L’evoluzione della terapia del diabete tipo 2 - Marchesini Giulio - L... · L’evoluzione della...

L’evoluzione della terapia del diabete tipo 2

Giulio Marchesini“Alma Mater” Università di BolognaDipartimento di Scienze Mediche e

Chirurgiche

DisclosuresGiulio Marchesini• Advisory Board: Lilly, Gilead• Honoraria: Sanofi, Merck Sharp & Dome, Novartis• Clinical Studies: Boehringer Ingelheim, Janssen Cilag,

Sanofi, Lilly, Novo Nordisk, Gilead, GENFIT, Glaxo

Draft della presentazione• Stato attuale del trattamento• Momenti topici nel cambiamento

– Proactive– NHI regulatory action– GLP-1RAs – DPP-4Is– Grandi trial (Advance – Accord – VADT)– SGLT-2Is– Degludec– EMPA-REG Outcome– TECOS – EXAMINE – SAVOR-TIMI– Biosimilare di Glargine– Glargine 300– GLP-1RAs settimanali– GLP-1RAs+Insulina basale

Trend di prevalenza e spesa negli anni

2017

0

50

100

150

200

250

300

350

0

1

2

3

4

5

619

97

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

Spes

a m

edia

per

trat

tato

(€)

Prev

alen

za

Anno

Prevalenza pop F Prevalenza pop M Spesa media trattato F Spesa media trattato M

ARNO 2015Costi diretti del diabete

2015

2898

1638

Chart1

Diabetes All casesDiabetes All casesDiabetes All casesDiabetes All casesDiabetes All cases

NO DiabetesNO DiabetesNO DiabetesNO DiabetesNO Diabetes

Non-diabetes drugs

Diabetes drugs

Hospital admission

Monitoring systems

Services

592

191

1396

119

600

356

842

440

Foglio1

Diabetes All casesNO Diabetes

Non-diabetes drugs592356

Diabetes drugs191

Hospital admission1396842

Monitoring systems119

Services600440

Categoria 44.5

Per ridimensionare l'intervallo di dati del grafico, trascinare l'angolo inferiore destro dell'intervallo.

Andamento della terapia con anti-iperglicemici non-insulinici

%

Anno

-1.6%Anti-iperglicemici non-insulinici

Miccoli R. – adattato da Rapporto ARNO-Diabete 2017

Andamento della terapia con anti-iperglicemici non-insulinici impiegati non in combinazione precostituita

Anno

% +500%Metformina

Sulfonilureee -46%

Incretine +500%


Andamento nella frequenza d’uso dei sulfoniluree+glinidi in relazione alle classi di età

%

Classi di età (anni)

-87% -75%

-66%

-60%

-52%

-46%


Trattamento insulinico in relazione all’età

Fra tutti i pazienti in terapia insulinica (26%), il 64% ha più di 65 anni. Solo il 6% ha meno di 35 anni.

6%

64%

Impiego dell’insulina umana (DNA-r) e degli analoghi dell’insulina nel corso degli anni

%

Anno

28%

22%


La scala dei farmaci del diabete

Cahn, Lancet Diabetes Endocrinol 2015

Superiority

Noninferiority

Noninferiority

Inferiority

Underpowered

Approvable;CV safety study post approvalmay not be required

Approvable; need for CV safety study

Not approvable

NoninferiorityBoundary

HR 1.3

NoninferiorityBoundary

HR 1.8

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2Hazard ratio

BEST

Statistical Criteria for Approval1

Five hypothetical examples of possible HRs, and regulatory consequences

Hirshberg B et al. Diabetes Care. 2011:34 (Suppl 2);S101–S106.

FDA = Food and Drug Administration; HR = hazard ratio; CV = cardiovascular.

