1. A review of potential therapeutic targets impacting CV outcomes in T2DM
Naveed Sattar, MD
University of Glasgow
United Kingdom
Asian Cardio Diabetes Forum
April 23 – 24, 2016 – Kuala Lumpur, Malaysia

2. Diabetes and CVD risk: changing patterns over time
CHD equivalent
CHD RISK
~ 5-15
years
Diagnosis
Age
Sattar (2013) Diabetologia (several studies support concept)

3. Empa slides
5 May 2015
Diabetes-related CV complications have declined with improved care, but substantial burden remains
Years
Notes
These data are from 4 large national US databases that compared the 20-year trend in incidences of acute MI and stroke among patients with diabetes and the standardised US population.
Diabetes-related complications have declined during this period with fewer cases per 10,000 of MI and 58.9 fewer cases per 10,000 of stroke.
However, despite this considerable improvement, the rates remain higher in patients with diabetes than in the non-diabetic population.
Furthermore, the absolute numbers of complications will continue to rise because of the large increase in the number of prevalent cases of diabetes.
2010 data:
Non-diabetes: MI = 25.8, stroke = 34.3.
Diabetes: MI = 45.5, stroke = 52.9.
Abbreviations
CV, cardiovascular; MI, myocardial infarction; T2D, Type 2 Diabetes.
CV, cardiovascular; MI, myocardial infarction.
Adapted from Gregg EW, et al. N Engl J Med. 2014;370:1514–1523.

4. Glucose-lowering vs CVD
Knowns and unknowns
Many ways to lower sugar –
Method more important than glucose-lowering per se?
What do we know about
Metformin / SU / TZDs?
DPP4i and GLP-1?

5. Evolution of T2D agents
DPP4 inhibitors
SGLT2 inhibitors
 Older T2D agents
Newer T2D agents 
1950
1960
1970
1980
1990
2000
2010
2012
2013
GLP1 receptor agonists
Lente class of insulins produced
Recombinant human insulin produced
Glimepiride: 3rd generation SU
Insulin degludec
SUs first used
2nd generation SUs available
Insulin glargine available2
Notes
Metformin was one of the earliest oral therapies introduced for T2D (in for the UK, in 1995 for the US).
The timings of DPP4i and GLP-1 agonists are adapted slightly from the paper, as in fact, they emerged at roughly the same time (e.g. saxagliptin approved in 2009; liraglutide approved 2009):
Abbreviations
DPP4, dipeptidyl peptidase-4; GLP, glucagon-like peptide; SGLT, sodium glucose cotransporter; SU, sulphonylurea; TZD, thiazolidinedione; T2D, Type 2 diabetes.
Reference
Lantus® Summary of Product Characteristics:
Metformin introduced
Metformin introduced in the UK
Three new classes introduced: -glucosidase inhibitors, meglitinides and TZDs
Adapted from 1. Kirby. Br J Diabetes Vasc Dis 2012;12:315– Lantus® SPC.

6. Metformin: MOA Metformin1  Hyperglycaemia Intestine Liver
Skeletal muscle
 Glucose utilisation
 Gluconeogenesis
 Glycogenolysis
 Fatty acid oxidation
 Insulin-mediated glucose uptake
 Glycogenesis
 Fatty acid oxidation
 Hyperglycaemia
Notes
Metformin is a first-line glucose-lowering agent and is most widely used to treat T2D.
Metformin decreases hyperglycaemia primarily by suppressing glucose production (inhibition of gluconeogenesis) by the liver.
In addition to its glucose-lowering effect, metformin has been found to provide various benefits, e.g., improving plasma lipid profile, as shown in large clinical trials.1
The effects of metformin on CV risk factors require further assessment, but may include improved lipid profiles, anti-atherogenic effects, decreased ischaemic injury and amelioration of oxidative stress.1
Recent research at the gut level reveals new pharmacological actions of metformin including alteration of bile acid recirculation and gut microbiota resulting in enhanced enteroendocrine hormone secretion (particularly GLP1)2
Abbreviations
CV, cardiovascular; MOA, mechanism of action; T2D, Type 2 diabetes.
Reference
1. Batchuluun et al. J Endocrinol Diabetes Obes 2014;2:1035
2. Napolitano A et al. PLoS ONE 2014; 9(7): e100778
In addition to its glucose-lowering effects, metformin may have potential effects on the CV system, e.g., improving plasma lipid profile2
Adapted from 1. Bailey & Feher. Therapies for Diabetes Batchuluun et al. J Endocrinol Diabetes Obes 2014;2:1035.

