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Diabetes: the key things to understand Naveed Sattar Professor of - - PowerPoint PPT Presentation
Diabetes: the key things to understand Naveed Sattar Professor of - - PowerPoint PPT Presentation
Diabetes: the key things to understand Naveed Sattar Professor of Metabolic Medicine Duality of Interest Declaration Consultant or speaker for: Eli Lilly, Boehringer Ingelheim, Janssen, AstraZeneca, Novo Nordisk, Sanofi Grants: Boehringer
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ERFC (2010) Lancet
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44% 29%
Rashwani et al (2017) NEJM
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Heterogeneity in risks
- By age of onset
- T1 vs T2DM
- When combined with prior CVD
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Sattar et al (2019) Circulation
8-12 years 3-6 yrs
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Younger age of T1DM diagnosis associated with greater loss of life years (~16 years in those diagnosed <10 years, most 12 years)
Rawshani et al (2018) Lancet
16 years 10-12 yrs
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HF data Scotland-wide data T1>T2>No diabetes
McAllister et al (2018) Circulation
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Average presentations & risk paradigm in T1DM vs T2DM
T1DM Age CV risk Teenage years
T2DM
Healthy 45-60 years
Hyperglycaemia dominant early on Risks higher before Diagnosis- obesity HBP, abn. Lipids etc
Sattar (unpublished)
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Heterogeneity in risks
- By age of onset
- T1 vs T2DM
- When combined with prior CVD
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ERFC et al. JAMA 2015;314:52–60.
Background: diabetes plus CVD means very high risk premature mortality
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Turnbull FM et al. Diabetologia 2009;52:2288
Meta-analysis including 27,049 participants and 2370 major vascular events
No evidence from prospective trials that more intensive glycaemic control reduces mortality
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Hazard ratio (95% CI) ACCORD 257 (1.41) 203 (1.14)
- 1.01
ADVANCE 498 (1.86) 533 (1.99)
- 0.72
UKPDS 123 (0.13) 53 (0.25)
- 0.66
VADT 102 (2.22) 95 (2.06)
- 1.16
Overall 980 884
- 0.88
ACCORD 137 (0.79) 94 (0.56)
- 1.01
ADVANCE 253 (0.95) 289 (1.08)
- 0.72
UKPDS 71 (0.53) 29 (0.52)
- 0.66
VADT 38 (0.83) 29 (0.63)
- 1.16
Overall 497 441
- 0.88
All-cause mortality Cardiovascular death Trials Number of events (annual event rate, %) More intensive Less intensive ∆HbA1c (%)
Favours more intensive Favours less intensive
Overall HR (95% CI) 1.04 (0.90, 1.20) 1.10 (0.84, 1.42)
0.5 2.0 1.0
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Incretins
- (GIP)
- GLP-1
Stimulate insulin release Inhibit glucagon release Reduce blood glucose
DPP-4 Breakdown products DPP-4 inhibitors (“gliptins”) GLP-1 agonists/analogues e.g. exenatide Inhibit renal re-absorption (SGLT2 inhibitors)
New approaches to reducing blood glucose low hypo risks, weight neutral or loss
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T2DM Obesity
Traditional focus Novel
Insights
Lipids Glucose BP Thrombotic tendency
Insulin Renal SGLT2 Glomerular hyperfiltration TGF
- ther mechanisms?
Na+ & glucose retention Intravascular volume increase Accelerated Atherogenesis Volume Status/ Hemodynamic & Glomerular stress MI, CVA, PAD Heart Failure Kidney disease
Sattar N, McGuire D. Circulation (2018)
Diabetes to CVD pathways: more than atheroma
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GLP-1R Agonist CV Outcome Trials
3-component MACE
0,5 1 2
favours GLP-1RA favours placebo
ELIXA EXSCEL LEADER SUSTAIN-6 Harmony Outcomes Overall HR 0.95 (0.86-1.06) HR 0.82 (0.75-0.90) HR 0.88 (0.80-0.96)
Exendin-4 based Human GLP-1 based Test for heterogeneity I2 = 59% p-value =0.044
Kristensen SL et al (2019) TLDE (+ PIONEER 6 overall 0.88 (0.82 to 0.94))
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GLP-1R Agonist CV Outcome Trials: other
- utcomes
CV Mortality
ELIXA EXSCEL LEADER SUSTAIN-6 Harmony Overall
0,5 1 2
HR 0.91 (0.81-1.03) HR 0.85 (0.74-0.97)
HR 0.88 (0.80-0.96) Myocardial Infarction
ELIXA EXSCEL LEADER SUSTAIN-6 Harmony Overall
0,5 1 2
HR 0.99 (0.90-1.10) HR 0.81 (0.72-0.91)
HR 0.90 (0.80-1.00)
0,5 1 2
All cause Mortality
ELIXA EXSCEL LEADER SUSTAIN-6 Harmony Overall HR 0.88 (0.80-0.98) HR 0.90 (0.81-1.00)
HR 0.89 (0.83-0.96)
Stroke
ELIXA EXSCEL LEADER SUSTAIN-6 Harmony Overall
0,5 1 2
HR 0.93 (0.72-1.21) HR 0.84 (0.72-0.98)
HR 0.87 (0.77-0.97)
Kristensen SL et al (2019) TLDE (+ PIONEER 6/REWIND)
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GLP-1RA lessen HF
Kristensen SL et al (2019) TLDE
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Treatment algorithm in patients with T2DM and ASCVD or high/very high CV risk - drug naïve (1) ESC/EASD guideline 2019
ASCVD, or high / very high CV risk (target organ damage or multiple risk factors)a
a) Type 2 DM - Drug naïve patients SGLT2 inhibitoror GLP-1 RAMonotherapyb MetforminMonotherapy If HbA1cabove target If HbA1cabovetarget AddMetformin If HbA1cabovetarget
DPP-4i GLP-1 RA SGLT2i if eGFR adequate TZD
+
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Diabetes top lines for cardiology
- Diabetes doubles CVD risk beyond usual risk factors
- Risks down: LLT, BP Rx. Less smoking
– Intensive glucose lowering, benefits non-fatal CVD modestly
- Lifetime risks higher when:
– Younger onset T2 / T1DM / CVD & diabetes
- CVOT: agent type matters more than glucose-lowering per se