Post on 20-Aug-2020
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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