1. Diabetes Therapies and Cardiovascular Outcomes
Larry Custer R.Ph.
Diabetes Coordinator
Metro Health Hospital

2. History of Cardiovascular Outcomes with Diabetes Therapies
UKPDS
5100 patients followed from
35% reduction in complications for every percentage point decrease in HbA1c
No significant decrease in CV complications
16% reduction in fatal and non-fatal MI, and sudden death (not statistically significant (P=0.052)
Metformin reduces overall risk of CV events
Diabetes Care, 2002

3. Rosiglitazone (Avandia)
June 2007, FDA publication of CV study results
The summary odds ratio for myocardial infarction was 1.43 in the rosiglitazone group (95% confidence interval [CI], 1.03 to 1.98; P=0.03). The odds ratio for death from cardiovascular causes in the rosiglitazone group, as compared with the control group, was 1.64 (95% CI, 0.98 to 2.74; P=0.06).Jun 14, 2007
June 2013, FDA publication concluded; Avandia does not increase risk of CV events
FDA Publication, 2007

4. FDA Guidance to Industry
Sponsors should establish an independent CV endpoint committee to prospectively adjudicate in a blinded fashion, CV events during all phase 2, phase 3 trials (MACE)
Sponsors should insure that clinical trials are designed to obtain study endpoints that include a meaningful estimate of CV risk, including advanced disease, elderly patients, and some degree of renal impairment
CV events should have an upper-bound two-sided confidence interval ratio of less than 1.8
See Lancet, 1998, 352: and

5. FDA guidance to Industry
If pre-marketing data show upper bound of two-sided 95% confidence interval is between 1.3 and 1.8, then a post-marketing trial must be performed to show an estimated risk of less than 1.3
If pre-marketing application shows an upper bound of two-sided 95% confidence interval less than 1.3, a post-marketing study may not be necessary
See Lancet, 1998, 352: and

6. Metabolic Defects of Type 2 Diabetes1
Decreased insulin secretion
Decreased incretin effect
Increased lipolysis
Islet α-cell
Hyperglycemia
Increased glucose reabsorption
Increased glucagon secretion
[Source: DeFronzo RA. Diabetes 2009;58: Pg 782, Figure 13; Pg 783, Figure 14]
Key Points1: [DeFronzo, Abstract and inferred from slide]
There are a number of mechanisms that feed into the hyperglycemia of type 2 diabetes.
The ‘traditional’ defects are in the liver and muscle uptake of glucose, and decreased insulin secretion by the pancreas.
There are a number of others that have emerged from more recent research:
Decreased incretin effect leads to a failure of the tight coupling of insulin release with meals.
Increased lipolysis increases the breakdown of fats, leading to higher levels of free fatty acids.
The pancreatic α-cells overwork, increasing the glucagon level, hence, driving up blood glucose.
The kidney reabsorbs glucose and so prevents its elimination via the urine; in diabetes, it appears to (maladaptively) increase its reuptake.
References:
DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58(4):
Increased hepatic glucose production
Decreased glucose uptake
Neurotransmitter
dysfunction +
DeFronzo RA. Diabetes 2009;58:773-95
Copyright ©2015 Eli Lilly and Company

8. Recent trials of newer glucose-lowering agents have been neutral on the primary CV outcome
HR: 1.0 (95% CI: 0.89, 1.12)
SAVOR-TIMI 53
HR: (95% CI: 0.88, 1.09)
TECOS
HR: (95% CI: UL ≤1.16)
EXAMINE
2013
2014
2015
HR: (95% CI: 0.89, 1.17)
ELIXA
DPP-4 inhibitors*
EMPA-REG OUTCOME®
Lixisenatide
Empagliflozin
CV, cardiovascular; HR, hazard ratio; DPP-4, dipeptidyl peptidase-4 *Saxagliptin, alogliptin, sitagliptin Adapted from Johansen OE. World J Diabetes 2015;6:

9. Randomised and treated
Trial design
Placebo (n=2333)
Screening
(n=11531)
Randomised and treated
(n=7020)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
Study medication was given in addition to standard of care
Glucose-lowering therapy was to remain unchanged for first 12 weeks
Treatment assignment double masked
The trial was to continue until at least 691 patients experienced an adjudicated primary outcome event