SAVOR-TIMI (Saxagliptin) 1

EXAMINE (Alogliptin) 2

TECOS (Sitagliptin)3

Recruitment Period

Sept 2010 Jan 2012 2009 2012 Dec 2008 July 2012

Primary Endpoint

Composite of CV death, nonfatal MI, nonfatal stroke

Composite ofCV death, nonfatal myocardial infarction, and nonfatal stroke

Composite of CV death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization

Analysis Population/ # of events

ITT for both NI and superiority

Powered for 1040 events

NI, then superiorityType of analysis not mentioned in design paper


PP for NI; ITT for superiority


Completion Date

Q3 2013 Q4 2013 Q4 2014

Comparison of CV Outcome Study Design

1-Scirica BM et al, Am Heart J 2011; 2-White W. et al Am Heart J 2011; 3-Clinicaltrials.gov accessed, 2013

ACCORD, ADVANCE & VADT –Effect of intensive treatment on glycaemic control

ACCORD1

VADT3 ADVANCE2

ACCORD1 ADVANCE2 VADT3

A1c at entry (%) 8.1 7.2 9.4

Target A1c

Time since diagnosis (years) Del Prato, Diabetologia 2009

Analisi di risultato

Factors associated with the probability to achieve hemoglobin A1c 80%.

R

R

R

Durata media del follow-up

EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome;SAVOR-TIMI= Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin. CV = cardiovascular; MI = myocardial infarction; UA = unstable angina.White WB et al. N Engl J Med. 2013;369:1327–1335. Scirica BM et al. N Engl J Med 2013;369:1317–1326. 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.

EXAMINE, SAVOR-TIMI e TECOS

SAVOR-TIMI2

TECOS3,4

EXAMINE1

6.5–8.0Morte CV ,

IM non fatale, oIctus non fatale o UA req.

ospedalizzazione

Randomizzazione Anno 3Anno 2Anno 1

Morte CV ,IM non fatale, oIctus non fatale

Morte CV ,IM non fatale, oIctus non fatale

Sitagliptin

Saxagliptin

Alogliptin

Placebo

Placebo

Placebo

6.5–12.0

6.5–11.0

HbA1c% End point PrimarioDurata del trattamento

Canaglifozin – Effects on body weight

Cefalù, ADA Chicago 2013

DURATION trials Change in body weight from baseline

†Exenatide QW is not indicated for the management of obesity, and weight change was a secondary endpoint in clinical trials.

Data from 24–30 Weeks. *P

Composite endpoint Hba1c

Zinman, N Engl J Med 2015

Death from CV causes, nonfatal MI, or nonfatal stroke

Zinman, N Engl J Med 2015

Wanner, N Engl J Med 2016

In the recent EMPA-REG OUTCOME trial, the primary goal was to assess cardiovascular outcomes. Here we report the results of a prespecified secondary objective of that trial, which was to examine the effects of empagliflozin on micro-vascular outcomes and, in particular, progression of kidney disease in patients with T2DM at high risk for cardiovascular events.

Wanner, N Engl J Med 2016

Neal, N Engl J Med 2017

Mahaffey, Circulation (in press)

Marso, N Engl J Med 2016

Primary composite outcome: first occurrence of death from cardiovascular causes, nonfatal (including silent) myocardial infarction, or nonfatal stroke.


Exploratory outcomes: composite cardiovascular outcome (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure), death from any cause, a composite renal and retinal microvascular outcome

DURATION trialsHbA1c reductions of −1.3% to −1.9%

Exenatide BID¶2N=295

30 weeks

Exenatide BID¶3N=252

24 weeks

Baseline (%)

Sitagliptin (100 mg QD) or pioglitazone (45 mg QD)¶1 N=491

26 weeksInsulin glargine#5

N=44826 weeks

Exenatide QW vs Liraglutide 1.8 mg¶4N=911

26 weeks

Sitagliptin Pioglitazoneexenatide QW LiraglutideExenatide BID Insulin glargine−1.9%†

−1.5% −1.6%‡

−0.9%

LS m

ean

chan

ge in

HbA

1c(%

)

0

−0.5

−1.0

−1.5

−2.0

−1.5%*

−1.2%

−0.9%

8.3 8.3 8.5 8.48.6 8.5 8.5 8.3 8.3

−1.5% −1.5%||−1.3%−1.3%§

8.5 8.4

Data from 24–30 Weeks. *P

Proportion of Patients Achieving HbA1c

Davies, JAMA 2016

Effetto dei farmaci ipoglicemizzanti sul MACE-3 nel DM2

EXSCEL EXENATIDE HR 0.91 95 % IC 0,83-1 P < 0.001 per non inferiorita , p 0.06 per superiorita

CANVAS HR 0,86 95 % IC 0.52-0,87 p 0,001 non inf eriorita , p0.02 per superiorita

Holman, N Engl J Med 2017

The primary composite out-come was the first occurrence of death from cardiovascular causes, nonfatal myo-cardial infarction, or nonfatal stroke.

