diabetes mellitus cases - staabsymposium.com€¦ · patients with diabetes remain at increased...

Robert S. Busch, MD, FACEDirector of Clinical ResearchAlbany Medical Faculty: Community Endocrine GroupAlbany, NY

2

Faculty

Disclosures

Robert S. Busch, MD, FACE serves as a speaker for Astra Zeneca, Eli Lilly, Boehringer Ingelheim and Novo Nordisk.

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Learning Objectives

1. Recognize the importance of C-V risk management in the patient with Type 2 DM

2. Describe the mechanism of action and capabilities of PCSK-9 therapies

4

↑ Risk50 – 80%

PATIENTS WITH DIABETES REMAIN ATINCREASED RISK FOR ASCVD EVENTS

5

1. Gregg EW, Li Y, Wang J, et al. Changes in Diabetes-Related Complications in the United States, 1990-2010. N Engl J Med. 2014;370(16):1514-23. Epub 2014/04/18. doi: 10.1056/NEJMoa1310799. PubMed PMID: 24738668.

0

20

40

60

80

100

120

140

160

1990 1995 2000 2005 2010

Even

ts P

er 1

0,00

0 Am

ong

Adul

ts

Diabetes/Acute MINo Diabetes/Acute MIDiabetes/StrokeNo Diabetes/Stroke

4S(1994)

HOPE(2000)

Type 2 DM is a Progressive Disease

Adapted from Type 2 Diabetes BASICS: International Diabetes Center; 2000.Years -10 -5 0 5 10 15 20 25 30

35030025020015010050

InsulinLevel

Insulin Resistance

Decreasing β-cell Function

250200150100500

FastingGlucose

Post-prandialGlucose

Glucose (mg/dl)

CLINICAL DIAGNOSIS

ClinicalFeatures

Macrovascular changes

Obesity IGT Diabetes Uncontrolled hyperglycemia

Microvascular changes

Compensatedβ-cell Function

Relative Insulin Resistance

6

The Ticking Clock Hypothesis

Type 2 DM is associated with microvascular and macrovascular complications.

Duration of DM and severity of glycemia are primarily associated with microvascular disease.

Metabolic disturbances during the prediabetic period may contribute to macrovascular disease.

Macrovascular complications: the clock starts ticking years before the onset of clinical diabetes.

Haffner SM et al. JAMA. 1990;263:2893-8.7

The ABC’s of Diabetes

A1C (and ASA) < 7.0% (ACE < 6.5%)

Blood Pressure* < 140/90 mmHg (125/75 mmHg)

Cholesterol** LDL-C < 100 mg/dL (<70 mg/dL?) Non-HDL-C < 130 mg/dL (<100 mg/dL?) HDL-C > 40 mg/dL (> 50 mg/dL in women) TG’s < 150 mg/dL

Smoking Cessation* JNC 8: < 140/90 mmHg AACE: <130/80** NCEP 4: high-dose statin therapy

recommended; >50% LDL-C reduction ADA. Standards of Medical Care in Diabetes – 2016. Diabetes Care 2016;39:S1-S106.

12

Steno Study Design

Gaede et al. N Engl J Med 2003;348:383-93.

160 type 2 diabetics with microalbuminuria Randomized treatment assignments

“Conventional”: Treatment for multiple risk factors from general practitioner, in accordance with 1988 Danish Medical Association guidelines

“Intensive”: Treatment for multiple risk factors by a project team (physician, nurse, dietician) at Steno Diabetes Center, involving strict treatment goals

Endpoints Primary: CV death, MI, CVA, revascularization, amputation Secondary: nephropathy, retinopathy, neuropathy

Eight-year follow-up

13

00 1 2 3 4 5 6 7 8

60

50

40

30

20

10

Conventional(n = 80)

Intensive(n = 80)

Years of Follow-Up

Perc

ent w

ith E

vent

53% RRRP = 0.01

Steno-2: Macrovascular Endpoints*

*CV death, MI, CVA, revascularization, amputation

Gaede et al. N Engl J Med 2003;348:383-93. 14

The Heart Outcomes Prevention Evaluation Study Investigators. NEJM. 2000;342:145-53.

