new drugs for diabetes - issues & answers 2020 · 2017. 10. 27. · the benefits of early tight...
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New drugs for diabetes
PCCJ conference 2015 Professor Mike Kirby FRCP University of Hertfordshire
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Declaration of interests • MK has received funding for research, conference
attendance, lecturing and advice from the pharmaceutical industry including Astellas, Pfizer, Takeda, Bayer, MSD, BI, Lilly, GSK, AZ and Menarini.
• Editor PCCJ • Also on several NHS advisory boards including the
Prostate cancer Risk Management Programme and the Prostate Cancer advisory Group.
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The benefits of early tight control: UKPDS 10 year post-trial follow-up
Holman RR et al. New Eng J Med 2008; 359: 1577–89 UKPDS. Lancet 1998: 352; 837–53
Benefits of Intensive Glucose Control Sustained for up to 10 Years Despite
Early Loss of HbA1c Level Advantage
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HbA1c control significantly benefits diabetes outcomes: UK Prospective Diabetes Study (UKPDS)
EVERY 1% reduction in
HbA1c
1%
Stratton et al. BMJ 2000; 321:405–12
Peripheral vascular disorders
P
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Modulation of the intensiveness of glucose lowering in type 2 diabetes.
Silvio E. Inzucchi et al. Dia Care 2015;38:140-149
©2015 by American Diabetes Association
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UK/EMP/00073a(2) | April 2015
Drug treatments for type 2 diabetes and their sites of action
DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose co-transporter 2
Reference Tahrani AA, et al. Lancet. 2011;378:182–197.
Hyperglycaemia
Increased glucose
production
Glucose absorption
Impaired insulin
secretion
Decreased glucose uptake
Increased glucose reabsorption
Acarbose
Metformin Pioglitazone Insulin
SGLT2 inhibitors Insulin Sulphonylureas
Meglitinides GLP-1 receptor agonists
DPP-4 inhibitors
Metformin GLP-1 receptor agonists
DPP-4 inhibitors Insulin
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NICE T2DM treatment algorithm Please refer to SmPc for each agent for contra-indications and side effects
HbA1C ≥ 6.5%*
HbA1C ≥ 6.5%* after trial of lifestyle measures
SU Where blood glucose control remains or becomes inadequate on metformin
Usual approach Alternatives§
Sitagliptin Where insulin is unacceptable
or inappropriate
Insulin (NPH insulin, long-acting insulin
analogues, pre-mix insulin) Monitor use and response and
adjust doses if necessary
Exenatide If BMI ≥35 kg/m2‡ and there are problems associated with high body weight; or BMI
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Antihyperglycemic therapy in type 2 diabetes: general recommendations.
Silvio E. Inzucchi et al. Dia Care 2015;38:140-149
©2015 by American Diabetes Association
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GLP-1 effects in humans understanding the natural role of incretins
Adapted from 1Nauck MA, et al. Diabetologia 1993;36:741–744; 2Larsson H, et al. Acta Physiol Scand 1997;160:413–422; 3Nauck MA, et al. Diabetologia 1996;39:1546–1553; 4Flint A, et al. J Clin Invest 1998;101:515–520; 5Zander et al. Lancet 2002;359:824–830.
GLP-1 secreted upon the ingestion of food
L-Cells
1.β-cell: Enhances glucose-dependent insulin
secretion in the pancreas1
3.Liver: reduces hepatic glucose output2
2.α-cell: Suppresses postprandial
glucagon secretion1
4.Stomach: slows the rate of gastric emptying3
5.Brain: Promotes satiety and
reduces appetite4,5
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DPP4
• Medications in the DPP-4 inhibitor family • Generic or proper name Brand or trade name • Sitagliptin Januvia • Sitagliptin + Metformin Janumet • Vildagliptin Galvus • Vildagliptin + Metformin Eucreas • Saxagliptin Onglyza • Alogliptin Vipidia • Alogliptin + Metformin Vipdomet • Linagliptin Trajenta • Linagliptin + Metformin Jentadueto • Saxagliptin + Metformin Kombolyze
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Use of alternative treatments to SUs
• DPP-4i associated with reduced risk of hypoglycaemia compared with SU1
• Primary care database; 1201 general practices in Germany • 2-year follow-up of T2DM patients from date of new prescription for a DPP-4 (+
/- metformin) or SU (+ /- metformin)
1. Rathmann et al. Diabetes Obes Metab 2013;15:55-61
DDP-4 + /- metformin (N=19,184)
SU (N=31,110)
Risk estimate (95% CI)
Mean age (years) 64 69
% males 56 51
Non-persistence (%) 39 49 HR: 0.74 (0.71–0.76)
≥1 hypoglycaemia episodes (%) 0.18 1.00 OR: 0.21 (0.08–0.57)
79% reduced risk of hypoglycaemia with DPP-4
compared with SU
Hypoglycaemia associated with a 60% significantly increased risk of incident
macrovascular complications
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Hypoglycaemia is more likely than hyperglycaemia to be associated with cardiac ischaemia
15
54 59
10
1 6
0 0
10
20
30
40
50
60
70
Hypoglycaemia Hyperglycaemia
No.
