Professional Documents
Culture Documents
management of diabetes
Dr Rajesh Jain
1
The size of
the
problem
CV Risk
in
Additional
Diabetes
risk factors Patho-
are
common in physiology
T2D
2
CVD is a significant global burden
7.4
million
due to
CHD
31% due
to CVD 6.7
million
due to
stroke
The size of
the
3 problem
1. WHO. CVD Fact sheet N°317, Jan 2015. http://www.who.int/mediacentre/factsheets/fs317/en/#.
T2D is increasingly prevalent and CVD is the
leading cause of death in this population
• Globally, 387 million people are • T2D approximately doubles the
living with diabetes1 risk of death2
1 1.5 2.0
4
Diabetes is associated with significant loss of
life years
Men Women
7 7
Non-vascular deaths
6 Vascular deaths 6
5 5
Years of life lost
4 4
3 3
2 2
1 1
0 0
0 40 50 60 70 80 90 0 40 50 60 70 80 90
Age (year) Age (year)
On average, a 50-year old with diabetes but no history of vascular disease is
~6 years younger at time of death than a counterpart without diabetes
Seshasai et al. N Engl J Med 2011;364:829-41.
5
Glucose-lowering studies confirmed benefit on microvascular
complications but mixed results on macrovascular outcomes
Mean duration of
Study Baseline HbA1C diabetes at
Control vs intensive baseline (years) Microvascular CVD Mortality
HR (95% CI)
20 1.2
Metformin vs 1.0
conventional
p = 0.01 0.8
10
0.6
0.4
0.0 1997 1999 2001 2003 2005 2007
0 3 6 9 12 15 No. of events:
Time from randomisation (years) Conventional 73 83 92 106 118 126
therapy
Metformin 39 45 55 64 68 81
Met-
for-
7 1. UKPDS 34. Lancet 1998;352:854–65. 2. http://www.medicines.org.uk/emc/medicine/23244/SPC.
3. Holman et al. N Engl J Med 2008;359:1577–89. min
Meta-analysis of SU CV safety trials (≥ 6 months) found no
consistent association with MACE risk
MH-OR (95% CI)
First author (year) Total # patients* Total # events*
Birkeland 1996 36 1
Chou 2008 452 3
Perriello 2006 283 9
Gerstein 2010 672 55
UKPDS 33 1998 3041 610
Hanefeld 2007 587 4
Seino 2010 400 4
Charbonnel 2005 630 14
Matthews 2005 1250 15
Rubin 2008 1805 46
Home 2009 2222 312
Arechavaleta 2011 1035 4
va der Laar 2004 96 2
Mazzone 2006 458 4
Riddle 1998 145 2
Giles 2010 300 26
Tolman 2009 2097 61
Kahn 2006 4351 72
Goke 2010 858 13
Garber 2009 495 13
Nissen 2008 543 24
Ristic 2007 262 5
Ferrannini 2009 2789 34
Bakris 2006 374 11
Gallwitz 2012 1551 38
Jain 2006 502 11
Johnston 1998 272 4
Nauck 2011 801 3
Seck 2010 1172 4
Overall 29,783 1495
9 1. Meinert et al. Diabetes 1970;19(suppl):789–830. 2. UGDP. Diabetes 1970;19(suppl 2):747–830. 3. UKPDS Group. SU
Lancet 1998;352:837–53. 4. Monami et al. Diabetes Obes Metab 2013;15:938–53.
Certain glucose-lowering therapies have been associated with
CV adverse events
2007
Rosiglitazone associated with increased risk • Withdrawn in the
for MI and CV-related death3 EU/India in 2010
ACCORD study: intensive glucose lowering was • Use restricted in the
2008 US and the restriction
associated with increased all-cause mortality4
HR 1.22 (95% CI: 1.01‒1.46); p = 0.04 were removed in 2014
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 FDA
10
2007;356:2457–71. 4. ACCORD Study Group. N Engl J Med 2008;358:2545–59. 5. FDA Guidance for Industry. 6. EMA
Guidelines. 7. FDA Safety Information.
mandate
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
11 1. Nissen & Wolski. N Engl J Med 2007;356:2457–71. 2. Lincoff et al. JAMA 2007;298:1180–8. TZD
CV safety of TZDs
‘Within the PPAR family, there is no “class effect” and each agent
must be considered unique. The FDA has mandated that each agent
within this class be evaluated individually in a variety of ways
including clinical outcome studies’4
12 1. AVANDIA US Prescribing information. 2. Dormandy et al. Lancet 2005;366:1279–89. 3. FDA Safety Information. TZD
4. Rosenson et al. Am Heart J. 2012;164:672–80.
Regulatory requirements for drug-specific CV outcome data
in T2DM
FDA 2008 Guidance for Industry1 EMA 2012 Guideline2
13
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.