7. UKPDS 34 CV effects of metformin in overweight patients
Risk of MI is 39% lower with metformin vs conventional therapy in obese patients1,2
Significant reduction in MI maintained over 10 years’ follow-up3
Myocardial infarction
Metformin vs conventional p = 0.01
Time from randomisation (years) 3 6 9 12 15
0.0 10 20 30
Proportion of patients with events (%)
Intensive (n = 951; events = 139)
Conventional (n = 411; events = 73)
Metformin (n = 342; events = 39)
1.4
1.2
1.0
0.8
0.6
0.4
HR (95% CI)
RR 0.611
p = 0.01
RR 0.67
p = 0.005
Overall values at study end in 1997
Annual values during 10-year post-trial monitoring period
Notes
UKPDS provides evidence for the beneficial CV effects of metformin.
In UKPDS 34, the metformin group had a 39% lower risk of MI than the conventional treatment group (p = 0.01).1
The significant reduction in MI risk was maintained over 10 years,2 as shown in the right-hand figure where all the upper CI limits are below the HR = 1.0 line.
Metformin added to SU vs SU alone was associated with increased risk of diabetes-related death (RR of 1.96, p=0.039) and all-cause mortality (RR of 1.60 p=0.041).1
Abbreviations
CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; RR, relative risk (in original study1); risk ratio (in follow-up study2); SU, sulphonylurea; UKPDS, United Kingdom Prospective Diabetes Study.
References
Metformin 500 mg tablets. Summary of Product Characteristics. Aurobindo Pharma Milpharm Ltd. Available at: Accessed 26 Jun 2015
1997
1999
2001
2003
2005
2007
No. of events:
Conventional therapy 73 83 92
106
118
126
Metformin 39 45 55 64 68 81
1. UKPDS 34. Lancet 1998;352:854– Holman et al. N Engl J Med 2008;359:1577–89

8. Sulphonylureas: MOA Notes
SUs are a common second-line therapy for T2D (after metformin).
SUs lower glucose by stimulating insulin secretion from the pancreas.
Normally, the metabolism of an influx of glucose causes the ATP/ADP ratio to rise, leading to closure of the KATP channel, depolarisation of the β-cell membrane, influx of calcium ions and, finally, the release of insulin from storage granules.
SUs bind to a specific receptor on the KATP channel, causing it to close and triggering the same series of events, and also causing impaired ischaemic pre-conditioning in cardiac myocytes.
Abbreviations
ADP, adenosine diphosphate; ATP, adenosine triphosphate; KATP, adenosine triphosphate-dependent potassium channel; MOA, mechanism of action; SU, sulphonylurea; SUR, SU receptor; T2D, Type 2 diabetes.
Reference
The figure was produced using Servier Medical Art:
Reproduced from 1. Gore and McGuire. Eur Heart J 2011;32:1832–4.

9. Meta-analysis SU CV safety trials (≥ 6 months) no consistent association with MACE risk1
0.01
0.1 1 10
100
Favours SUs
Favours comparators
MH-OR (95% CI)
First author (year)
Birkeland 1996
Chou 2008
Perriello 2006
Gerstein 2010
UKPDS
Hanefeld 2007
Seino 2010
Charbonnel 2005
Matthews 2005
Rubin 2008
Home 2009
Arechavaleta 2011
va der Laar 2004
Mazzone 2006
Riddle 1998
Giles 2010
Tolman 2009
Kahn 2006
Goke 2010
Garber 2009
Nissen 2008
Ristic 2007
Ferrannini 2009
Bakris 2006
Gallwitz 2012
Jain 2006
Johnston 1998
Nauck 2011
Seck 2010
Overall
Notes
A meta-analysis was conducted of trials of duration ≥ 6 months that compared an SU with a non-SU agent in patients with T2D.
MH-ORs were calculated for MACE.
There was variability among trials, but overall the risk of MACE was not increased in patients treated with SUs vs other agents (p = 0.52).
However, the authors concluded that the CV safety of SUs cannot be considered established unless evaluated in long-term CVOTs.
Abbreviations
CI, confidence interval; CV, cardiovascular; CVOT, cardiovascular outcomes trial; MACE, major adverse cardiovascular events; MH-OR, Mantel-Haenszel odds ratio; SU, sulphonylurea; T2D, Type 2 Diabetes.
Overall MACE risk estimate: MH-OR 1.08 (0.86–1.36)
Mortality MH-OR: 1.22 (1.01–1.49)
Monami et al. Diabetes Obes Metab 2013;15:938–53.

