Prof. Dr. Stephan Jacob Internist, endocrinologist, diabetologist, - - PowerPoint PPT Presentation

AG Herz und Diabetes

• Prof. Dr. Stephan Jacob

Internist, endocrinologist, diabetologist, clinical hypertension specialist ESH Cardio-Metabolic-Institute Villingen-Schwenningen

Faculty Disclosure Stephan Jacob

I I have received a research grant(s)/ in kind support

A From current sponsor(s) NO B From any institution NO

II I have been a speaker or participant in accredited CME/CPD

A From current sponsor(s) YES B From any institution YES NO

III I have been a consultant/strategic advisor etc

A For current sponsor(s) YES NO B For any institution YES NO

IV I am a holder of (a) patent/shares/stock ownerships

A Related to presentation NO B Not related to presentation NO

Declaration of financial interests For the last 3 years and the subsequent 12 months:

Faculty Disclosure

Declaration of non-financial interests: German diabetes association (DDG) Board member of working group diabetes and the heart Board member of working group diabetes prevention German Hypertension Association (DHL) board member of commission Hypertension and metabolism

Coronary heart disease Coronary death Non-fatal myocardial infarction Cerebrovascular disease Ischaemic stroke Haemorrhagic stroke Unclassified stroke Other vascular deaths 2.00 (1.83 – 2.19) 2.31 (2.05 – 2.60) 1.82 (1.64 – 2.03) 1.82 (1.65 – 2.01) 2.27 (1.95 – 2.65) 1.56 (1.19 – 2.05) 1.84 (1.59 – 2.13) 1.73 (1.51 – 1.98) HR (95% CI) 26 505 11 556 14 741 11 176 3799 1183 4973 3826 Number

• f cases

64 (54 – 71) 41 (24 – 54) 37 (19 – 51) 42 (25 – 55) 1 (0 – 20) 0 (0 – 26) 33 (12 – 48) 0 (0 – 26) I2 (95% CI)

1 2 4

Hazard Ratio (diabetes vs. no diabetes) Outcome

Data from 528,877 participants – adjusted for age sex, cohort, SBP, smoking, and BMI BMI, body mass index; CI, confidence interval; HR, hazard ratio; SBP, systolic blood pressure Seshasai SR et al. Lancet. 2010; 375: 2215–2222

AND MICROVASCULAR COMPLICATIONS

A simplified view Diabetes= Hyper- glycemia

measured as

HbA1c

as a measure of MEAN glycemia

HbA1c

Renal problems Retino- pathy Poly- Neuropathy CHD PVD Stroke CHF DEATH

Type 2 Diabetes… close associations epidemiology

Jacob 2018

Epidemiology

Adjusted incidence per 1000 person years (%)

HbA1c, glycosylated haemoglobin. Stratton et al. Diabetologia 2006;49:1761–9

Incidence rate and 95% confidence intervals for any end point related to diabetes by category of updated mean haemoglobin HbA1c concentration, adjusted for age, sex, and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean duration of diabetes of 10 years Updated mean haemoglobin HbA1c concentration (%) 160 140 120 100 80 40 60 20 5 7 6 8 9 10 11

Higher HbA1c predicts higher CV risk

Reference category (hazard ratio 1.0) is HbA1c <6% with log linear scales CV, cardiovascular; HbA1c, glycosylated haemoglobin; MI, myocardial infarction; PVD, peripheral vascular disease Stratton IM et al. BMJ 2000;321:405–412

Hazard ratio Hazard ratio 10 10

p<0.0001

1 Amputation/death from PVD 6 5 7 8 9

p=0.021

Heart failure 6 5 7 8 9 10 10 1 10 1

p<0.0001

Fatal & non-fatal MI 10 6 5 7 8 9

p=0.035

Fatal & non-fatal stroke 10 1 6 5 7 8 9 10

HbA1c (%) HbA1c (%) 43% decrease per 1% reduction in HbA1c 16% decrease per 1% reduction in HbA1c 14% decrease per 1% reduction in HbA1c 12% decrease per 1% reduction in HbA1c

A simplified view Diabetes= Hyper- glycemia

measured as

HbA1c

as a measure of MEAN glycemia

Diabetes

• Management

=

HbA1c-

Management

A simple consequence

• UKPDS

7 vs 7.9

• ADVANCE

6.3 vs 7

• VADT

6.9 vs 8.4

• ACCORD

6.4 vs 7.5

HbA1c, glycosylated haemoglobin

MAX diff. 1.5%

What could we expect?

