THE BIG PICTURE

CV Disease and Risk forType 2DM.

CV Protection – a Priority
Sarova Whitesands 03.09.2022

Dr SWALEH BREIK MISFAR

Consultant Physician / Cardiologist
Agakhan Hospital , Mombasa
DISCLOSURE
• Bohringer Ingelheim - Honoraria
OUTCOMES
Whats next? Target HBA1c
• What would you add?
• Insulin
• Sulphanylurea ( Glibenclamide, Glimepiride or Gliclazide )
• Glitazones ( Pioglitazone, Rosiglitazone)
• Acretins
• GLP1 Agonists
• SGLT2 Inhibitors
Evolution of T2D agents
DPP4 SGLT2 inhibitors
inhibitors

 Older T2D agents Newer T2D agents 

1950 1960 1970 1980 1990 2000 2010 2012 2013

GLP1 receptor
agonists
Lente class of Recombinant Glimepiride: Insulin
insulins human insulin 3rd generation SU degludec
produced produced

SUs first used 2nd generation

SUs available Insulin glargine
available2
Metformin
Metformin Three new classes introduced:
introduced -glucosidase inhibitors, meglitinides
introduced
and TZDs
in the UK
Adapted from 1. Kirby. Br J Diabetes Vasc Dis 2012;12:315–20. 2. Lantus® SPC.

13
In 2007, separate meta-analyses suggested differing CV effects of drugs
within the TZD class
Rosiglitazone meta-analysis1 Pioglitazone meta-analysis2

MI
MI
HR 0.81 (95% CI: 0.64‒1.02)
OR 1.43 (95% CI: 1.03‒1.98)
p = 0.08
p = 0.03

Death
CV death HR 0.92 (95% CI: 0.76‒1.11)
OR 1.64 (95% CI: 0.98‒2.74) p = 0.38
p = 0.06

0.5 1.0 2.0 0.5 1.0 2.0

Favours rosiglitazone Favours control Favours pioglitazone Favours control

No clinical trial directly compares the CV effects of pioglitazone and rosiglitazone

1. Nissen & Wolski. N Engl J Med 2007;356:2457–71. 2. Lincoff et al. JAMA 2007;298:1180–8.

14
 Adverse CV events led the FDA to require demonstration of
CV safety for new glucose-lowering drugs

1961 UGDP trial: tolbutamide discontinued due to increased

CV mortality vs other treatment groups1

Muraglitazar found to potentially increase CV risk • Sponsor withdrew

2005 application1
during FDA assessment2
Rosiglitazone associated with increased risk • Withdrawn in the EU1
2007
for MI and CV-related death3 • Use restricted in US1*
2008 ACCORD trial: intensive glucose lowering was *In 2013, FDA panel voted to reduce safety
associated with increased all-cause mortality 4 restrictions on rosiglitazone7

HR 1.22 (95% CI 1.01‒1.46); p = 0.04

2008 New FDA requirements5

2012 New EMA requirements6
New diabetes drugs should demonstrate CV safety with
meta-analysis and a CV outcome trial (CVOT)

1. Nissen. Ann Intern Med 2012;157:671–2. 2. Nissen et al. JAMA 2005;294:2581–6. 3. Nissen et al. N Engl J Med 2007;356:2457–71.
4. ACCORD Study Group. N Engl J Med 2008;358:2545–59.
5. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/%20guidances/ucm071627.pdf
6. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf
7.http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm376683.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery

15
Regulatory requirements for drug-specific CV outcome data in T2D
FDA 2008 Guidance for Industry1 EMA 2012 Guideline2
‘To establish the safety of a new anti-
diabetes drug to treat T2D, sponsors ‘A fully powered CV safety assessment,
should demonstrate that the therapy will e.g., based on a dedicated CV outcome
not result in an unacceptable increase in study, should be submitted before
CV risk.’ marketing authorisation whenever a
• Important CV events should be safety concern is intrinsic in the
analysed molecule/MOA or has emerged from pre-
• High-risk population to be included clinical/clinical registration studies.’
• Long-term data required (≥ 2 years)
Two approaches are recommended:
• Prospective adjudication of CV events
• Meta-analysis of safety events
by an independent committee • Specific long-term controlled outcome
• Phase II and III trials designed and study with at least 18–24 months’
conducted to permit meta-analysis to follow-up
be performed at completion
1. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.
2. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf.