22% RRR

19

SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR

0 1 2 3 4 5 60

5

10

15

20

25

30

Years of follow-up

5(3) 20(4) 35(5)

SIMVASTATIN

PLACEBO

46(5) 54(7) 60(18)Benefit/1000 (SE):

Peop

le s

uffe

ring

even

ts (%

)

21

SIMVASTATIN: CAUSE-SPECIFIC MORTALITY

(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI

STATIN better PLACEBO betterCause ofdeath

Vascular

587 707Coronary194 230Other vascular

(7.6%) (9.1%)17% SE 4reduction

781 937

(2P<0.0001)

ANY VASCULAR

Non-vascular

359 345Neoplastic90 114Respiratory82 90Other medical16 21Non-medical

(5.3%) (5.6%)5% SE 6reduction

547 570

(NS)

NON-VASCULAR

(12.9%) (14.7%)13% SE 4reduction

1328 1507

(2P<0.001)

ALL CAUSES

0.4 0.6 0.8 1.0 1.2 1.422

SIMVASTATIN: MAJOR VASCULAR EVENTS

(10269) (10267)SIMVASTATIN PLACEBO Rate ratio & 95% CI

STATIN better PLACEBO betterVascularevent

898 1212Major coronary

444 585Any stroke

939 1205Revascularisation

(19.8%) (25.2%)24% SE 3reduction

2033 2585

(2P<0.00001)

ANY OF ABOVE

0.4 0.6 0.8 1.0 1.2 1.4

25

CARDS

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CARDS Eligibility CriteriaType 2 diabetes

Males or females

40-75 years of age

No clinical history of coronary, cerebrovascular or severe peripheral vascular disease

LDL-C ≤4.14 mmol/L (≤160 mg/dL)

TG ≤6.78 mmol/L (≤600 mg/dL)

One of :– Hypertension defined as receiving antihypertensive treatment or SBP ≥140

mm Hg or DBP ≥90 mm Hg

– Retinopathy

– Microalbuminuria or macroalbuminuria

– Current smoking 27

CARDS Endpoints

• Acute CHD death• Non-fatal MI including silent MI• Hospitalised unstable angina• Resuscitated cardiac arrest• Coronary revascularisation• Stroke

Major coronary events

Primary Efficacy Parameters

Secondary Efficacy Parameters• Total mortality• Any cardiovascular endpoint• Lipid and lipoproteins

CARDS Patient Baseline Lipids*

1.3 (1.2-1.6)52 (45-60)

1.4 (1.2-1.6)53 (46-61)

HDL-cholesterol (mmol/L)(mg/dL)

3.1 (2.6-3.6)119 (100-138)

3.1 (2.6-3.6)118 (100-137)

LDL-cholesterol (mmol/L)(mg/dL)

5.4 (4.8-5.9)207 (186-228)

5.4 (4.8-5.9)207 (185-229)

Total cholesterol (mmol/L)(mg/dL)

AtorvastatinMedian (IQR)

PlaceboMedian (IQR)

* Subject to final verification

Lipid Levels by Treatment Total cholesterol (mmol/L) LDL cholesterol (mmol/L)

0 2 3 41 4.5 2 3 41 4.5

Years of Study Years of Study

00

1

2

3

4

0

2

4

6

Placebo Atorvastatin

Average difference 26%

1.4 mmol/L (54mg/dL) p<0.0001

Average difference 40%

1.2 mmol/L (46mg/dL) p<0.0001

Cumulative Hazard for Primary EndpointRelative Risk Reduction 37% (95% CI: 17-52)

Years

328305

694651

10741022

13611306

13921351

AtorvaPlacebo

14281410

Placebo127 events

Atorvastatin83 events

Cum

ulat

ive

Haz

ard

(%)

0

5

10

15

0 1 2 3 4 4.75

P=0.001

Cumulative Hazard for All Cause Mortality

Relative Risk Reduction 27% (95%CI: -1-48) p=0.059

Cum

ulat

ive

Haz

ard

(%)