FDA requirements for CV outcome data:
Meta-analysis* limits and outcome trial requirements
Increased
risk
1.3 – 1.8
Relative CV risk
Postmarketing CV trial(s)
Postmarketing CV trial(s)
needed to show Inadequate data to support
generally not necessary if
definitively < 1.3 if the risk approval
the risk ratio is reassuring*
ratio is reassuring*
Safe
*Studies included in the meta-analysis must be appropriately designed and specifically include patients at higher risk of CV
events to obtain sufficient endpoints to allow a meaningful estimate of risk. 1. FDA Guidance for Industry.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.
Evolution of T2D agents
Only the newer agents have dedicated CVOTs
The CV safety of older drugs are ascertained through other studies
DPP4 SGLT2
inhibitors inhibitors
GLP1 receptor
agonists
Lente class Recombinant Glimepiride: Insulin
of insulins human insulin 3rd generation SU degludec
produced produced
CVOT
Timings represent estimated completion dates as per ClinicalTrials.gov. interpre-
16 Adapted from Johansen. World J Diabetes 2015; in press (references 1–18 expanded in slide notes) tation
The size of
the
problem
CV Risk
in
Additional
Diabetes
risk factors Patho-
are
common in physiology
T2D
17
Modifiable CV risk factors are common in patients
with T2D1,2
1. Svensson et al. Diab Vasc Dis Res 2013;10:520–9. 2. Das et al. Am Heart J 2006;151:1087–93.
18
CV death is increased in patients with diabetes and
multiple risk factors
Diabetes
140
No diabetes
Age-adjusted CVD death
risk/10,000 person-years
120
100
80
60
40
20
0
0 1 2 3
Number of risk factors
Risk factors were serum cholesterol ≥200 mg/dL, current smoker, SBP ≥120 mmHg
Stamler et al. Diabetes Care 1993;16:434.
19
Control of
LDL-
cholesterol
Antihypertensive Antiplatelet
therapy therapy
↓CV
risk
Reducing CV risk in T2D requires a multifactorial approach
Weight loss
Glycaemic
and lifestyle
control
intervention*
20
Steno-2: Intensive multifactorial control of CV risk factors
reduces CV risk in patients with T2D and microalbuminuria
60
Conventional
Primary composite
40
30 Intensive
(33 events)
20
10
0
0 12 24 36 48 60 72 84 96
Months of follow-up
Composite endpoint: CV death, non-fatal MI, non-fatal stroke revascularisation and amputation.
Gaede et al. N Engl J Med 2003;348:383–93.
21
Management
of Diabetes
Minimize Sustained
FPG Hypertension
Hypoglycemia glycemic control
Minimize
PPG Dyslipidemia Reduce CV risk
Weight gain
Reduce
Minimize other
HbA1c Obesity progression of
side effects
nephropathy
22
GLP1 has various potential effects on the CV system:
Data derived from non-clinical and mechanistic proof-of-concept studies
Pancreas Brain
↑ Insulin secretion
↓ Glucagon secretion
Heart
↑ Insulin biosynthesis ↓ Appetite
↑ β-cell proliferation ↑ Neuroprotection
↓ β -cell apoptosis ↑ Endothelial function
↑ Nitric oxide production
Clinical trial data shows that GLP1 analogues are associated with small increases in heart
rate and modest reductions in body weight and blood pressure3
GLP1
23 1.3. Jax. Clin Res Cardiol 2009;98:75–9. 2. Grieve. Br J Pharmacol 2009;157:1340–51 (modified).
Robinson et al. BMJ Open 2013;3:pii e001986.
agonists
Selected mechanistic trials indicate CV effects
of the DPP4 inhibitor class
Myocardial Endothelial
infarct size1,2 function3
Inflammation and
Triglycerides8 oxidative stress4
Left
Atherosclerotic
ventricular
plaque volume5
function6,7
1. Ye et al. Am J Physiol Heart Circ Physiol 2010;298:H1454–65. 2. Hocher et al. Int J Cardiol 2013;167:87–93.
3. van Poppel et al. Diabetes Care 2011;34:2072–77. 4. Kröller-Schön et al. Cardiovasc Res 2012;96:140–9. DPP4
25 5. Ta et al. J Cardiovasc Pharmacol 2011;58:157–66. 6. Sauvé et al. Diabetes 2010;59:1063–73.