10. Pre-specified primary and key secondary outcomes
Primary outcome
3-point MACE: Time to first occurrence of CV death, non-fatal MI or non-fatal stroke
Key secondary outcome
4-point MACE: Time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalisation for unstable angina
CV, cardiovascular; MI, myocardial infarction; MACE, Major Adverse Cardiovascular Event

11. Baseline characteristics: CV complications
Placebo 
(n=2333)
Empagliflozin 
10 mg 
(n=2345)
Empagliflozin 
25 mg 
(n=2342)
Any CV risk factor
2307 (98.9%)
2333 (99.5%)
2324 (99.2%)
Coronary artery disease
1763 (75.6%)
1782 (76.0%)
1763 (75.3%)
Multi-vessel coronary artery disease
1100 (47.1%)
1078 (46.0%)
1101 (47.0%)
History of MI
1083 (46.4%)
1107 (47.2%)
1083 (46.2%)
Coronary artery bypass graft
563 (24.1%)
594 (25.3%)
581 (24.8%)
History of stroke
553 (23.7%)
535 (22.8%)
549 (23.4%)
Peripheral artery disease
479 (20.5%)
465 (19.8%)
517 (22.1%)
Single vessel coronary artery disease
238 (10.2%)
258 (11.0%)
240 (10.2%)
Cardiac failure*
244 (10.5%)
222 (9.5%)
tlr-1245_0025final— Table : 1 Baseline cardiovascular high risk factors − treated set
1245_0025final— Table : 3 Cardiac failure (narrow SMQ ) diagnosis at baseline − treated set
CAD defined as any of the components of history of MI, CABG, multivessel CAD, or single vessel CAD. Information on single vessel coronary artery disease was not available for one patient in the placebo group. Cardiac failure: based on narrow standardised MedDRA query ‘cardiac failure’.
Data are n (%) in patients treated with ≥1 dose of study drug
*Based on narrow standardised MedDRA query “cardiac failure”

12. Primary outcome: 3-point MACE
HR 0.86
(95.02% CI 0.74, 0.99)
p=0.0382*
Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)

13. Patients with event/analysed
CV death, MI and stroke
Patients with event/analysed
Empagliflozin
Placebo HR
(95% CI)
p-value
3-point MACE
490/4687
282/2333
0.86
(0.74, 0.99)*
0.0382
CV death
172/4687
137/2333
0.62
(0.49, 0.77)
<0.0001
Non-fatal MI
213/4687
121/2333
0.87
(0.70, 1.09)
0.2189
Non-fatal stroke
150/4687
60/2333
1.24
(0.92, 1.67)
0.1638
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Favours empagliflozin
Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI

14. All-cause mortality HR 0.68 (95% CI 0.57, 0.82) p<0.0001
Kaplan-Meier estimate. HR, hazard ratio

15. CV death Empagliflozin 10 mg HR 0.65 (95% CI 0.50, 0.85) p=0.0016
Cumulative incidence function. HR, hazard ratio

16. HbA1c
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
1245_0025final study-report-body. Table : 1 HbA1c (%) change from baseline MMRM results over time − FAS (OC−AD) 12 28 40 52 66 80 94
108
122
136
150
164
178
192
206
Placebo
2294
2272
2188
2133
2113
2063
2008
1967
1741
1456
1241
1109
962
705
420
151
Empagliflozin 10 mg
2296
2272
2218
2150
2155
2108
2072
2058
1805
1520
1297
1164
1006
749
488
170
Empagliflozin 25 mg
2296
2280
2212
2152
2150
2115
2080
2044
1842
1540
1327
1190
1043
795
498
195
All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

17. EMPA-REG OUTCOME®: Summary
Empagliflozin reduced risk for 3-point MACE by 14%
Empagliflozin was associated with a reduction in HbA1c without an increase in hypoglycaemia, reductions in weight and blood pressure, and small increases in LDL cholesterol and HDL cholesterol
Empagliflozin was associated with an increase in genital infections but was otherwise well tolerated
MACE, Major Adverse Cardiovascular Event; HDL, high density lipoprotein; LDL, low density lipoprotein

18. Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk 56
High CV risk
38% diabetes, 46% hypertension
Ramipril2
for 5 years
Empagliflozin
for 3 years 39
T2DM with high CV risk
92% hypertension
Simvastatin1
for 5.4 years 30
High CV risk
5% diabetes, 26% hypertension
All cause death
Simva: 182 / 2221 (8,2%), placebo :256 / 2223 (11,5%) HR= 0,71[0,59;0,85]
pooled empa : 269 (5.7%)/2333, placebo : 194 (8.3%)/ HR= 0.68 (0.57,0.82)
Ramipril: 482 / 4645 (10,4%), placebo : 569 / 4652 (12,2%) HR=0,85[0,76;0,95]
Pre-ACEi/ARB era
<29% statin
>80% ACEi/ARB
>75% statin
Pre-statin era
1994
2000
2015
1. 4S investigator. Lancet 1994; 344: , HOPE investigator N Engl J Med 2000;342:145-53,

19. EMPA-REG Conclusion Sub-group analysis for diabetic kidney disease
Class effect?

20. LEADER TRIAL

21. Ussher JR, Drucker DJ. Circ Res 2014;114:1788–803.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

22. LEADER: Study design Reference: Primary manuscript Supplement
CV: cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA: glucagon-like peptide-1 receptor agonist; HbA1c: glycated hemoglobin; MEN-2: multiple endocrine neoplasia type 2; MTC: medullary thyroid cancer; OAD: oral antidiabetic drug; OD: once daily; T2DM: type 2 diabetes mellitus.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

23. Primary and key secondary outcomes
Reference: Primary manuscript Supplement
CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

24. Baseline cardiovascular risk profile
Reference: Primary manuscript Supplement
Documented CHD: documented by positive exercise stress test or any cardiac imaging or unstable angina with ECG changes.
Documented asymptomatic ischemia: Documented by positive nuclear imaging test, exercise test or dobutamine stress echo
Chronic kidney disease: eGFR <60 mL/min/1.73m2 per Modification of Diet in Renal Disease formula or <60 mL/min/1.73m2 per Cockcroft-Gault formula
Source: EOT Table /ID _t_inclusion1_of_2.txt
Data are number of patients (%).
CHD: coronary heart disease; CKD: chronic kidney disease; CVD: cardiovascular disease; eGFR: estimated glomerular filtration rate; NYHA: New York Heart Association; TIA: transient ischemic attack.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

25. Baseline cardiovascular risk profile
Reference: Primary manuscript Supplement
Source: EOT Table /ID _t_inclusion1_of_2.txt
Data are number of patients (%).
CVD: cardiovascular disease.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

26. LEADER: A Global Trial GLOBALLY 6 continents 31 countries 413 sites
More than people involved in the study
9,340 subjects
1,500+site staff
250+NN staff
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

27. Primary outcome CV death, non-fatal myocardial infarction, or non-fatal stroke
The primary outcome was the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal (including silent) myocardial infarction (MI), or nonfatal stroke.
Reference: Primary manuscript
Source: KM plot: EOT Figure / ID
HR: EOT Table /ID _primary_analysis_fas.txt
P-value: EOT Table /ID _primary_analysis_pvalues_fas.txt
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

28. Expanded MACE CV death, non-fatal MI, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure
Time to first expanded composite cardiovascular outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure)
Reference: Primary manuscript Supplement
Source: KM plot: EOT Figure /ID
HR: EOT Table /ID _first_expanded_mace_fas.txt
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; MACE: major adverse cardiovascular event; MI: myocardial infarction.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

29. Number needed to treat to prevent one…
CV: cardiovascular; MACE: major adverse cardiovascular event.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

30. Future Therapies and CV Outcomes
SGLT-2 inhibitors and long term clinical trials (Diabetic Kidney Disease)
Liraglutide derivatives (Semaglutide, once weekly)
Liragluitde high dose (Saxenda for weight loss)
Comibination Therapies
Soliqua (Glargine/Lixisenatide)
Xultophy (Degludec/Liraglutide)