Years

AtorvaPlacebo

Placebo82 deaths

Atorvastatin61 deaths

351332

730709

11101094

14011370

14181395

14281410

1 2 3 4 4.750

2

4

6

8

10

0

June 3, 201536

Ominous Octet

DeFronzo RA. Diabetes. 2009;58:773-795. 38

Pro-Active

Lancet 2005;366:1279-89. 39

NEJM Feb 17, 2016 DOI: 10.1056/NEJMoa1506930

24% RRR

43

White et al. N Engl J Med 2013;369:1327–35; Sciria et al. N Engl J Med 2013;369:1317–26; Green et al. N Engl J Med 2015;16;373:232–42; Pfeffer et al. N Engl J Med2015;373:2247–57

ACS, acute coronary syndrome; CI, confidence interval; CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes: Alogliptin vs. Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome; HR, hazard ratio; MI, myocardial infarction; SAVOR TIMI-53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53; T2D, type 2 diabetes; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; UA, unstable angina

Alogliptin (6.25, 12.5 or 25 mg/day*) + standard of care

T2D; HbA1c 6.5–11.0%; ACS within 15–90 days (n=5380)

Placebo + standard of care

Saxagliptin (2.5 or 5 mg/day**) + standard of care


T2D; HbA1c 6.5–12.0%; ≥40 years + CVD; ≥55 (men) or ≥60 (women) years + CV risk factors (n=16,492)

Lixisenatide (10 or 20 µg/day†) + standard of care


T2D; HbA1c 5.5–11.0%; ACS within 180 days (n=6068)

T2D; HbA1c 6.5–8.0%; ≥50 years; CVD history (n=14,671)

Sitagliptin (100 or 50 mg/day***) + standard of care


SAVOR-TIMI-53 EXAMINE

TECOS ELIXA

Time (days) Time (months)

Time (months)

Time in the trial (months)

Pati

ents

wit

h en

dpoi

nt (

%)

Pati

ents

wit

h en

dpoi

nt (

%)

Pati

ents

wit

h en

dpoi

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%)

Pati

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wit

h en

dpoi

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%)

EMPA-REG1 LEADER4 SUSTAIN-65

Population T2D + high CV risk T2D + high CV risk T2D

Drug (Class)

Empagliflozin(SGLT-2i)

Liraglutide (GLP-1RA)

Semaglutide (GLP-1RA)

Objective Non-inferiority Non-inferiority Non-inferiority

Endpoint 3-point MACE 3-point MACE 3-point MACE

Results HR 0.86 HR 0.87 HR 0.74

Selected CVOTs:Assessing CV benefit with antiglycemic agents

1. Zinman et al. N Engl J Med 2015;373:2117–28; 2. Green et al. N Engl J Med 2015;373:232–42; 3. Pfeffer et al. N Engl J Med 2015;373:2247–57; 4. Marso et al. N Engl J Med 2016;375:311–22; 5. Marso et al. N Engl J Med 2016;375:1834–44

3-point MACE: first occurrence of CV death, nonfatal MI or nonfatal stroke; MACE+: CV death, nonfatal MI, nonfatal stroke and hospitalisation for UA procedure ACS, acute coronary syndrome; CV, cardiovascular; CVOT, cardiovascular outcomes trial; GLP-1RA, glucagon-like peptide-1 receptor agonist; HR, hazard ratio; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; MACE, major adverse cardiovascular event; MI, myocardial infarction; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; T2D, type 2 diabetes; UA, unstable angina

Image: http://images.agoramedia.com/everydayhealth/gcms/10-Amazing-Facts-About-Blood-Vessels-722x406.jpg

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CARDIOVASCULAR OUTCOMEDATA FOR SGLT2 INHIBITORS

SGLT-2 Inhibitors: Mechanism of Action (cont)

