The Contemporary management of Type 2 Diabetes in the Older Adult

Professor Jonathan Shaw

Disclosures

• Advisory Committee: Astra Zeneca; Sanofi; Novo Nordisk; MSD; Eli Lilly; Abbott

• Lectures: Mylan, Astra Zeneca; Sanofi; Boehringer Ingelheim

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Outline

• Guidelines in the elderly

• Glucose-lowering drugs to prevent CVD and kidney disease

• Cholesterol lowering and BP lowering in the elderly

Learning objectives

• What glycaemic targets should be used in the elderly

• Which glucose-lowering drugs prevent CVD and kidney disease

• Which glucose-lowering could cause problems in the elderly

• What are the benefits and risks of cholesterol lowering and BP lowering in the elderly

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American Diabetes Association 2019

12.5 Older adults who are otherwise healthy with few coexisting chronic illnesses and intact cognitive function and

functional status should have lower glycemic goals (such as A1C <7.5% [58 mmol/mol]), while those with multiple

coexisting chronic illnesses, cognitive impairment, or functional dependence should have less stringent glycemic goals

(such as A1C <8.0–8.5% [64–69 mmol/mol]). C

12.6 Glycemic goals for some older adults might reasonably be relaxed as part of individualized care, but

hyperglycemia leading to symptoms or risk of acute hyperglycemia complications should be avoided in all patients. C

12.7 Screening for diabetes complications should be individualized in older adults. Particular attention should be paid

to complications that would lead to functional impairment. C

12.8 Treatment of hypertension to individualized target levels is indicated in most older adults. C

12.9 Treatment of other cardiovascular risk factors should be individualized in older adults considering the time frame

of benefit. Lipid-lowering therapy and aspirin therapy may benefit those with life expectancies at least equal to the time

frame of primary prevention or secondary intervention trials. E

PERSONAL USE ONLY

Guideline recommendations for key clinical outcomes for older people with diabetes from Diabetes Canada (DC), American Diabetes Association (ADA) and International Diabetes Federation (IDF)Measure ADA DC IDF

A1C Healthy:<7.5%

Complex/Intermediate:<8.0%

Very Complex/Poor Health:<8.5%

Functionally Independent: < 7.0%Functionally Dependent: 7.1‐8.0%Frail and/or Dementia:7.1‐8.5%End of Life: A1C measurement not recommended. Avoid symptomatic hyperglycemia and any hypoglycemia.

Functionally Independent: 7.0‐7.5%Functionally Dependent: 7.0‐8.0%Sub‐level Frail: <8.5%Sub‐level Dementia: <8.5%End of Life: avoid symptomatic hyperglycemia

Blood Pressure Healthy: <140/80 mmHg

Complex/Intermediate: <140/80 mmHg

Very Complex/Poor Health:  <150/90 mmHg

Functionally independent with life expectancy > 10 yrs:  <130/80 mmHg  

Functionally dependent, orthostasis or limited life expectancy: individualize BP targets

Functionally Independent: <140/90 mmHgFunctionally Dependent: <140/90 mmHgSub‐level Frail: <150/90 mmHgSub‐level Dementia: <140/90 mmHgEnd of Life: strict BP control may not be necessary

LDL‐C <1.8 mmol/L <2.0 mmol/L <2.0 mmol/L and adjusted based on CV risk 

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YES

• Insulin

• Sulphonylureas

Drugs causing hypoglycaemia

NO

• Metformin

• Acarbose

• DPP4 inhibitors

• GLP1 agonists

• SGLT2 inhibitors

• Thiazolidinediones

Do glucose lowering agents prevent CVD?

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Does aggressive glucose-lowering prevent MI and stroke in T2DM?

Yes - probably

Small benefits in some trials, not in others

Maybe trials were too short

Maybe drugs that cause hypos or weight gain are not ideal

Turnbull et al. Diabetologia. 2009;52:2288-98.

Major CV events - 9% reduction

MI - 15% reduction

DPP4i and CV outcome trials

Does saxagliptin (DPP4 i) prevent CVD?