10. TZDs (PPAR-γ agonists): MOA
Skeletal muscle
Adipose
Liver
 Glucose uptake
PPAR activation
 Gluconeogenesis
Adipogenesis
 Fatty acid uptake
 Lipogenesis
 Glucose uptake
Notes
PPAR activation regulates the expression of multiple target genes involved in glucose homeostasis, fatty acid oxidation and lipid metabolism.
In addition to improving glucose control and insulin sensitivity, TZDs reduce concentrations of atherogenic lipoproteins and decrease inflammatory mediators.
Abbreviations
FFA, free fatty acid; PPAR, peroxisome proliferator-activated receptor; TZD, thiazolidinedione.
 Plasma FFA
 Hyperglycaemia
Adapted from Bailey & Feher. Therapies for Diabetes 2004.

11. In 2007, separate meta-analyses suggested differing CV effects of drugs within the TZD class
Rosiglitazone meta-analysis1
1.0
2.0
Favours rosiglitazone
Favours control
MI OR 1.43 (95% CI: 1.03‒1.98) p = 0.03
CV death OR 1.64 (95% CI: 0.98‒2.74) p = 0.06
Pioglitazone meta-analysis2
1.0
2.0
Favours pioglitazone
Favours control
MI HR 0.81 (95% CI: 0.64‒1.02) p = 0.08
Death HR 0.92 (95% CI: 0.76‒1.11) p = 0.38
Notes
Examination of similar endpoints within two separate meta-analyses for rosiglitazone and pioglitazone (compared with placebo or active comparator) suggests differing CV effects of the 2 agents, despite being of the same class.
Compared with controls, rosiglitazone was associated with a significantly increased risk of MI and an increased risk of CV-related death that was of borderline significance.1
By contrast, there was a tendency for fewer incidences of MI (HR 0.81) or death (HR 0.92) with pioglitazone:
Pioglitazone was also associated with a significantly lower risk of death, MI or stroke (the composite primary endpoint; HR 0.82; 95% CI: 0.72–0.94; p = 0.005), but a significantly increased risk of serious HF (HR 1.41; 95% CI: 1.14–1.76; p = 0.002).2
Rosiglitazone meta-analysis
Included 42 trials (inclusion criteria were study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for MI and death from CV causes).
Pioglitazone meta-analysis
Included 19 trials (inclusion criteria were that studies be randomized, double-blinded, and controlled with placebo or active comparator).
The primary objective of most of the trials was to determine the efficacy of pioglitazone (with or vs insulin, metformin, SUs or rosiglitazone) in improving glycaemic control.
Six trials had other primary endpoints: hepatic toxicity (OPI-506 study), triglyceride levels (GLAI study), changes in carotid intima-medial thickness (CHICAGO trial), CV outcomes among patients with established vascular disease (PROactive), walking distance among patients with mild cardiac disease (OPI-520 study), or heart failure progression among patients with advanced CHF (OPI-504).
Of the total 16,390 patients included in the meta-analysis; PROactive was the largest single trial (n = 5,238).
Abbreviations
CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; OR, odds ratio.
References
1. Nissen & Wolski. N Engl J Med 2007;356:2457– Lincoff et al. JAMA 2007;298:1180–8.
No clinical trial directly compares the CV effects of pioglitazone and rosiglitazone
1. Nissen & Wolski. N Engl J Med 2007;356:2457– Lincoff et al. JAMA 2007;298:1180–8.