Juxtoglomerular Complex

Proximal Convoluted

Tubules

Loop of Henle

Free Filtration of Solute

Active Reabsorption

Glucose

SGLT-2

SGLT-1

Glucose

Type 2 Diabetes

SGLT2 Inhibition Lowers Tmax, Allowing Elimination of Excess Glucose

Overexpression of SGLT2 shifts Tmax to the right, allowing excess glucose to be reabsorbed

SGLT2 inhibition shifts Tmax to the left, eliminating excess glucose

Chao E, et al. Nature Rev Drug Discov. 2010;9:551-559; Bays H. Curr Med Res Opin. 2009;25:671-681; DeFronzoRA, et al. Diabetes Obes Metab. 2012;14:5-14; Gerich JE. Diabet Med. 2010;27:136-142; Kim Y, et al. Diabetes Metab Syndr Obes. 2012;5:313-327. 50

300250200150100500

25

50

75

100

125

Urin

ary

Glu

cose

Exc

retio

n

(g/d

ay)

Plasma Glucose (mg/dL)

Tmax

SGLT2inhibition

Normal

T2DM 240 mg/dL

T2DMBlockade of SGLT2

EMPA-REG

NEJM, Nov 26 2015;373:2117-28

14% reduction of primary composite outcome: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke38% relative risk reduction of death from cardiovascular causes32% relative risk reduction of death from any cause35% relative risk reduction of hospitalization for heart failure

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52

Primary Outcome ResultsEMPA-REG OUTCOME (EMPAGLIFLOZIN)8

1.6% ARR

14% RRR

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Primary Outcome ResultsEMPA-REG OUTCOME (EMPAGLIFLOZIN)8

OutcomePooled

Empagliflozin(n = 4687)

Placebo(n = 2333)

Hazard Ratio(95% CI)

Primary Composite Outcome, n (%) 490 (10.5) 282 (12.1) 0.86

(0.74 to 0.99)

Assessment of Individual Primary Outcome Events

Death from CardiovascularCauses, n (%) 172 (3.7) 137 (5.9) 0.62

(0.49 to 0.77)

Nonfatal Myocardial Infarction, n (%) 213 (4.5) 121 (5.2) 0.87

(0.70 to 1.09)

Nonfatal Stroke, n (%) 150 (3.2) 60 (2.6) 1.24(0.92 to 1.67)

Abbreviation: CI – confidence interval

June 14, 2016

39% reduction of incident or worsening nephropathy 44% relative risk reduction of doubling of serum creatinine55% relative risk reduction of renal-replacement therapy

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EMPA-REG Trial-Demonstrates Rapid Improvement in 3-Point MACE

aCumulative incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.N=7020 patients with T2DM at high risk of cardiovascular events.Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128.

Patie

nts W

ith

Even

t, %

Empagliflozin

P=0.04 for superiorityHazard ratio, 0.86 (95.02% CI, 0.74–0.99)

Placebo2015

510

00 126 18 24 30 36 42 48

Cumulative Incidence of the Primary Outcomea

Patie

nts W

ith

Even

t, %

Empagliflozin

P<0.001Hazard ratio, 0.62 (95% CI, 0.49–0.77)

Placebo9

3

6

00 126 18 24 30 36 42 48

Cumulative Incidence of Death From CV Causes

Patie

nts W

ith

Even

t, %

Empagliflozin

P=0.002Hazard ratio, 0.65 (95% CI, 0.50–0.85)

Placebo7645

00 126 18 24 30 36 42 48

Month

Hospitalization for Heart Failure

321

55

38% risk reduction

14% risk reduction

35% risk reduction

Death from a CV event, non-fatal MI, or strokeEmpa 10, 25 mg or standard of care

Empa-Reg Renal Data

56Warner C, et al. NEJM. DOI: 10.1056/NEJMoa1515920

Incidence of nephropathy by 39 %

Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

57

CANVAS and CANVAS-R

Image: https://www.google.com/search?q=canvas&safe=off&rlz=1C1NHXL_enUS702US702&source=lnms&tbm=isch&sa=X&ved=0ahUKEwjl6Obczr7UAhUMVT4KHZSUAakQ_AUICygC&biw=1364&bih=613#safe=off&tbm=isch&q=canvas+paint+clipart&imgrc=y4C-q7myhxZKjM:

Study DesignCANVAS AND CANVAS-R (CANAGLIFLOZIN)9

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Key Inclusion Criteria T2DM 7% ≤ HbA1c ≤ 10.5% Antidiabetic medication naïve OR

treated with ≥ 1 approved agent ≥ 30-years-old with symptomatic

ASCVD OR≥ 50-years-old with ≥ 2 CV risk factors

eGFR ≥ 30 mL/min/1.73 m2

≥ 80% adherence during the 2-week placebo run-in period

Key Exclusion Criteria T1DM Antidiabetic regimen not stable for at

least 8 weeks ≥ 1 severe hypoglycemic episode

≤ 6 months prior to screening Acute ASCVD event occurring

≤ 3 months before screening eGFR < 30 mL/min/1.73 m2

MULTICENTER, INTERNATIONAL, DOUBLE-BLIND, NON-INFERIORITY TO SUPERIORITY,

PLACEBO-CONTROLLED, RANDOMIZED TRIAL

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Baseline CharacteristicsCANVAS AND CANVAS-R (CANAGLIFLOZIN)9

Baseline Characteristics Canagliflozin(n = 5795)

Placebo(n = 4347)

Male, n (%) 3759 (64.9) 2750 (63.3)

Age, years 63.2 ± 8.3 63.4 ± 8.2

Diabetes Duration, years 13.5 ± 7.7 13.7 ± 7.8

HbA1c (%) 8.2 ± 0.9 8.2 ± 0.9

Body Mass Index (kg/m2) 31.9 ± 5.9 32.0 ± 6.0

Established Cardiovascular Disease, n (%) 3756 (64.8) 2900 (66.7)

eGFR, MDRD (mL/min/1.73 m2) 76.7 ± 20.3 76.2 ± 20.8

Median Urine Albumin-to-Creatinine Ratio (mg/g), [interquartile range]

12.4[6.71 to 40.9]

12.1[6.57 to 43.9]

Neuropathy, n (%) 1787 (30.8) 1323 (30.4)

Current Smoker, n (%) 1020 (17.6) 786 (18.1)

Low-Density Lipoprotein Cholesterol (mg/dL) 88.9 ± 34.8 88.9 ± 34.8

Abbreviations: ± – standard deviation; eGFR – estimated glomerular filtration rate; MDRD – Modification of Diet in Renal Disease

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Baseline MedicationsCANVAS AND CANVAS-R (CANAGLIFLOZIN)9

Baseline Class/Medication Use Canagliflozin(n = 5795)

Placebo(n = 4347)

Antihypertensives, n (%) Not Available Not AvailableRenin-Angiotensin-Aldosterone System Inhibitors, n (%) 4645 (80.2) 3471 (79.8)

Beta Blockers, n (%) 3039 (52.4) 2382 (54.8)

Diuretics, n (%) 2536 (43.8) 1954 (45.0)

Antilipemics, n (%) Not Available Not AvailableStatins, n (%) 4329 (74.7) 3270 (75.2)

Ezetimibe, n (%) Not Available Not Available

Antithrombotics, n (%) 4233 (73.0) 3233 (74.4)Aspirin, n (%) Not Available Not Available

Antihyperglycemics, n (%) Not Available Not AvailableInsulin, n (%) 2890 (49.9) 2205 (50.7)

Metformin, n (%) 4447 (76.7) 3378 (77.7)

Sulfonylureas, n (%) 2528 (43.6) 1833 (42.2)

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Primary Outcome ResultsCANVAS AND CANVAS-R (CANAGLIFLOZIN)9

4.6*ARR

14% RRR

*Events per 1000 patient

years

62

Primary Outcome ResultsCANVAS AND CANVAS-R (CANAGLIFLOZIN)9

OutcomeCanagliflozin

(n = 5795)Placebo

(n = 4347) Hazard Ratio(95% CI)Number of Participants with an

Event per 1000 Patient Years

Primary Composite Outcome 26.9 31.5 0.86(0.75 to 0.97)