16
FDA guidance for CV outcome data: meta-analysis limits and outcome trial
requirements

Upper bound of 2-sided 95% CI

Post-marketing If overall risk–benefit Inadequate

CV trial(s) may analysis supports data to
not be necessary approval, post- support
if < 1.3 marketing CV trial(s) approval
needed to prove < 1.3

0.5 1.0 1.3 1.8 2.0

RR of incidence of CV events with
investigational agent vs control

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.

17
Overview of CVOTs of glucose-lowering drugs
SAVOR-TIMI 531 OMNEON13 CAROLINA®11
(n = 16,492) (n = 4000) (n = 6000)
1,222 3P-MACE 4P-MACE ≥ 631 4P-MACE
EXAMINE2 TECOS4 CARMELINA12
(n = 5380) (n = 14,724) (n = 8300)
621 3P-MACE ≥ 1300 4P-MACE 4P-MACE + renal

2013 2014 2015 2016 2017 2018 2019 2021

ELIXA3 EXSCEL14 REWIND16

(n = 6068) SUSTAIN-67
(n = 3297) (n = 14,000) (n = 9622)
≥ 844 4P-MACE ≥ 1591 3P-MACE ≥ 1067 3P-MACE
3P-MACE
ITCA CVOT9 DECLARE-TIMI 5815
(n = 4000) (n = 17,150)
LEADER6 4P-MACE ≥ 1390 3P-MACE
DPP4 inhibitor CVOTs (n = 9340) CREDENCE17
CANVAS10
≥ 611 3P-MACE (n = 4365) (n = 3700)
SGLT2 inhibitor ≥ 420 3P-MACE Renal + 5P-MACE
CVOTs EMPA-REG
OUTCOME®5 Ertugliflozin CVOT18
(n = 7034) CANVAS-R8
GLP1 CVOTs (n = 5700) (n = 3900)
≥ 691 3P-MACE HARMONY 3P-MACE
Albuminuria
Outcomes19
(n = 9400) 3P-MACE

Timings represent estimated completion dates as per ClinicalTrials.gov.

Adapted from Johansen. World J Diabetes 2015;6:1092–96.(references 1–19 expanded in slide notes)

18
HBA1c-centric versus Patient-centric
SGLT2 Inhibitors Trials – a rethink on
Diabetes to Cardiovascular Disease Pathways
New recommendations (8)
Recommendations Class
Risk factors and interventions at the individual level (continued)
In persons with type 2 DM and ASCVD, the use of a GLP-1RA or SGLT2 inhibitor with
proven outcome benefits is recommended to reduce CV and/or cardiorenal I
outcomes.
In patients with type 2 DM and CKD, the use of an SGLT2 inhibitor is recommended to
I
improve ASCVD and/or cardiorenal outcomes.
In patients with type 2 DM and HFrEF, use of an SGLT2 inhibitor with proven outcome
I
benefits is recommended to lessen HF hospitalizations and CV death.
Participation in a medically supervised, structured, comprehensive, multidisciplinary
EBCR and prevention programme for patients after ASCVD events and/or
I
revascularization, and for patients with HF (mainly HFrEF), is recommended to
improve patient outcomes.

©ESC
2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
www.escardio.org/guidelines
(European Heart Journal 2021 – doi:10.1093/eurheartj/ehab484)
New recommendations (11)
Recommendations Class
Risk factors and interventions at the individual level (continued)
In patients with type 2 DM and TOD, the use of an SGLT2 inhibitor or GLP-1RA with
proven outcome benefits may be considered to reduce future CVD and total IIb
mortality.
For primary prevention patients at very high risk, but without FH, if the LDL-C goal is
not achieved on a maximum tolerated dose of a statin and ezetimibe, combination IIb
therapy including a PCSK9 inhibitor may be considered.
In high-risk (or above) patients with triglycerides >1.5 mmol/L (135 mg/dL) despite
statin treatment and lifestyle measures, n-3 PUFAs (icosapent ethyl 2 X 2 g/day) may IIb
be considered in combination with a statin.
Initiation of statin treatment for primary prevention in older people aged ≥70 may be
IIb
considered, if at high risk or above.

