hyperlipidemia

• H/o CAD s/p PTCA

• Recent hospitalization for

heart failure with EF -32%

• Background retinopathy

• No prior foot ulcers

• Proteinuria

• CKD with eGFR - 48ml/min

• OSA on CPAP

On maximal dose of

• Metformin

• ARB

• Beta blockers

• Statin

• Aspirin

Pt :SC60 yr male with T2 Diabetes with A1c of 7.5

Established ASCVD with HF and CKD

NEJM July 28, 2016

Renal Outcomes of EMPA –REG study

Meta-analysis of SGLT-2 inhibitors – Renal Composites in the presence of

Established ASCVD

SGLT2 inhibitors and renal outcomes in kidney

disease – CREDENCE

• N=~4400; 34% women; 50% with ASCVD

• Included eGFR 30-90ml/min/1.73m2; uACR 300-5000 mg/g

• Primary outcome: ESKD, doubling of serum creatinine, and renal or CV

death

• Stopped early for efficacy (2.6y)

Perkovic V et al N Engl J Med 2019 April; Cherney and Verma Cell Metabolism 2019

Additional benefits of SGLT -2 inhibitors

• Weight loss of 1.5 to 2 kg

• Low risk for hypoglycemia when combined

with metformin

• Additional effect – BP reduction

• Drop in systolic BP by 3 to 5 mm Hg

McGill JB and Subramanian S Am J Cardiol.2019 Dec 15;124 Suppl 1 S45-S52

10 -11%

Caution in

elderly

SGLT-2 inhibitors – take home points

• 11% reduction in MACE

• 23% reduction in hospitalization for heart

failure and CV death

• 45% reduction in the risk of progression in

renal disease

• Reduction of A1c -0.7 to 0.9%

Zelniker T et al Lancet 2019;393:31-39

• Obese

• HTN, Hyperlipidemia

• H/o CAD s/p recent PTCA x2

• LVEF - preserved

• Background retinopathy

• No prior foot ulcers

• Microalbuminuria

• NASH

On maximal dose of

• Metformin

• Sulfonyl urea

• Insulin Glargine 40 units

once

daily

• ARB

• Beta blockers

• Statin

• Aspirin

Pt : AD68 yr female with T2 Diabetes with A1c of 8.9

T2 D with predominant ASCVD

Glucagon – Like – Peptide-1(GLP -1) receptor

agonists

Mechanisms of action

• Enhances insulin secretion in a glucose

dependent fashion

• Suppresses glucagon in a glucose

dependent way

• Slows gastric emptying

• Enhances satiety

Overall reduction of A1c-1 to 1.5%

GLP-1 receptor agonists and CV outcomes

9340 patients with type 2 diabetes and high cardiovascular risk

randomized to receive Liraglutide or placebo.

Median follow up 3.8 years

• Patients in the liraglutide group had a lower risk of the primary outcome

–first occurrence of cardiovascular death, non fatal myocardial infarction

or non fatal stroke

• The number of patients needed to be treat to prevent one event in 3

years was 66

• Fewer hospitalizations for heart failure in the liraglutide group although

the difference was not significant .

REWIND - Dulaglutide

• Dulaglutide 1.5mg weekly

• N=9,901

• Multicenter study -24 countries

• T2D ~10y, A1C 7.3%

• Mean age 66y

• Higher proportion of women (46%)

• 31% with ASCVD

• Decreased 3 point MACE;

demonstrated superiority

• Magnitude of effect – modest but

consistent with effect size seen in

meta-analyses

Gerstein H et al Lancet 2019;394:121-30

RR-12%

RR -24%

Meta-analysis of CVOTs with GLP-1

receptor agonist and MACE

Giugliano et al Diabetes Obes Metab.2019;21:2576-2580

Sheahan KH et al Postgrad Med J 2019;0:1-6

Meta-analysis of CVOTs with GLP-1 receptor

agonist and HF

Giugliano et al Diabetes Obes Metab.2019;21:2576-2580

No single GLP-1 receptor agonists was associated with a

significant reduction in HF risk

• GLP-1 receptor agonists reduced risk of broad

composite kidney outcome significantly by 17% mainly

driven by a reduction in macroalbuminuria (24%) without

affecting the decline in eGFR

• Meta-analysis of GLP-1 receptor agonists found a 15%

risk reduction of nonfatal stroke in patients with T2

diabetes (REWIND and PIONEER study)

Giugliano et al Diabetes Obes Metab.2019;21:2576-2580

Zelniker et al Circulation 2019;139;2022-2031

Aroda V lancet Diabetes Endocrinol.2020 Feb ;8(2):90-92

Heuvelman V et al ESC cardiovascular Research (2020)0,1-15

Mechanisms of CV protection by GLP-1 receptor agonists

Dosage Renal adjustment

Exenatide (Byetta) Start 5mcg bid,

increase to 10mcg after

1 month

Not recommended if

eGFR

Side effect profile of GLP-1 receptor

agonists

• GI side effects – 13 to 44% primarily nausea,

diarrhea and vomiting

• No hypoglycemia with monotherapy, can occur

in combination therapies

• Cases of acute pancreatitis have been reported

Not used if

• Family history of medullary thyroid cancer

• Prior history of medullary thyroid cancer

• Multiple endocrine neoplasia -2

Combination therapies

• Insulin glargine and

lixisenatide (100/33)

• Insulin degludec and

liraglutide (100/3.6)

Take home points

• There is a paradigm shift in using glucose lowering

therapies for improving cardio renal outcomes

• SGLT-2 inhibitors have robust benefits on reducing

hospitalization for heart failure and progression of renal

disease with moderate benefits on MACE outcomes

• GLP-1 receptor agonists have moderate benefits in

reducing major cv events with reduction in nonfatal

stroke and macroalbuminuria

Take home points

• Comprehensive cardiovascular risk reduction

that include smoking cessation, blood pressure

control, lipid management with priority to statin

medications must continue to be major focus of

therapy

• All treatment decisions, where possible, should

be made in conjunction with the patient, focusing

on his/her preferences, needs and values

UW MEDICINE DIABETES INSTITUTE

Combining diabetes care, research and education

Clinical Services

• Diabetes care clinic• Group education class• Insulin pump and CGM class• Implantable glucose sensors• Nutrition support• Young Adult transition clinic• Mental health services• Lipid clinic• Cardiology clinic• Echo services• Surgical weight loss clinic• Nephrology clinic

Thank you