Days79838071

77617836

72677313

48554920

851847

PlaceboSaxagliptin 

82128280

Patients W

ith Endpoints (%) 1

412108

6

4

2

00 1

80

360

540

720

900

HR 1.00; 95% CI, 0.89–1.12P<0.001 (NI)P=0.99 (superiority)

Saxagliptin: 7.3%*Rate/100 person‐yrs – 3.7

Placebo: 7.2%*Rate/100 person‐yrs – 3.7

White et al. NEJM 2014; 370:483‐484Scirica BM, et al. NEJM 2013; 369:1317‐1326Green JB et al. NEJM 2015 373:232‐242

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Dapagliflozin

Empaglifozin

Canagliflozin

SGLT2 inhibitors and CV outcomes

Trial design

Study medication was given in addition to standard of care Glucose-lowering therapy was to remain unchanged for first 12 weeks

All participants had established CVD

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Randomised and treated

(n=7020)

Empagliflozin 10 mg(n=2345)

Empagliflozin 25 mg (n=2342)

Placebo (n=2333)

Screening(n=11531)

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Empagliflozin

Primary outcome: 3-point MACE – 14% reduction

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HR 0.86(95.02% CI 0.74, 0.99)

p=0.0382*

Cumulative incidence function. HR, hazard ratio Zinman. NEJM. 2015;373(22):2117-28

EmpagliflozinCV death – 38% reduction

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HR 0.62(95% CI 0.49, 0.77)

p<0.0001

Zinman. NEJM. 2015;373(22):2117-28Cumulative incidence function. HR, hazard ratio

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EmpagliflozinHospitalisation for heart failure – 35% reduction

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HR 0.65(95% CI 0.50, 0.85)

p=0.0017

Zinman. NEJM. 2015;373(22):2117-28Cumulative incidence function. HR, hazard ratio

EmpagliflozinAll-cause mortality – 32% reduction

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HR 0.68(95% CI 0.57, 0.82)

p<0.0001

Zinman. NEJM. 2015;373(22):2117-28Kaplan Meier. HR, hazard ratio

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EmpagliflozinRenal outcomes – reduced by 40-45%

17Wanner. N Engl J Med 2016;375:323-34

Canagliflozin CV outcome trial CANVAS

Primary outcome14% reductionp=0.02

Neal et al. NEJM 2017

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Canagliflozin CV outcome trial CANVAS

Primary (3‐pt MACE) outcome:  14% reduction; p=0.02

Neal et al. NEJM 2017

Cardiovascular death:  13% reduction; p=NS

Hospitalization for heart failure:  33% reduction; p<0.01

Renal outcomes:  40% reduction; p<0.01

Dapagliflozin effect on CV and renal events

CVD/HHF4.9% vs 5.8%HR 0.83 (0.73‐0.95)P(Superiority) 0.005

Dapagliflozin

Placebo

Wiviott. NEJM 2018. DOI: 10.1056/NEJMoa1812389

Dapagliflozin is not indicated to reduce the risk of CV events, CV death or hHF or treatment of CKD

Renal Composite EP 40%↓ eGFR, ESRD, Renal or CV death

4.3% vs. 5.6%HR 0.76 (0.67‐0.87)P<0.001

N=17,160 (60% primary prevention)

No significant benefit for MACE or mortality

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Effect of SGLT2i on MACE (MI, stroke and CV death)

Zelnicker. Lancet 2018

Dapagliflozin is not indicated to reduce the risk of CV events, CV death or hHF or treatment of CKD

Effect of SGLT2i on heart failure/CV death

Zelnicker. Lancet 2018

Dapagliflozin is not indicated to reduce the risk of CV events, CV death or hHF or treatment of CKD

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Renal outcomes – stratified by baseline renal function

Zelnicker. Lancet 2018Dapagliflozin is not indicated to reduce the risk of CV events, CV death or hHF or treatment of CKD

Exenatide – twice daily/once weekly

Liraglutide

Lixisenatide

Dulaglutide

Semaglutide

GLP 1 agonists and CV outcomes

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GLP1 agonists and CV outcomes

Liraglutide

CV death, non-fatal

MI or CVA – reduced

by 13%

Marso. N Engl J Med. 2016;375:311-22

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Does semaglutide prevent CVD?