• 1.5%

>6.5 years

Hazard ratio Hazard ratio 10 10

p<0.0001

1 Amputation/death from PVD 6 5 7 8 9

p=0.021

Heart failure 6 5 7 8 9 10 10 1 10 1

p<0.0001

Fatal & non-fatal MI 10 6 5 7 8 9

p=0.035

Fatal & non-fatal stroke 10 1 6 5 7 8 9 10

HbA1c (%) HbA1c (%) 43% decrease per 1% reduction in HbA1c 16% decrease per 1% reduction in HbA1c 14% decrease per 1% reduction in HbA1c 12% decrease per 1% reduction in HbA1c

Higher HbA1c predicts higher CV risk

Reference category (hazard ratio 1.0) is HbA1c <6% with log linear scales CV, cardiovascular; HbA1c, glycosylated haemoglobin; MI, myocardial infarction; PVD, peripheral vascular disease Stratton IM et al. BMJ 2000;321:405–412

VADT –1.5%

?

And no reduction in microvascular!!

CAVE! ……legacy

Good glycaemic control ….matters in T2DM

10- and 20-year follow-up data from UKPDS

*p<0.05; intensive vs. conventional treatment. MI, myocardial infarction; UKPDS, UK Prospective Diabetes Study; T2DM, type 2 diabetes mellitus

• 1. Adapted from: Holman et al. N Engl J Med 2008;359:1577–1589; 2. UKPDS Group. Lancet 1998;352:837–853

1977–1991 Randomisation 2008 (20-year follow-up) 10-year post-trial follow-up period (non-interventional) UKPDS original results: Intensive vs. conventional treatment 12%* 25%* 16% 1998 (10-year follow-up)

Any diabetes-related endpoint MI Microvascular disease

9%* 24%* 15%*

“…During years 6 to 10, because of funding constraints, … questionnaires were used to follow all patients remotely. After the censoring date of post-trial monitoring (September 30, 2007), final questionnaires were sent to all remaining patients”

Keep in mind: Co-medication

ASA, acetylsalicylic acid

Do we still have these UKPDS- patients?

VADT Legacy

2013 No reduction of MACE Some reduction of microvascular Hypos and weight

Insulin degludec

Anti-hyperglycaemic medication in the last 90 years

LAR, long-acting release; SGLT-2, sodium-glucose cotransporter-2. Adapted from: Schernthaner G. Internist 2012;53:1399–1410

12 in 25 years

5 in 70 years

Animal Insulin Sulfonylureas Metformin Human Insulin Acarbose Insulin Lispro Glitazone (Pioglitazone) Glinide Insulin Glargine Insulin Aspart Insulin Detemir Pramlintide Exenatide/Liraglutide Sitagliptin/Vildagliptin Saxagliptin/Linagliptin Exenatide LAR SGLT-2 inhibitors

”OUTCOME“ Studies

Safety Efficacy

No Harm with new TX

[NNH]

Benefit

• f new TX

[NNT]

Jacob 2015

FDA requirement

CVOTs in diabetes

• *Estimated enrolment.

CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase-4 inhibitor; ER, extended release; GLP-1RA, glucagon-like peptide-1 receptor agonist; ITCA 650, continuous subcutaneous delivery of exenatide; PPAR- receptors-αγ, peroxisome proliferator‐activated receptors-α and γ; QW, once weekly; SGLT-2i, sodium-glucose cotransporter 2 inhibitor; SU, sulphonylurea; T2DM, type 2 diabetes mellitus. ClinicalTrials.gov. Accessed 20 September 2017

2019 2015 2020 2013 2014 2016 2017 2018 2021

Published results Ongoing

Insulin SGLT-2i GLP-1RA DPP-4i PPAR-αγ 2022

TECOS (Sitagliptin, DPP-4i) n=14671; duration ~3 yrs Q4 2014 – RESULTS DEVOTE (Insulin degludec, insulin) n=7637; duration ~2 yrs Q2 2017 – RESULTS CAROLINA (Linagliptin, DPP-4i vs SU) n=6072; duration ~8 yrs completion Q1 2019 CARMELINA (Linagliptin, DPP-4i) n=8300*; duration ~4 yrs completion Q4 2018 SAVOR TIMI-53 (Saxagliptin, DPP-4i) n=16492; follow-up ~2 yrs Q2 2013 – RESULTS FREEDOM-CVO (ITCA 650, GLP-1RA in DUROS) n=4000; duration ~2 yrs completion Q2 2016 EXSCEL (Exenatide ER, QW GLP-1RA) n=14752; follow-up ~3 yrs Q3 2017 – RESULTS PIONEER 6