Death from Cardiovascular Causes 11.6 12.8 0.87

(0.72 to 1.06)

Nonfatal Myocardial Infarction 9.7 11.6 0.85(0.69 to 1.05)

Nonfatal Stroke 7.1 8.4 0.90(0.71 to 1.15)


Outcome Canagliflozin(Per 1000 Patient Years)

Placebo(Per 1000 Patient Years)


History of Amputation

Yes 96.30 59.16 2.15(1.11 to 4.19)

No 4.68 2.48 1.88 (1.27 to 2.78)

History of Peripheral Vascular Disease

Yes 12.09 8.16 1.39(0.80 to 2.40)

No 5.20 2.41 2.34(1.53 to 3.58)


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Safety DataCANVAS AND CANVAS-R (CANAGLIFLOZIN)9

EFFECTS OF CANAGLIFLOZIN ON ATRAUMATIC LOWERLIMB AMPUTATION IN KEY SUBGROUPS

HIGHEST LEVEL ATRAUMATIC LOWER-LIMBAMPUTATIONS IN THE CANVAS PROGRAM

Outcome Canagliflozin* Placebo* P ValueNumber of Participants with an Event per 1000 Patient Years

Any Serious Adverse Event 104.3 120.0 0.04Adverse Events Leading to Discontinuation 35.5 32.8 0.07

Adverse Events of Interest from the CANVAS ProgramAmputation 6.3 3.4 < 0.001Diabetic Ketoacidosis 0.6 0.3 0.14Fracture, All 15.4 11.9 0.02Fracture, Low-Trauma 11.6 9.2 0.06Genital Infections, Male 34.9 10.8 < 0.001

Adverse Events of Interest from CANVASHypoglycemia 50.0 46.4 0.20Mycotic Genital Infections, Female 68.8 17.5 < 0.001Volume Depletion 26.0 18.5 0.009n* – population size varies depending on the data set being analyzed

64

Cardiovascular Outcomes Data for Sodium-Glucose Cotransporter-2 InhibitorsAgent Empagliflozin (Jardiance) Canagliflozin (Invokana)

Clinical Trial EMPA-REG8 CANVAS/CANVAS-R9

Study Design DB, INT, MC, NI S,PC, R trial

DB, INT, MC, NI S, PC, R trial

Intervention Empagliflozin 10 or 25 mg PO once daily

Canagliflozin 100 mg to 300 mg PO once daily

Patient Population

≥ 18-years-old; acute coronary event> 2 months before informed consent; T2DM (57% > 10 years duration); baseline HbA1c: 8.1%; 99% with CV disease

≥ 30-years-old with a coexisting CV condition or ≥ 50-years-old with ≥ 2 CV risk factors; T2DM (mean: 14 years); baseline HbA1c: 8.2%; 65% with CV disease

Primary Composite Endpoint

Death from CV causes, nonfatal MI (excluding silent MI), nonfatal stroke

Death from CV causes, nonfatal MI (excluding silent MI), nonfatal stroke

Primary Composite Endpoint Outcome,

P vs. I

12.1% vs. 10.5%[HR 0.86; 95% CI: 0.74 – 0.99; p < 0.001 for NI; p = 0.04 for S]

31.5 vs. 26.9*[HR 0.86; 95% CI: 0.75 – 0.97;p < 0.001 for NI; p = 0.02 for S]

ARR / RRR 1.6% / 13.2% 4.6* / 14.6%

NumberNeeded to Treat 63 patients over 3.1 years

* Number of participants with an event per 1000 patient yearsAbbreviations: ARR – absolute risk reduction; CI – confidence interval; CV – cardiovascular; DB – double-blind; HR – hazard ratio; I – intervention; INT – international; MC – multi-center; MI – myocardial infarction; NI – noninferiority; P – placebo; PC – placebo-controlled; PO – by mouth; R – randomized; RRR – relative risk reduction; S – superiority; T2DM – type 2 diabetes mellitus