Marso. N Engl J Med 2016; DOI: 10.1056/NEJMoa1607141.

GLP1 Agonists and CV outcomes

Lixisenatide

Liraglutide

Semaglutide

Exenatide

Lixisenatide

Liraglutide

Semaglutide

Exenatide

Bethel. Lancet Diabetes Endocrinol 2018; 6: 105–13

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REWIND trial - dulaglutide

Baseline characteristics of 9901 participants

Title

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Title

ADA, American Diabetes Association; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; CVOTs, cardiovascular outcome trials; EASD, European Association for the Study of Diabetes; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycated haemoglobin; HF, heart failure; SGLT2, sodium-glucose cotransporter 2; SGLT2i, SGLT2 inhibitors; T2D, type 2 diabetes.Davies MJ, et al. Diabetologia. 2018. 2018;61:2461-2498.

If SGLT2i not tolerated or contraindicated or if eGFR less than adequate, add GLP-1 RA

with proven CVD benefit

HF or CKD predominates

GLP-1 RAwith provenCVD benefit

SGLT2iwith provenCVD benefit,

if eGFR adequate

SGLT2i with evidence of reducingHF and/or CKD progression in CVOTs

if eGFR adequate

EITHER/OR

OR

PREFERABLY

First-line therapy is metformin and comprehensive lifestyle modification(including weight management and physical activity).

If HbA1c above target proceed as below

The 2018 ADA-EASD T2D consensus report

ASCVD predominates

Dapagliflozin is not indicated to reduce the risk of CV events, CV death or hHF or treatment of CKD

Precautions – SGLT2i

• Risk of polyuria (caution with loop diuretics) and genital infections

• Risk of DKA

• Stop during intercurrent acute illness and 3/7 pre-surgery

• Less glucose lowering with worse renal function

• eGFR <60 – dapagliflozin contra-indicated

• eGFR <45 – empagliflozin contra-indicated

• WATCH THIS SPACE

• ? Avoid in those at risk of amputation

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Precautions – GLP1 agonists

• Nausea – usually disappears after 2-3/52

• Renal impairment

• Dulaglutide – ‘not recommended’ if eGFR <30

• Exenatide – ‘contra-indicated’ if eGFR <30

• Patient administration vs clinic administration

• Avoid in people with prior pancreatitis

Effects of blood pressure lowering in the elderly – SPRINT trial

Williamson. JAMA. 2016;315(24):2673‐2682.

Broad range of CV benefits for BP lowering

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Effects of blood pressure lowering in the elderly – SPRINT trial

Williamson. JAMA. 2016;315(24):2673‐2682.

Benefits of BP‐lowering were present irrespective frailty status

Effects of blood pressure lowering in the elderly –SPRINT trial

Williamson. JAMA. 2016;315(24):2673‐2682.

Adverse effects of blood pressure lowering in the elderly – SPRINT trial

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Aspirin for primary prevention in diabetes – ASCEND

ASCEND. NEJM 2018. DOI: 10.1056/NEJMoa1804988

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Effect of aspirin on death in older people

McNeil. NEJM 2018. DOI: 10.1056/NEJMoa1803955

Effect of aspirin on cardiovascular events in older people

McNeil. NEJM 2018. DOI: 10.1056/NEJMoa1805819

Major haemorrhageCVD events

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Effect of aspirin on disability (death, dementia or permanent disability)

in older people

McNeil. NEJM 2018. DOI: 10.1056/NEJMoa1800722

CTC Trialists. Lancet 2019; 393: 407–15

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Effects of statins in different age-groups

CTC Trialists. Lancet 2019; 393: 407–15

Effects of statins in different age-groups

CTC Trialists. Lancet 2019; 393: 407–15

‘Interpretation:Statin therapy produces significant reductions in major vascular events irrespective of age, but there isless direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease.’

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Summary

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