of e
piso
des
Total episodes
Episodes with angina
ECG abnormalitiesdetected
21 patients with T2DM and coronary heart disease were studied using simultaneous
CGMS (for 72 hours) and cardiac ECG (Holter)
monitoring
Desouza et al. Diabetes Care 2003;26:1485–9
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Sulphonylureas and cardiovascular risk
Sulphonylurea monotherapy is associated with increased mortality and cardiovascular risk compared with metformin
Schramm TK et al. Eur Heart J 2011; 32; 1900–8
Study limitations: •Unknown effect of unmeasured confounders •Potential use of metformin in people without overt diabetes •Possible confounding by indication
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CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; CAD = coronary artery disease; CVD = cardiovascular disease; PAD = peripheral artery disease; ACS = acute coronary syndrome; EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome; SAVOR-TIMI 53 = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction 53; TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CARMELINA = Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk. 1. White W et al. N Engl J Med. 2013;369:1327–1335. 2. Scirica BM et al. N Engl J Med. 2013;369:1317–1326. 3. Bethel MA et al. Diabetes Obes Metab. 2015; 17:395–402. 4. Green JB et al. N Engl J Med. 2015 Jun 8.[Epub ahead of print]. 5. CARMELINA: Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. ClinicalTrials.gov web site. http://clinicaltrials.gov/ct2/show/ NCT01703298. Accessed September 12, 2014.
Baseline Risk of Patient Populations Enrolled in CV Safety Trials of DPP-4 Inhibitors
Vildagliptin does not have an ongoing CV safety trial
Linagliptin CARMELINA (N=8,300)5 Pre-existing CVD + albuminuria or impaired renal function End Jan 2018
Sitagliptin TECOS (N=14,671)3,4 Pre-existing CVD
Presented Jun 2015
Alogliptin EXAMINE (N=5,380)1 ACS within 15–90 days
Presented Sept 2013
Saxagliptin SAVOR-TIMI 53 (N=16,492)2 Pre-existing CVD or multiple risk factors for CVD
Presented Sept 2013
Risk Factors Stable CAD-CVD-PAD Post ACS patients
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EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome; SAVOR-TIMI 53 = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction 53; TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin. CV = cardiovascular; MI = myocardial infarction; UA = unstable angina. 1. White WB et al. N Engl J Med. 2013;369:1327–1335. 2. Scirica BM et al. N Engl J Med 2013;369:1317–1326. 3. Green JB et al. Am Heart J. 2013;166:983–989.e7. 4. Bethel MA et al. Diabetes Obes Metab. 2015; 10.1111/dom.12441. 5. Green JB et al. New Engl J Med 2015 Jun 8.[Epub ahead of print].
DPP4 EXAMINE, SAVOR-TIMI 53, and TECOS CV Safety Trials
Median Duration of Follow-up
SAVOR- TIMI 532
TECOS3–5
EXAMINE1
6.5–8.0
CV death, Nonfatal MI,
Nonfatal stroke, or UA req. hospitalization
Randomization Year 3 Year 2 Year 1
CV death, Nonfatal MI, or Nonfatal stroke
CV death, Nonfatal MI, or Nonfatal stroke
Saxagliptin
Alogliptin
Placebo
Placebo
6.5–12.0
6.5–11.0
HbA1c Range, % Primary End point Duration of Treatment (as part of usual care)
R
R
R
Sitagliptin
Placebo
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Heart failure • Insulin, induces sodium retention and thiazolidinediones
increase the risk of heart failure.