(Oral semaglutide, QW GLP-1RA) n=3176; duration ~2 yrs completion Q4 2018

CREDENCE (cardio-renal) (Canagliflozin, SGLT-2i) n=4466; duration ~5.5 yrs completion Q2 2019 EXAMINE (Alogliptin, DPP-4i) n=5380; follow-up 1.5 yrs Q3 2013 – RESULTS LEADER (Liraglutide, GLP-1RA) n=9340; duration 3.5–5 yrs Q2 2016 – RESULTS CANVAS-R (Canagliflozin, SGLT-2i) n=5813; duration ~3 yrs Q2 2017 - RESULTS HARMONY OUTCOME (Albiglutide, QW GLP-1RA) n~9400; duration ~4 yrs completion Q2 2018 VERTIS CV (Ertugliflozin, SGLT-2i) n=8000; duration ~6.3 yrs completion Q4 2019 ALECARDIO (Aleglitazar, PPAR-αγ ) n=7226; follow-up 2 yrs

• Termin. Q3 2013 – RESULTS

EMPA-REG OUTCOME (Empagliflozin, SGLT-2i) n=7020; duration up to 5 years Q3 2015 – RESULTS CANVAS (Canagliflozin, SGLT-2i) n=4330; duration 4+yrs Q2 2017 - RESULTS REWIND (Dulaglutide, QW GLP-1RA) n=9622; duration ~6.5 yrs completion Q3 2018 DECLARE-TIMI-58 (Dapagliflozin, SGLT-2i) n=17276; duration ~6 yrs completion Q2 2019 SCORED (sotagliflozin, SGLT-2i) n=10500*; duration ~4.5 yrs completion Q1 2022 ELIXA (Lixisenatide, GLP-1RA) n=6068; follow-up ~2 yrs Q1 2015 – RESULTS SUSTAIN 6 (Semaglutide, GLP-1RA) n=3297; duration ~2.8 yrs Q3 2016 – RESULTS ACE (Acarbose, AGI) n=6526; duration ~8 yrs Q2 2017 – RESULTS TOSCA IT (Pioglitazone, TZD) n=3371; duration ~10 yrs completion Q4 2018

AGI TZD

DPP-4i CVOTs

TIME TO FIRST OCCURRENCE OF CV DEATH, NON-FATAL MI, OR NON-FATAL STROKE*

• *Ischaemic stroke for SAVOR-TIMI 53 and EXAMINE. †Primary outcome includes unstable angina requiring hospitalisation
• CI, confidence interval; CV, cardiovascular; CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase-4 inhibitor; HR, hazard ratio; MI, myocardial infarction
• 1. Scirica BM et al. N Engl J Med 2013;369:1317–1326; 2. White WB et al. N Engl J Med 2013;369:1327–1335; 3. Green JB et al. N EnglJ Med 2015;16;373:232–242

SAVOR-TIMI 531

10 8 14 12 2 6 4 180 360 540 720 900 Patients with endpoint (%) Days Saxagliptin Placebo

HR 1.00 (95% CI 0.89 ; 1.12) p<0.001 for non-inferiority p=0.99 for superiority

EXAMINE2

Months 24 12 6 18 6 12 30 18 24 Placebo Alogliptin Cumulative incidence of primary endpoint events (%)

HR 0.96 (upper boundary of the one-sided repeated CI 1.16)

TECOS3 †

Patients with endpoint (%) Months 4 8 12 18 24 30 36 42 48 5 10 15 Sitagliptin Placebo

HR 0.98 (95% CI 0.88 ; 1.09) p<0.001 for non-inferiority

After years of frustrations...

EMPA-REG

PRIMARY AND SECONDARY OUTCOMES

NNT, number needed to treat. Zinman B et al N Engl J Med 2015;373:2117‒2128

6 12 18 24 30 36 42 48 5 10 15 20

Primary endpoint

Time to first occurrence of CV death, non-fatal MI†, or non-fatal stroke

Months since randomisation Patients with event (%)

HR: 0.86 95% CI (0.74;0.99) p=0.04 for superiority

Hospitalisation for heart failure

6 12 18 24 30 36 42 48 7 6 5 4 3 2 1

Months since randomisation Patients with event (%)

HR: 0.65 95% CI (0.50;0.85) p=0.002

6 12 18 24 30 36 42 48 5 10 15

Death from any cause

Months since randomisation Patients with event (%)