inhibitors
7. Read et al. Circ Cardiovasc Imaging 2010;3:195–201. 8. Matikainen et al. Diabetologia 2006;49:2049–57.
3 possible results of CV outcome trials
Empagliflozin
CV PROTECTION
Superiority to placebo
+ CV SAFETY
Non-inferiority to placebo
Sitagliptin,
Saxagliptin
INCREASES CV RISK
- Inferiority to placebo Muraglitazar
CV Risk
in
Additional
Diabetes
risk factors Patho-
are
common in physiology
T2D
28
Visceral adiposity is related to inflammation, insulin
resistance, dyslipidaemia and atherosclerosis
Interactions are complex, inter-related and not necessarily causal
Dyslipidaemia
Adiponectin Endothelial
T2D dysfunction
Insulin
resistance
inflammatory Age
cytokines*
Oxidative
stress
29
Impact of current anti-diabetic agents on diabetes
management
Anti-diabetic Efficacy Minimize Effect on Impact on Reduce CV Reduce
drug hypoglycemia weight co- risk progression of
morbidities nephropathy
Metformin Potential effect
in subgroup of
UKPDS
Sulfonylureas
TZDs
AGIs
DPP4
inhibitors
GLP-1 RA
Insulin
30
Recent trials of newer glucose-lowering agents have been
neutral on the primary CV outcome until EMPA REG
OUTCOME
HR: 1.0 SAVOR-TIMI 53 HR: 0.98 TECOS
(95% CI: 0.89, 1.12) (saxagliptin) (95% CI: 0.88, 1.09) (sitagliptin)
31
Patients with T2D at
11,531 >97 % >99 % high CV risk
pts screened completed vital status
trial available
7020 pts
randomized
Placebo
On top of
Empagliflozin 10 mg standard of
Randomisation care*
Empagliflozin 25 mg
Target: ≥691 CV events
* Good quality standard of care including background glucose lowering agents and cardiovascular
32 therapy common to both arms. CV, cardiovascular.
Participating countries
590 sites from 42 countries
Indian
patients*
Asia
North America, Australia,
New Zealand
Latin America
Europe
Africa * 280 Indian patients enrolled, 163 randomized
33
14% RRR
Primary outcome: In CV Death +
MI + Stroke
3-point MACE
HR 0.86
(95.02% CI 0.74, 0.99)
p=0.0382*
CV death 38% RRR
In CV Death
HR 0.62
(95% CI 0.49, 0.77)
p<0.0001
35
CV death, MI and stroke
HR 0.65
(95% CI 0.50, 0.85)
p=0.0017
37
All-cause mortality 32% RRR
In Death due
to any cause
HR 0.68
(95% CI 0.57, 0.82)
p<0.0001
38
Heart failure outcomes and all-cause European Heart
Journal Jan 2016
hospitalization
Outcome Placebo (N=2333) Empagliflozin (N=4687)
HR
n (%) Rate/1000 n (%) Rate/1000 p-value
(95% CI)
pt-years pt-years
Heart failure hospitalisation or 198 (8.5) 30.1 265 (5.7) 19.7 0.66 (0.55–0.79) <0.001
CV death
Hospitalisation for or death 104 (4.5) 15.8 129 (2.8) 9.6 0.61 (0.47–0.79) <0.001
from heart failure
Hospitalisation for heart 95 (4.1) 14.5 126 (2.7) 9.4 0.65 (0.50–0.85) 0.002
failure
Investigator-reported heart 143 (6.1) 22.0 204 (4.4) 15.3 0.70 (0.56–0.87) 0.001
failure*
Investigator-reported serious 136 (5.8) 20.9 192 (4.1) 14.4 0.69 (0.55–0.86) 0.001
heart failure*†
All-cause hospitalisation 925 (39.6) 183.3 1725 (36.8) 161.9 0.89 (0.82–0.96) 0.003
40 Cox regression analysis. HF, heart failure; CV, cardiovascular; HR, hazard ratio; CI, confidence interval.
David Fitchett, et al. Eur Heart J 2016 [Epub ahead of print].
SGLT2 inhibitors modulate a range of factors
related to CV risk
Based on clinical and mechanistic studies
Novel
Pathways (?)
Blood pressure
Arterial
stiffness Albuminuria
SNS
SNS
activity (?) Uric Acid
activity (?) Glucose
Insulin
Weight LDL-C
Visceral HDL-C
adiposity Triglycerides
Oxidative
stress
41
Number needed to treat (NNT) to prevent one death across
major trials in patients with high CV risk
(lower the NNT, the better)
44 • Based on 1000 T2D patients receiving empagliflozin on top of standard of care for 3 years
EMPA-REG OUTCOME
“Empagliflozin is the first of the recently approved diabetes
treatments associated with a lower risk of cardiovascular
disease.”
45
In the only SGLT-2 inhibitor cardiovascular outcomes trial
reported to date, empagliflozin was associated with
significantly lower rates of all-cause and cardiovascular death
and lower risk of hospitalization for heart failure
46
Unmet Medical Need: Complementary action
49
CV safety of metformin
Met-
FOR INTERNAL USE ONLY, for-
50 DO NOT DETAIL OR DISTRIBUTE min