• Increase in the risk of admission to hospital for heart failure in patients treated with the dipeptidylpeptidase-4 (DPP4) inhibitor, saxagliptin, compared with placebo. (SAVOR TIMI- 53)
• There was also a trend toward an increased risk of heart-failure events among type 2 diabetic patients treated with alogliptin (Nesina, Takeda) in the EXAMINE study.
• TECOS: No CVD Risks or Heart Failure With Sitagliptin in High-Risk Diabetic Patients
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UK/TB/0213/0017a February 2013
Dapagliflozin, Canagliflozin & Empaglifozin: A novel insulin-independent approach to remove excess glucose
Proximal tubule
Glucose filtration
1. FORXIGA Summary of Product Characteristics
Dapagliflozin & emplgliflozin selectively inhibits SGLT2 in the renal proximal tubule1
SGLT2
Glucose
Dapagliflozin
SGLT2
Dapagliflozin Canagliflozin empagliflozin
Increased urinary glucose
excretion
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UK/EMP/00073a(2) | April 2015
In healthy individuals,
the renal glomeruli filter ~180 g
of glucose per day
Virtually all of the filtered glucose is re-absorbed in the proximal tubules
through SGLT2 and SGLT1 with SGLT2
accounting for ~ 90% in the S1
and S2 segments and SGLT1
accounting for ~ 10% in the S3 segment
Filtered glucose load 180 g/day
SGLT1
SGLT2
~ 10%
~ 90%
Renal glucose re-absorption under healthy conditions1,2
SGLT, sodium glucose co-transporter.
References 1. Adapted from: Gerich JE. Diabet Med. 2010;27:136–142. 2. Bakris GL, et al. Kidney Int. 2009;75;1272–1277.
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UK/EMP/00073a(2) | April 2015
Renal glucose re-absorption in patients with diabetes1,2
SGLT1
SGLT2
~ 10%
~ 90%
When blood glucose increases
above the renal threshold (~ 11 mmol/l or 190 mg/dL), the capacity of the transporters is
exceeded, resulting in urinary glucose
excretion
Filtered glucose load > 180 g/day
SGLT, sodium glucose co-transporter.
References 1. Adapted from: Gerich JE. Diabet Med. 2010;27:136–142. 2. Bakris GL, et al. Kidney Int. 2009;75;1272–1277.
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UK/EMP/00073a(2) | April 2015
Urinary glucose excretion via SGLT2 inhibition1
SGLT, sodium glucose co-transporter. * Loss of ~ 78 g of glucose per day2, equating to 240-320 kcal/day. References 1. Bakris GL, et al. Kidney Int. 2009;75;1272–1277. 2. Empagliflozin summary of product characteristics.
SGLT2 SGLT2 inhibitor
SGLT1
SGLT2 inhibitors reduce glucose re-absorption
in the proximal tubule, leading to
urinary glucose excretion* and
osmotic diuresis
Filtered glucose load > 180 g/day
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Dapagliflozin
www.thelancet.com Vol 385 May 23, 2015
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Cardiovascular outcomes Silvio E Inzucchi
Professor of Medicine, Yale University School of Medicine, New Haven, CT, USA
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Key inclusion and exclusion criteria
• Key inclusion criteria – Adults with type 2 diabetes – BMI ≤45 kg/m2 – HbA1c 7–10%* – Established cardiovascular disease
• Prior myocardial infarction, coronary artery disease, stroke, unstable angina or occlusive peripheral arterial disease
• Key exclusion criteria
– eGFR 10% compared to the dose at randomisation
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Trial design
• 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
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Randomised and treated
(n=7020)
Empagliflozin 10 mg (n=2345)
Empagliflozin 25 mg (n=2342)
Placebo (n=2333)
Screening (n=11531)
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HbA1c
6.0
6.5
7.0
7.5
8.0
8.5
9.0
Ad
just
ed m
ean
(SE)
Hb
A1c
(%)
Week
Placebo Empagliflozin 10 mg Empagliflozin 25 mg
2294 2296 2296
Placebo Empagliflozin 10 mg Empagliflozin 25 mg
2272 2272 2280