12. Rosiglitazone: RECORD study results showed no increase in CV death
Rosiglitazone N = 2220
Active control N = 2227 HR
95% CI
Primary endpoint
CV death or CV hospitalisation
321
323
0.99
0.85–1.16
Secondary endpoint
All-cause death
136
157
0.86
0.68–1.08
CV death 60 71
0.84
0.59–1.18 MI 64 56
1.14
0.80–1.63
Stroke 46 63
0.72
0.49–1.06
CV death, MI or stroke
154
165
0.93
0.74–1.15
Heart failure 61 29
2.10
1.35–3.27
CV outcomes for RECORD trial (original data)1,2
Notes
The RECORD study showed no increase in CV death with rosiglitazone.1
In 2013, the FDA reduced safety restrictions on rosiglitazone.2
However, controversy still remains, as there are no long-term prospective CV safety data for this agent.3
Abbreviations
CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration; HR, hazard ratio; MI, myocardial infarction; RECORD, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes.
References
AVANDIA US prescribing Information: /en/Prescribing_Information/Avandia/pdf/AVANDIA-PI-MG.PDF.
FDA safety information: m htm
Rosenson et al. Am Heart J 2012;164:672–80.
In 2013, FDA panel voted to reduce safety restrictions on rosiglitazone3
1. AVANDIA US Prescribing information. 2. Home et al. Lancet 2009;373:2125– FDA Safety Information. 4. Rosenson et al. Am Heart J 2012;164:672–80.

13. Published on-line: February 17, 2016 DOI: 10.1056/NEJMoa1506930
U.S. National Institute of
Neurological Disorders and Stroke
(Grant # U01NS044976)
Published on-line: February 17, 2016
DOI: /NEJMoa

14. IRIS Secondary Outcomes
Pioglitazone (N=1939)
Placebo (N=1937)
Outcome* %
(No.)
 Hazard Ratio
(95% CI)  P
Stroke
6.5
(127)
8.0
(154)
0.82
0.19
ACS
5.0
(96)
6.6
(128)
0.75
0.11
Stroke/MI/HF
10.6
(206)
12.9
(249) DM
3.8
(73)
7.7
(149)
0.48
<.0001
Death
7.0
(136)
7.5
(146)
0.93
0.52
*ACS=Acute coronary syndrome (unstable angina or MI).
*HF=heart failure
Kernan WN et al. N Engl J Med, published on-line Feb 17, 2016 DOI: /NEJMoa

15. IRIS: Summary
Among insulin resistant, non-diabetic patients with ischemic stroke/TIA, pioglitazone over 5 yrs prevented:
Stroke or MI
Relative Risk Reduction 24%
Absolute Risk Reduction 2.9%
Diabetes
Relative Risk Reduction 52%
Absolute Risk Reduction 3.9%
However, serious bone fracture was more common with pioglitazone (5.1% vs. 3.2%)
Kernan WN et al. N Engl J Med, published on-line Feb 17, 2016 DOI: /NEJMoa

16. Summary on TZDs
Evidence for PIO and CVD (stroke and MI) prevention exists
But more fluid retention, weight gain, fractures, HF
No evidence of CVD death benefit
Rosiglitazone likely no net CVD harm
Pio – good glycaemia effect – use lower doses to minimise side effects?

17. EFFECT of Glucose lowering per se
Potentially independent of mode

18. Benefit of different interventions per 200 diabetes pts treated for 5 years
Per 0.9% lower
HbA1c
Per 4mmHg lower SBP
Per 1mmol/L lower LDL-C
Ray et al Lancet 2009 Meta-analysis of intensive glucose-lowering trials 18

19. Totality of evidence: glucose lowering data
hard to decipher but lowering HbA1c per se
- lowers microvascular risk (better earlier in disease; later reduction less beneficial?) - Slow burn benefit impact on CVD - If lower too aggressively, potential harm (ACCORD) - Glucose-lowering agents ≠  CVD