Among patients with T2DM w/woprevious CVD, the incidence of major adverse CV events did not differ significantly between patients who received exenatide and those who received placebo.

Confirmed hypoglycaemia

SASComparisons: Estimates adjusted for multiple covariates

18% risk reduction, p=0.036

IDeg OD (n=753)IGlar OD (n=251)

Time (weeks)

Con

firm

ed h

ypog

lyca

emia

(cum

ulat

ive

even

ts p

er p

atie

nt)

Garber A et al. Lancet 2012;379:1498-507

Chart1

00

0.14285714290.1428571429

0.28571428570.2857142857

0.42857142860.4285714286

0.57142857140.5714285714

0.71428571430.7142857143

0.85714285710.8571428571

11

1.14285714291.1428571429

1.28571428571.2857142857

1.42857142861.4285714286

1.57142857141.5714285714

1.71428571431.7142857143

1.85714285711.8571428571

22

2.14285714292.1428571429

2.28571428572.2857142857

2.42857142862.4285714286

2.57142857142.5714285714

2.71428571432.7142857143

2.85714285712.8571428571

33

3.14285714293.1428571429

3.28571428573.2857142857

3.42857142863.4285714286

3.57142857143.5714285714

3.71428571433.7142857143

3.85714285713.8571428571

44

4.14285714294.1428571429

4.28571428574.2857142857

4.42857142864.4285714286

4.57142857144.5714285714

4.71428571434.7142857143

4.85714285714.8571428571

55

5.14285714295.1428571429

5.28571428575.2857142857

5.42857142865.4285714286

5.57142857145.5714285714

5.71428571435.7142857143

5.85714285715.8571428571

66

6.14285714296.1428571429

6.28571428576.2857142857

6.42857142866.4285714286

6.57142857146.5714285714

6.71428571436.7142857143

6.85714285716.8571428571

77

7.14285714297.1428571429

7.28571428577.2857142857

7.42857142867.4285714286

7.57142857147.5714285714

7.71428571437.7142857143

7.85714285717.8571428571

88

8.14285714298.1428571429

8.28571428578.2857142857

8.42857142868.4285714286

8.57142857148.5714285714

8.71428571438.7142857143

8.85714285718.8571428571

99

9.14285714299.1428571429

9.28571428579.2857142857

9.42857142869.4285714286

9.57142857149.5714285714

9.71428571439.7142857143

9.85714285719.8571428571

1010

10.142857142910.1428571429

10.285714285710.2857142857

10.428571428610.4285714286

10.571428571410.5714285714

10.714285714310.7142857143

10.857142857110.8571428571

1111

11.142857142911.1428571429

11.285714285711.2857142857

11.428571428611.4285714286

11.571428571411.5714285714

11.714285714311.7142857143

11.857142857111.8571428571

1212

12.142857142912.1428571429

12.285714285712.2857142857

12.428571428612.4285714286

12.571428571412.5714285714

12.714285714312.7142857143

12.857142857112.8571428571

1313

13.142857142913.1428571429

13.285714285713.2857142857

13.428571428613.4285714286

13.571428571413.5714285714

13.714285714313.7142857143

13.857142857113.8571428571

1414

14.142857142914.1428571429

14.285714285714.2857142857

14.428571428614.4285714286

14.571428571414.5714285714

14.714285714314.7142857143

14.857142857114.8571428571

1515

15.142857142915.1428571429

15.285714285715.2857142857

15.428571428615.4285714286

15.571428571415.5714285714

15.714285714315.7142857143

15.857142857115.8571428571

1616

16.142857142916.1428571429

16.285714285716.2857142857

16.428571428616.4285714286

16.571428571416.5714285714

16.714285714316.7142857143

16.857142857116.8571428571

1717

17.142857142917.1428571429

17.285714285717.2857142857

17.428571428617.4285714286

17.571428571417.5714285714

17.714285714317.7142857143

17.857142857117.8571428571

1818

18.142857142918.1428571429

18.285714285718.2857142857

18.428571428618.4285714286

18.571428571418.5714285714

18.714285714318.7142857143

