DIABETES MELLITUS AND

HEART FAILURE –
KMA ANNUAL CONFERENCE KISUMU

DR SWALEH BREIK MISFAR

CONSULTANT PHYSICIAN / CARDIOLOGIST
SPECIAL INTEREST IN HEART FAILURE
OUTCOMES
HFrEF: Prevalence of Diabetes
An Insidious Disease that Starts Before the

First Symptoms
Outcomes for HF Compared With the
General US Population
HF-DM Interaction: 2-Way
Pathophysiologic Link
 Paradigm Shift in the Management of
Type 2 Diabetes
 Person-centric
 Gluco-centric
 A1C-lowering important,
 A1C-lowering primary but comorbidities and
consideration risks also considered

American Diabetes Association. Diabetes Care. 2020;43:S1-S212. Slide credit: clinicaloptions.com

HBA1c-centric versus Patient-centric
SGLT2 Inhibition Improves Hemodynamic
Parameters in Patients With T2DM, Leading to
Cardiorenal Protection
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.

12
 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Rosiglitazone associated with increased risk • Withdrawn in the EU1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

13
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.

14
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-marketing support
if < 1.3 CV trial(s) needed to approval
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.

15
SGLT2 Inhibitors Trials – a rethink on Diabetes
to Cardiovascular Disease Pathways
 ADA 2020: Using a Person-Centered
Approach
Lifestyle modification
plus metformin
If above A1C target, proceed below

High risk or established ASCVD, HF, or CKD?

Yes No

A1C irrelevant; Start

Add GLP-1 RA or SGLT-2 inhibitor A1C-based therapy

American Diabetes Association. Diabetes Care. 2020;43:S98. Slide credit: clinicaloptions.com

 ADA 2020: Using a Person-Centered
Approach
All patients: lifestyle modification
Most patients: metformin

High risk or established ASCVD, CKD, or HF,

regardless of A1C

ASCVD predominates HF or CKD predominates

SGLT2 with evidence of reducing HF and/or

GLP-1 RA with SGLT2 with proven CKD progression in CVOTs if eGFR adequate
EITHER/OR
proven CVD CVD benefit, OR
benefit if eGFR adequate If SGLT2 not tolerated or contraindicated or
if eGFR less than adequate, add GLP-1 RA with
proven CVD benefit

American Diabetes Association. Diabetes Care. 2020;43:S98. Slide credit: clinicaloptions.com

 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