20. Uncertainty: guidelines - HbA1c targets vary by patient characteristics
Near diagnosis: 6.5% sensible
But 7 to 7.5% fine for most
Relax: elderly, long duration, frail, short life expectancy, hypoglycaemia risk, CVD
Inzucchi et al (2015) Diabetes Care

21. New approaches to reducing blood glucose
Inhibit gastro-
intestinal absorption
(α-glucosidase inhib’s)
GLP-1 agonists/analogues
e.g. exenatide
Stimulate insulin
release
Incretins
(GIP)
GLP-1
Reduce
blood glucose
Inhibit glucagon
release
DPP4
Breakdown
products
Inhibit renal
re-absorption
(SGLT2 inhibitors)
DPP4 inhibitors
(“gliptins”)

22. CV safety trials: 5 down, many to come
CANVAS-R8
(n = 5700)
Albuminuria
2013
2014
2015
2016
2017
2018
2019
SAVOR-TIMI 531
(n = 16,492)
1,222 3P-MACE
EXAMINE2
(n = 5380)
621 3P-MACE
TECOS4
(n = 14,724)
≥ P-MACE
LEADER6
(n = 9340) ≥ 611 3P-MACE
SUSTAIN-67
(n = 3297)
3P-MACE
DECLARE-TIMI 5815
(n = 17,150)
≥ P-MACE
EMPA-REG OUTCOME®5
(n = 7034)
≥ 691 3P-MACE
CANVAS10
(n = 4365)
≥ 420 3P-MACE
CREDENCE17
(n = 3700)
Renal + 5P-MACE
CAROLINA®11
(n = 6000)
≥ 631 4P-MACE
ITCA CVOT9
(n = 4000)
4P-MACE
EXSCEL14
(n = 14,000)
≥ P-MACE
DPP4 inhibitor CVOTs
SGLT2 inhibitor CVOTs
GLP1 CVOTs
Ertugliflozin CVOT18
(n = 3900)
OMNEON13
CARMELINA12
(n = 8300)
4P-MACE + renal
REWIND16
(n = 9622)
≥ P-MACE
2021
ELIXA3
(n = 6068)
≥ 844 4P-MACE
Notes
This overview indicates all of the ongoing (and two completed – SAVOR-TIMI 53 and EXAMINE) CVOTs for the newer T2D agents.
The trial name, the estimated recruitment and the primary outcome are indicated
The timings indicate the estimated completion dates of the trial
Planned or actual event rates are indicated in some cases (e.g. EXAMINE, ELIXA etc)
Abbreviations
CANVAS, Canagliflozin Cardiovascular Assessment Study
CANVAS-R, Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM
CARMELINA®, Cardiovascular Safety & Renal Microvascular Outcome Study with Linagliptin
CAROLINA®, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes
CREDENCE, Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy
CVOT, cardiovascular outcomes trial
DPP4, dipeptidyl peptidase 4
DECLARE-TIMI, Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events
ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome
EMPA-REG OUTCOME® [cardiovascular outcomes trial of empagliflozin]
EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care
EXSCEL, The EXenatide Study of Cardiovascular Event Lowering
GLP1, glucagon-like peptide 1
LEADER®, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results
OMNEON™ [randomised, double-blind, placebo-controlled, multicenter study to assess cardiovascular outcomes following treatment OMNEON™ is full title]
REWIND, Researching Cardiovascular Events With a Weekly Incretin in Diabetes
SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus - Thrombolysis in Myocardial Infarction
SGLT2, sodium glucose cotransporter 2
SUSTAIN, Trial to Evaluate Cardiovascular and Other Longterm Outcomes With Semaglutide in Subjects With Type 2 Diabetes
T2D, Type 2 diabetes
TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin
3P-MACE, 3-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction or non-fatal stroke)
4P-MACE, 4-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke or unstable angina requiring hospitalisation)
References
1. Scirica et al. N Engl J Med 2013;369:1317–26.
2. White et al. N Engl J Med 2013;369:1327–35
3. Bentley-Lewis et al. Am Heart J 2015;0:1–8.e7.
4. Bethel et al. Diabetes Obes Metab 2015;17:1395–402
5. Zinman et al. Cardiovasc Diabetol 2014;13:102
6. NCT
7. NCT
8. NCT
9. NCT
10. NCT
11. NCT
12. NCT
13. NCT
14. NCT
15. NCT
16. NCT
17. NCT
18. NCT
19. NCT
Timings estimated from ClinicalTrials.gov.

