New drugs for diabetes - Issues & Answers 2020 · 2017. 10. 27. · The benefits of early tight...

New drugs for diabetes

PCCJ conference 2015 Professor Mike Kirby FRCP University of Hertfordshire

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.

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

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

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

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

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

Antihyperglycemic therapy in type 2 diabetes: general recommendations.

Silvio E. Inzucchi et al. Dia Care 2015;38:140-149

©2015 by American Diabetes Association

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

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

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

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

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

18

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

19

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

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

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

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.

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.

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

Dapagliflozin

www.thelancet.com Vol 385 May 23, 2015

Cardiovascular outcomes Silvio E Inzucchi

Professor of Medicine, Yale University School of Medicine, New Haven, CT, USA

34

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

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

36

Randomised and treated

(n=7020)

Empagliflozin 10 mg (n=2345)

Empagliflozin 25 mg (n=2342)

Placebo (n=2333)

Screening (n=11531)

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


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

37

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

Weight

80

82

84

86

88

90

Ad

just

ed m

ean

(SE)

wei

ght (

kg)

Week 2285 2290 2283


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

38

28 52 108 0 164 220 12


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


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


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


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


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


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

3-point MACE

42

Empagliflozin 10 mg HR 0.85

(95% CI 0.72, 1.01) p=0.0668


(95% CI 0.73, 1.02) p=0.0865

Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio

CV death

43


(95% CI 0.50, 0.85) p=0.0016


(95% CI 0.45, 0.77) p=0.0001

Cumulative incidence function. HR, hazard ratio

Hospitalisation for heart failure

44

HR 0.65 (95% CI 0.50, 0.85)

p=0.0017

Cumulative incidence function. HR, hazard ratio

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

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

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

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

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)

49

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

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

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