2188 2218 2212
2133 2150 2152
2113 2155 2150
2063 2108 2115
2008 2072 2080
1967 2058 2044
1741 1805 1842
1456 1520 1540
1241 1297 1327
1109 1164 1190
962 1006 1043
705 749 795
420 488 498
151 170 195
12 28 52 94 108 80 122 66 136 0 150 164 178 192 206 40
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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
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Weight
80
82
84
86
88
90
Ad
just
ed m
ean
(SE)
wei
ght (
kg)
Week 2285 2290 2283
Placebo Empagliflozin 10 mg Empagliflozin 25 mg
1915 1893 1891
2215 2238 2226
2138 2174 2178
1598 1673 1678
1239 1298 1335
425 483 489
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
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28 52 108 0 164 220 12
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
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Waist circumference
101
102
103
104
105
106
107
Ad
just
ed m
ean
(SE)
wa
ist
circ
umfe
renc
e (c
m)
Week
2259 2272 2273
Placebo Empagliflozin 10 mg Empagliflozin 25 mg
1869 1836 1857
2183 2219 2209
2110 2155 2157
1562 1644 1648
1220 1285 1329
418 475 486
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
28 52 108 0 164 220 12
39
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
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Systolic blood pressure
40
125
127
129
131
133
135
137
139
141
143
145
Ad
just
ed m
ean
(SE)
sys
tolic
b
lood
pre
ssur
e (m
mH
g)
Week 2322 2322 2323
Placebo Empagliflozin 10 mg Empagliflozin 25 mg
2235 2250 2247
2203 2235 2221
2161 2193 2197
2133 2174 2169
2073 2125 2129
2024 2095 2102
1974 2072 2066
1771 1853 1878
1492 1556 1571
1274 1327 1351
1126 1189 1212
981 1034 1070
735 790 842
450 518 528
171 199 216
Placebo
Empagliflozin 10 mg Empagliflozin 25 mg
16 28 52 94 108 80 122 66 136 0 150 164 178 192 206 40
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
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Diastolic blood pressure
41
70
71
72
73
74
75
76
77
78
79
80
Ad
just
ed m
ean
(SE)
dia
stol
ic
blo
od p
ress
ure
(mm
Hg)
Week 2322 2322 2323
Placebo Empagliflozin 10 mg Empagliflozin 25 mg
2235 2250 2247
2203 2235 2221
2161 2193 2197
2133 2174 2169
2073 2125 2129
2024 2095 2102
1974 2072 2066
1771 1853 1878
1492 1556 1571
1274 1327 1351
1126 1189 1212
981 1034 1070
735 790 842
450 518 528
171 199 216
Placebo
Empagliflozin 10 mg Empagliflozin 25 mg
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
16 28 52 94 108 80 122 66 136 0 150 164 178 192 206 40
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3-point MACE
42
Empagliflozin 10 mg HR 0.85
(95% CI 0.72, 1.01) p=0.0668
Empagliflozin 25 mg HR 0.86
(95% CI 0.73, 1.02) p=0.0865
Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio
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CV death
43
Empagliflozin 10 mg HR 0.65
(95% CI 0.50, 0.85) p=0.0016
Empagliflozin 25 mg HR 0.59
(95% CI 0.45, 0.77) p=0.0001
Cumulative incidence function. HR, hazard ratio
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Hospitalisation for heart failure
44
HR 0.65 (95% CI 0.50, 0.85)
p=0.0017
Cumulative incidence function. HR, hazard ratio
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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
45
MACE, Major Adverse Cardiovascular Event; HDL, high density lipoprotein; LDL, low density lipoprotein
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EMPA-REG OUTCOME®: Summary
• Empagliflozin reduced hospitalisation for heart failure by 35%
• Empagliflozin reduced CV death by 38%
• Empagliflozin improved survival by reducing all-cause mortality by 32%
46
CV, cardiovascular
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EMPA-REG OUTCOME®: Important features
• Population studied – A high CV risk population with modest hyperglycaemia on
standard glucose-lowering and CV therapy