23. New approaches to reducing blood glucose
GLP-1 agonists/analogues
e.g. exenatide
Stimulate insulin
release
Incretins
(GIP)
GLP-1
Reduce
blood glucose
Inhibit glucagon
release
DPP-4
Breakdown
products
Inhibit renal
re-absorption
(SGLT2 inhibitors)
DPP-4 inhibitors
(“gliptins”)

24. 0.2-0.3% 0.36% 0.3% 0.27% 0.3-0.5% Saxagliptin (DPP-4 inhibitor)
Therapy
Trial N
Population
Follow-up duration
HbA1c difference
during follow-up
Primary outcome
Saxagliptin
(DPP-4 inhibitor)
SAVOR-TIMI 53
16,492
+CVD (80%) or –CVD at high risk (20%)
24 months %
CVD death, NF MI or stroke
Alogliptin
EXAMINE
5,380
MI or UA within last days
18 months
0.36%
Sitagliptin
TECOS
14,671
+CVD
36 months
0.3%
CVD death, NF MI or stroke, hospitalization for UA
Lixisenatide
(GLP-1R agonist)
ELIXA
6,068
MI or UA within last 180 days
25 months
0.27%
Empagliflozin
(SGLT2 inhibitor)
EMPA-REG Outcomes
7,020
37 months %

25. Effects on other risk factors and CVD?
DPP-4 inh.
GLP-1 agonist
SGLT2 inh.
Hypo risk
Low
Weight
Neutral
Lower BP
Lipids
Improved
HDL /LDL-c?
CVOT results
Neutral CVD
ELIXA
???
Other points
Small HF signal Saxa
WAIT FOR LEADER
EXSCEL
Infections?
DKA?

26. PRIMARY OUTCOMES for DPP4i trials all negative
No CVD benefit in major trials – EXAMINE, SAVOR-TIMI, TECOS
Should we surprised? No
HbA1c difference only 0.3%
Median durations of follow-up short <2 years
No other risk factors altered
Medications would have needed very strong ‘pleiotropic’ actions to yield CVD benefit

27. Cardiovascular outcome trials in T2D GLP-1 agents
Treatment
Inclusion criteria
Primary endpoint
Number of patients
EXSCEL
Placebo
Exenatide
Once weekly
T2D
HbA1c ≥ 7.0−< 10.0%
CVD in 60%
CV death, MI or stroke
>14000
ELIXA
Lixisenatide
ACS
HbA1c ≥ 6.0−≤ 10.0%
CV death, MI, UA or stroke
6000
LEADER
Liraglutide
HbA1c ≥ 7.0%
≥ 50 years + CVD
≥ 60 years + CV risk factors
8754
ACS, acute coronary syndrome; CV, cardiovascular; CVD, cardiovascular disease; GLP-1, glucagon-like peptide-1; HbA1c, glycosylated haemoglobin; MI, myocardial infarction; T2D, Type 2 Diabetes; UA, unstable angina.

28. Method, more than absolute glucose reduction may matter to CVD risks
Small reductions in glucose alone for short time will not lower CVD
DPP4; ORIGIN (early insulin)
Drugs must do more than just lower glucose
Proven for CVD benefit
Metformin (UKPDS, less weight, no hypos)
Pioglitazone (Stroke, MI, but increases HF, weight etc)
Empagaflozin (hear later)
Liraglutide (data coming)

29. Summary: CVD in DM: lipids, BP, smoking and specific diabetes agents?
Clear evidence  CVD in DM over several decades
Better management CVD risk factors big part
BP and LDL-c reduction >> glucose reduction
But many sub-optimally treated; high death rates if DM & CVD
Lower HbA1c targets early in disease but relax if CVD or long duration or frail
Recent trial data enormously beneficial – not necessarily how much we lower glucose, but how we target it - “paradigm shift”?