Proposed Cardioprotective Effects with SGLT2i15

SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS

65

↑ Uric acid excretion

↓ Extracellular Fluid Volume

↓ Preload

↑ Angiotensin 1-7 AT2

↓ Afterload

↓ Blood pressure

↓ Systemic vascular resistance

Weight loss

ADIPOSE TISSUE

LIVER

↓ Aortic Stiffness and Wall Stress

Improvedglycemiccontrol

PANCREATICALPHA CELLS

↑ FFA

↑ Glucagon↑ Ketones

↑ NaCl/H2O excretion

Clinical ConsiderationsSODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS

66

Advantages Disadvantages

Appreciable reductions in HbA1c Decrease in blood pressure and serum

uric acid Placebo-like risk for hypoglycemia Positive cardiovascular outcomes

data8,9

Potential renal-9,12 and heart failure-protective13,14 effects

Weight loss

Amputationso Potentially unique to canagliflozin

Cost Diabetic ketoacidoisis Genitourinary tract infections Increased LDL-C Polyuria Transient increase in serum creatinine Urinary tract infections leading to

pyelonephritis and urosepsis Volume

depletion/dizziness/hypotension

Abbreviation: LDL-C – low-density lipoprotein cholesterol

10. American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment. Sec. 8. In Standards of Medical Care in Diabetes-2017. Diabetes Care 2017;40(Suppl. 1):S64–S7411. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2017 Executive Summary. Endocr Pract. 2017;23(2):207-38. Epub 2017/01/18. doi: 10.4158/ep161682.cs. PubMed PMID: 28095040.

Patient education Polyuria Hydration Hygiene Signs and symptoms of DKA

When to hold therapy16

Patients at increased risk for amputations Glycosuria

2+

67

Image: http://www.nephrologynews.com/wp-content/uploads/2015/06/TS_Diabetes_167164767.jpg16. Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College Of Endocrinology Position Statement on the Association of SGLT-2 Inhibitors and Diabetic Ketoacidosis. Endocr Pract. 2016;22(6):753-62. Epub 2016/04/16. doi: 10.4158/ep161292.ps. PubMed PMID: 27082665.

Clinical ConsiderationsSODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS

NEJM, Dec 3, 201568

ELIXA

69

13% reduction of primary composite outcome: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke

22% relative risk reduction of death from cardiovascular causes

15% relative risk reduction of death from any causeNo change in relative risk reduction of hospitalization for

heart failure

NEJM June 13, 2016.

70

Study DesignTHE LEADER TRIAL (LIRAGLUTIDE)29

72

Key Inclusion Criteria T2DM HbA1c ≥ 7% Antidiabetic medication naïve OR

treated with ≥ 1 oral antidiabetic medication and/or long-acting, NPH or premixed insulin

≥ 50-years-old with established CVD or chronic renal failure OR≥ 60-years-old with ≥ 1 CV risk factor

Key Exclusion Criteria T1DM Use of a GLP-1 RA, DPP-4 inhibitor,

pramlintide or rapid-acting insulin Family or personal history of MEN2 or

medullary thyroid cancer Acute coronary or cerebrovascular

event occurring ≤ 14 days before randomization

MULTICENTER, INTERNATIONAL, DOUBLE-BLIND, NON-INFERIORITY TO SUPERIORITY, PLACEBO-CONTROLLED, RANDOMIZED TRIAL

Primary outcomes in LEADER and EMPA-REG Timing of separation of treatment arms suggest different cardioprotective MoAs

LEADER1

Placebo

Liraglutide

Prop

ortio

n of

indi

vidu

als

with

a M

AC

E ev

ent (

%)

Time from randomisation (months)

HR: 0.86 (95% CI: 0.74;0.99)p=0.04 (superiority)

HR: 0.87 (95% CI: 0.78;0.97)p=0.01 (superiority)

Placebo

Empaglifozin

20

15

10

5

0

0 6 12 18 24 30 36 42 48 54

20

15

10

5

0

0 6 12 18 24 30 36 42 48

EMPA-REG2

3-point MACE: first occurrence of CV death, nonfatal MI or nonfatal strokeCI, confidence interval; HR, hazard ratio; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; MACE, major adverse cardiovascular event; MoA, mode of action