18.857142857118.8571428571

1919

19.142857142919.1428571429

19.285714285719.2857142857

19.428571428619.4285714286

19.571428571419.5714285714

19.714285714319.7142857143

19.857142857119.8571428571

2020

20.142857142920.1428571429

20.285714285720.2857142857

20.428571428620.4285714286

20.571428571420.5714285714

20.714285714320.7142857143

20.857142857120.8571428571

2121

21.142857142921.1428571429

21.285714285721.2857142857

21.428571428621.4285714286

21.571428571421.5714285714

21.714285714321.7142857143

21.857142857121.8571428571

2222

22.142857142922.1428571429

22.285714285722.2857142857

22.428571428622.4285714286

22.571428571422.5714285714

22.714285714322.7142857143

22.857142857122.8571428571

2323

23.142857142923.1428571429

23.285714285723.2857142857

23.428571428623.4285714286

23.571428571423.5714285714

23.714285714323.7142857143

23.857142857123.8571428571

2424

24.142857142924.1428571429

24.285714285724.2857142857

24.428571428624.4285714286

24.571428571424.5714285714

24.714285714324.7142857143

24.857142857124.8571428571

2525

25.142857142925.1428571429

25.285714285725.2857142857

25.428571428625.4285714286

25.571428571425.5714285714

25.714285714325.7142857143

25.857142857125.8571428571

2626

26.142857142926.1428571429

26.285714285726.2857142857

26.428571428626.4285714286

26.571428571426.5714285714

26.714285714326.7142857143

26.857142857126.8571428571

2727

27.142857142927.1428571429

27.285714285727.2857142857

27.428571428627.4285714286

27.571428571427.5714285714

27.714285714327.7142857143

27.857142857127.8571428571

2828

28.142857142928.1428571429

28.285714285728.2857142857

28.428571428628.4285714286

28.571428571428.5714285714

28.714285714328.7142857143

28.857142857128.8571428571

2929

29.142857142929.1428571429

29.285714285729.2857142857

29.428571428629.4285714286

29.571428571429.5714285714

29.714285714329.7142857143

29.857142857129.8571428571

3030

30.142857142930.1428571429

30.285714285730.2857142857

30.428571428630.4285714286

30.571428571430.5714285714

30.714285714330.7142857143

30.857142857130.8571428571

3131

31.142857142931.1428571429

31.285714285731.2857142857

31.428571428631.4285714286

31.571428571431.5714285714

31.714285714331.7142857143

31.857142857131.8571428571

3232

32.142857142932.1428571429

32.285714285732.2857142857

32.428571428632.4285714286

32.571428571432.5714285714

32.714285714332.7142857143

32.857142857132.8571428571

3333

33.142857142933.1428571429

33.285714285733.2857142857

33.428571428633.4285714286

33.571428571433.5714285714

33.714285714333.7142857143

33.857142857133.8571428571

3434

34.142857142934.1428571429

34.285714285734.2857142857

34.428571428634.4285714286

34.571428571434.5714285714

34.714285714334.7142857143

34.857142857134.8571428571

3535

35.142857142935.1428571429

35.285714285735.2857142857

35.428571428635.4285714286

35.571428571435.5714285714

35.714285714335.7142857143

35.857142857135.8571428571

3636

36.142857142936.1428571429

36.285714285736.2857142857

36.428571428636.4285714286

36.571428571436.5714285714

36.714285714336.7142857143

36.857142857136.8571428571

3737

37.142857142937.1428571429

37.285714285737.2857142857

37.428571428637.4285714286

37.571428571437.5714285714

37.714285714337.7142857143

37.857142857137.8571428571

3838

38.142857142938.1428571429

38.285714285738.2857142857

38.428571428638.4285714286

38.571428571438.5714285714

38.714285714338.7142857143

38.857142857138.8571428571

3939

39.142857142939.1428571429

39.285714285739.2857142857

39.428571428639.4285714286

39.571428571439.5714285714