©ESC
2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
www.escardio.org/guidelines
(European Heart Journal 2021 – doi:10.1093/eurheartj/ehab484)
Revised recommendations (2)
Risk factors and interventions at the individual level
2016 CVD Prevention Guidelines
Drug treatment should be considered
in patients with grade 1 or 2
hypertension who are at high CVD risk.
In patients with type 2 DM and CVD,
use of an SGLT2 inhibitor should be
considered early in the course of the
disease to reduce CVD and total
mortality.
www.escardio.org/guidelines
Class 2021 CVD Prevention Guidelines Class
For grade 1 hypertension, treatment
initiation based on absolute CVD risk,
IIa I
estimated lifetime benefit, and the
presence of HMOD is recommended.
In persons with type 2 DM and ASCVD,
the use of a GLP-1RA or SGLT2
IIa inhibitor with proven outcome benefits I
is recommended to reduce CV and/or
cardiorenal outcomes.
©ESC
2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
(European Heart Journal 2021 – doi:10.1093/eurheartj/ehab484)
Recommendations for treatment of diabetes mellitus (4)
Recommendations Class Level
Treatment of hyperglycaemia and ASCVD/cardiorenal risks
Metformin is recommended as first-line therapy, following evaluation of
renal function, in the majority of patients without previous ASCVD, CKD, I B
or HF.
In persons with type 2 DM with ASCVD, metformin should be considered,
IIa B
unless contraindications are present.
Avoidance of hypoglycaemia and excessive weight gain should be
IIa B
considered.

©ESC
2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
www.escardio.org/guidelines
(European Heart Journal 2021 – doi:10.1093/eurheartj/ehab484)
Recommendations for treatment of diabetes mellitus (5)
Recommendations Class Level
Treatment of hyperglycaemia and ASCVD/cardiorenal risks (continued)
In persons with type 2 DM and ASCVD, the use of a GLP-1RA or SGLT2
inhibitor with proven outcome benefits is recommended to reduce CV I A
and/or cardiorenal outcomes.
In patients with type 2 DM and TOD,a the use of an SGLT2 inhibitor or GLP-
1RA with proven outcome benefits may be considered to reduce future CV IIb B
and total mortality.
In patients with type 2 DM and CKD, the use of an SGLT2 inhibitor is
I A
recommended to improve ASCVD and/or cardiorenal outcomes.

©ESC
2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
www.escardio.org/guidelines
(European Heart Journal 2021 – doi:10.1093/eurheartj/ehab484)
Recommendations for treatment of diabetes mellitus (6)
Recommendations Class Level
Treatment of hyperglycaemia and ASCVD/cardiorenal risks (continued)
In patients with type 2 DM and HFrEF, use of an SGLT2 inhibitor with
proven outcome benefits is recommended to lessen HF hospitalizations I A
and CV death.
In patients with type 2 DM but without ASCVD, HF, or CKD, use of an
SGLT2 inhibitor or GLP-1RA should be considered based on estimated
IIa B
future risks (e.g. with the ADVANCE risk score or DIAL model) for adverse
CVD or cardiorenal outcomes from risk factor profiles.

©ESC
2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
www.escardio.org/guidelines
(European Heart Journal 2021 – doi:10.1093/eurheartj/ehab484)
Recommendations in patients with chronic kidney disease:
best medical therapy
Recommendations Class Level
Treatment with an ACE inhibitor or an ARB is recommended in patients
with DM, hypertension, and albuminuria. These medications should be I B
titrated to the highest approved dose that is tolerated.
An SGLT2 inhibitor with proven outcome benefits should be considered
for the prevention of renal deterioration and mortality in patients with IIa B
CKD.
Combination treatment with ACE inhibitors and ARBs is not
III C
recommended.

©ESC
2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
www.escardio.org/guidelines
(European Heart Journal 2021 – doi:10.1093/eurheartj/ehab484)
 Cardiovascular risk and risk factor treatment
in patients with type 2 diabetes mellitus

©ESC
2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
www.escardio.org/guidelines
(European Heart Journal 2021 – doi:10.1093/eurheartj/ehab484)
THANK YOU