1. Marso et al. N Engl J Med 2016;375:311–22; 2. Zinman et al. N Engl J Med 2015;373:2117–28

3 Point MACE improvement not driven by glycemic efficacy!

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Primary Outcome ResultsTHE LEADER TRIAL (LIRAGLUTIDE)

Outcome Liraglutide(n = 4668)

Placebo(n = 4672)


Primary Composite Outcome, n (%) 608 (13.0) 694 (14.9) 0.87

(0.78 to 0.97)


Death from CardiovascularCauses, n (%) 219 (4.7) 278 (6.0) 0.78

(0.66 to 0.93)Nonfatal Myocardial Infarction, n (%) 281 (6.0) 317 (6.8) 0.88

(0.75 to 1.03)

Nonfatal Stroke, n (%) 159 (3.4) 177 (3.8) 0.89(0.72 to 1.11)

Abbreviation: CI – confidence interval29. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-22. Epub 2016/06/14. doi: 10.1056/NEJMoa1603827. PubMed PMID: 27295427; PubMed Central PMCID: PMCPMC4985288.

GLP-1RA and SGLT-2iProposed cardioprotective MoA

Increased urinary glucose excretion

Glomeruli

Proximaltubule

Distaltubule

SGLT-2i

Empagliflozin

GLP-1RAIncreasedglucosefiltration

Liraglutide Vasodilation

Plaque stability

Blood flow

Endothelialfunction

Inflammation

Smooth muscle proliferation

Platelet aggregation

GLP-1R

Proposed cardioprotective MoA3

• Fluid reduction• Hemodynamic effects• Heart metabolism• Established effects

• Hyperglycaemia• Weight• Visceral adiposity• BP

Increased glucose uptake and glucagon synthesis (adipose, muscle, liver)

Decreased appetite and food intake (brain)

Increased insulin secretion, decreased glucagon secretion (pancreas)

Proposed cardioprotective MoA1,2

• Anti-atherosclerotic • Reduced platelet aggregation• Anti-inflammatory effects• Established effects

• Hyperglycaemia• Weight• Visceral adiposity• BP

BP, blood pressure; GLP-1RA, glucagon-like peptide-1 receptor agonist; MoA, mode of action; SGLT-2i, sodium-glucose cotransporter-2 inhibitor

1. Marso N Engl J Med 2016;375:311–22; 2. Drucker. Cell Metab 2016;24:15–30; 3. Zinman et al. N Engl J Med 2015;373:2117–28

NEJM, Sep 16, 2016

76

NEJM, Sep 16, 201678

Pending Diabetes CV Outcome Studies

Schnell et al. Cardiovasc Diabetol. 2016;15:139-51.

80

Diabetes CV Outcome Studies

81

PCSK9 (Proprotein convertase subtilisin/kexin type 9)

A secreted protein which targets the LDL receptor for degradation

Gain of function mutations cause high LDL-CLoss of function mutations cause low LDL-C Inhibition lowers LDL-C levelsUp-regulated by statin therapy

82

How is cholesterol removed from blood?

LIVER

Circulating LDL particles (which contain a large ApoBprotein) are “grabbed” by an

LDL receptor

83


LIVER

The entire complex is then internalized into the hepatocyte for LDL destruction

84


LIVER Before the LDL particle is destroyed, the LDL

receptor migrates back to the hepatocyte cell surface so that it can

grab more LDL molecules

Then the LDL particle is destroyed

85


LIVER

When PCSK9 is present, however, the LDL-C receptor

gets “stuck” and cannot migrate back to the surface

It therefore gets destroyed along

with the LDL

And the number of LDL-C receptors on the cell surface is depleted

86

The theory behind PCSK9 inhibitors

LIVER

If PCSK9 is inhibited, the LDL-C receptor can migrate

back to the cell surface

And surface LDL receptors will be restored which will reduce the

serum LDL-C level

X

87

DOI: 10.1056/NEJMoa1615664

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