HR: 0.68 95% CI (0.57;0.82) p<0.001

Empagliflozin (n=4,687) Placebo (n=2,333)

Months since randomisation Patients with event (%)

Death from CV causes

HR: 0.62 95% CI (0.49;0.77) p<0.001

NNT ~ 33/3y

CANVAS

PRIMARY AND SECONDARY OUTCOMES

Neal B at al. N Engl J Med. 2017; 377:644–657

Primary endpoint

HR: 0.86 95% CI (0.75;0.97) p<0.001 for non-inferiority p=0.02 for superiority

52 260 312 104 156 208 26 78 130 182 234 286 338 20 18 16 14 12 10 8 6 4 2 Patients with an event (%) Weeks since randomisation 52 260 312 104 156 208 26 78 130 182 234 286 338 100 98 80 70 60 50 40 30 20 10

Death from cardiovascular causes

HR: 0.87 95% CI (0.72;1.06)

Patients with an event (%) Weeks since randomisation

52 260 312 104 156 208 26 78 130 182 234 286 338 12 10 8 6 4 2 1

Canagliflozin Placebo

Patients with an event (%) Weeks since randomisation

100 90 80 70 60 50 40 20 26 52 78 104 130 156 182 208 234 260 286 312 338

HR: 0.87 95% CI (0.74;1.01)

30 10

Death from any cause*

2 20 18 16 14 12 10 8 4 26 52 78 104130156182208234260286312338 6

Patients with an event (%) Weeks since randomisation

100 90 80 70 60 50 40 20 26 52 78 104 130 156 182 208 234 260 286 312 338

HR: 0.67 95% CI (0.52;0.87)

30 10

Hospitalisation for heart failure

1 8 7 6 5 4 3 2 26 52 78 104 130 156 182 208 234 260 286 312 338

6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 5 1 0 1 5 2 0

P la c e b o

Patients with an event (%) Time from randomisation (months)

Primary outcome

CV death, non-fatal myocardial infarction, or non-fatal stroke

Patients at risk Liraglutide Placebo 4668 4672 4593 4588 4496 4473 4400 4352 4280 4237 4172 4123 4072 4010 3982 3914 1562 1543 424 407 HR=0.87 95% CI (0.78 ; 0.97) p<0.001 for non-inferiority p=0.01 for superiority

The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non- fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio. Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827. 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 5 1 0 1 5 2 0

L ira g lu tid e

6 12 18 24 30 36 42 48 54 5 10 15 20

Summary of efficacy results at 3 years

Treatment Difference –0.4% 95% CI (–0.45 ; –0.34) p<0.001 Treatment Difference –2.3 kg 95% CI (–2.54 ; –1.99) p<0.001 Small decreases in TC, LDL-C and TGs Small increase in HDL-C Treatment Difference –1.2 mmHg 95% CI (–1.9 ; –0.5) p<0.001

HbA1c Body Weight SBP Lipids

These minor positive changes probably do not expain the difference

Multifactorial effects!

Jacob 2016

Hypertension/ pulse pressure Microalbuminuria renal protection Inflammation / Weight / Oxidative stress Lipids (TG/HDL/ LDL)

Glucose ✓✓

GLP1-RA SGLT2-i

✓✓ ✓✓ ✓✓ ✓✓

Aim of Diabetes management

Glucose control REDUCTION of COMPLICATIONS

STENO 2

Evolution of type 2 diabetes management: REDUCE....

Jacob 2017.

Pre-2008 2008–… 2017

HbA1c

• The lower,

the better HbA1c

• The lower,

the better

• But w/o

hypos and weight gain CV EVENTS

• Blood pressure
• Low-density

lipoprotein cholesterol

• Glucose: but use

agents with proven safety and efficacy

NEW 2018 ADA

Conclusion

• While bad glycemic control (=high HbA1c) is associated w/CV

complications in epidemiology, anti-hyperglycemic intervention has failed to reduce CVD (consistently)

• Treatment induced AE could have played an important role
• Wrong tx targets (is …HbA1c the good marker?)
• New interventions with GLP1-RA and SGLT2-i showed a reduction CV and

total mortality in CV risk patients- w/ optimal cv TX

• …which seems to be independent of improved glycemic control…
• Potential mechanisms are currently discussed
• New TX recommendations target CV effects first…

Change of paradigm needed

Modified according to Ralph de Fronzo

TREAT THE PATIENT NOT THE SUGAR REDUCE THE CV RISK NOT ONLY THE HbA1c