• Follow-up and retention – 97.0% of patients completed the study and vital status was
available for 99.2% of patients
• Two doses of empagliflozin (10 mg and 25 mg) studied – Similar magnitude of reduction with both doses for CV death,
all-cause mortality and hospitalisation for heart failure
47
CV, cardiovascular
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Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk
48
1. 4S investigator. Lancet 1994; 344: 1383-89, http://www.trialresultscenter.org/study2590-4S.htm; 2. HOPE investigator N Engl J Med 2000;342:145-53, http://www.trialresultscenter.org/study2606-HOPE.htm
Simvastatin1 for 5.4 years
High CV risk 5% diabetes, 26% hypertension
1994 2000 2015
Pre-statin era
High CV risk 38% diabetes, 46% hypertension
Ramipril2 for 5 years
Pre-ACEi/ARB era
80% ACEi/ARB
>75% statin
http://www.trialresultscenter.org/study2590-4S.htmhttp://www.trialresultscenter.org/study2590-4S.htmhttp://www.trialresultscenter.org/study2590-4S.htmhttp://www.trialresultscenter.org/study2590-4S.htmhttp://www.trialresultscenter.org/study2606-HOPE.htmhttp://www.trialresultscenter.org/study2606-HOPE.htmhttp://www.trialresultscenter.org/study2606-HOPE.htmhttp://www.trialresultscenter.org/study2606-HOPE.htmhttp://www.trialresultscenter.org/study2606-HOPE.htm
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EMPA-REG OUTCOME®: Therapeutic considerations
• Empagliflozin, as used in this trial, for 3 years in 1,000 patients with type 2 diabetes at high CV risk:
– 25 lives saved (82 vs 57 deaths)
• 22 fewer CV deaths (59 vs 37)
– 14 fewer hospitalisations for heart failure (42 vs 28)
– 53 additional genital infections (22 vs 75)
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Empagliflozin modulates several factors related to CV risk
Adapted from Inzucchi SE,Zinman, B, Wanner, C et al. Diab Vasc Dis Res 2015;12:90-100 50
BP Arterial stiffness
Glucose Insulin
Albuminuria
Uric acid
Other
↑LDL-C ↑HDL-C
Triglycerides
Oxidative stress
Sympathetic nervous system
activity
Weight Visceral adiposity
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New drugs for diabetesDeclaration of interestsSlide Number 3The benefits of early tight control: �UKPDS 10 year post-trial follow-upHbA1c control significantly benefits diabetes outcomes: UK Prospective Diabetes Study (UKPDS)Slide Number 6Slide Number 7Drug treatments for type 2 diabetes and their sites of actionNICE T2DM treatment algorithmSlide Number 10GLP-1 effects in humans understanding �the natural role of incretinsDPP4Slide Number 13Use of alternative treatments to SUsHypoglycaemia is more likely than hyperglycaemia to be associated with cardiac ischaemiaSulphonylureas and cardiovascular riskSlide Number 17Baseline Risk of Patient Populations Enrolled in CV Safety Trials of DPP-4 Inhibitors DPP4 EXAMINE, SAVOR-TIMI 53, and TECOS CV Safety TrialsHeart failureSlide Number 21Slide Number 22Slide Number 23Slide Number 24Slide Number 25Dapagliflozin, Canagliflozin & Empaglifozin: A novel insulin-independent approach to remove excess glucoseRenal glucose re-absorption under healthy conditions1,2Renal glucose re-absorption in patients with diabetes1,2Urinary glucose excretion via SGLT2 inhibition1Slide Number 30Slide Number 31Slide Number 32DapagliflozinCardiovascular outcomesKey inclusion and exclusion criteriaTrial designHbA1c Weight Waist circumference Systolic blood pressure Diastolic blood pressure 3-point MACECV death Hospitalisation for heart failureEMPA-REG OUTCOME®: SummaryEMPA-REG OUTCOME®: SummaryEMPA-REG OUTCOME®: Important featuresNumber needed to treat (NNT) to prevent one death across landmark trials in patients with high CV riskEMPA-REG OUTCOME®:�Therapeutic considerationsEmpagliflozin modulates several factors related to CV riskSlide Number 51Slide Number 52Slide Number 53Slide Number 54Slide Number 55Slide Number 56Slide Number 57