39.714285714339.7142857143

39.857142857139.8571428571

4040

40.142857142940.1428571429

40.285714285740.2857142857

40.428571428640.4285714286

40.571428571440.5714285714

40.714285714340.7142857143

40.857142857140.8571428571

4141

41.142857142941.1428571429

41.285714285741.2857142857

41.428571428641.4285714286

41.571428571441.5714285714

41.714285714341.7142857143

41.857142857141.8571428571

4242

42.142857142942.1428571429

42.285714285742.2857142857

42.428571428642.4285714286

42.571428571442.5714285714

42.714285714342.7142857143

42.857142857142.8571428571

4343

43.142857142943.1428571429

43.285714285743.2857142857

43.428571428643.4285714286

43.571428571443.5714285714

43.714285714343.7142857143

43.857142857143.8571428571

4444

44.142857142944.1428571429

44.285714285744.2857142857

44.428571428644.4285714286

44.571428571444.5714285714

44.714285714344.7142857143

44.857142857144.8571428571

4545

45.142857142945.1428571429

45.285714285745.2857142857

45.428571428645.4285714286

45.571428571445.5714285714

45.714285714345.7142857143

45.857142857145.8571428571

4646

46.142857142946.1428571429

46.285714285746.2857142857

46.428571428646.4285714286

46.571428571446.5714285714

46.714285714346.7142857143

46.857142857146.8571428571

4747

47.142857142947.1428571429

47.285714285747.2857142857

47.428571428647.4285714286

47.571428571447.5714285714

47.714285714347.7142857143

47.857142857147.8571428571

4848

48.142857142948.1428571429

48.285714285748.2857142857

48.428571428648.4285714286

48.571428571448.5714285714

48.714285714348.7142857143

48.857142857148.8571428571

4949

49.142857142949.1428571429

49.285714285749.2857142857

49.428571428649.4285714286

49.571428571449.5714285714

49.714285714349.7142857143

49.857142857149.8571428571

5050

50.142857142950.1428571429

50.285714285750.2857142857

50.428571428650.4285714286

50.571428571450.5714285714

50.714285714350.7142857143

50.857142857150.8571428571

5151

51.142857142951.1428571429

51.285714285751.2857142857

51.428571428651.4285714286

51.571428571451.5714285714

51.714285714351.7142857143

51.857142857151.8571428571

5252

IDeg OD (n=753)

IGlar OD (n=251)

0

0

0.0146082337

0.0199203187

0.0279061061

0.0398406375

0.0438848011

0.0478087649

0.0611950541

0.0677290837

0.0891577705

0.1035856574

0.1344307399

0.1235856574

0.1783721513

0.1435856574

0.2076664256

0.1757141714

0.2236451207

0.199810557

0.24634205

0.2239069425

0.2663687522

0.2480033281

0.2984114759

0.2720997136

0.3277839725

0.3283246132

0.3599124866

0.3684852558

0.382670184

0.4046298341

0.4041466941

0.4126943502

0.4202540767

0.4247911244

0.4430728686

0.4449524147

0.4873681706

0.4772104792

0.5437440095

0.5457588663

0.5827749651

0.5941459631

0.6110387605

0.6183395115

0.6299066851

0.650597576

0.6487746096

0.6828556405

0.6676425341

0.7070491889

0.720203181

0.7594685438

0.7646775746

0.7997911244

0.8146100982

0.8562427373

0.8417103692

0.8643072534

0.8688106402

0.8885008018

0.8837562924

0.9046951338

0.8960011903

0.9370837978

0.9408991495

0.9735210447

0.9844365645

1.0302012067

1.0388583332

1.0706870366

1.0742324828

1.0909299516

1.0932801019

1.1314157816

1.1123277209

1.1516586966

1.1382132795

1.1799987775

1.1804476119

1.2407275225

1.240393116

1.2933591014

1.2990561447

1.3581364293

1.3359413906

1.3824279273

1.3591654343

1.4067194253

1.3783172811

1.4270446286

1.4098241304

1.4595649538

1.4481802948

1.4880202383

1.5070844044

1.56119097

1.5481802948

1.6018413765

1.5687564265

1.6302966611

1.5838455897

1.6587519456

1.611280432

1.6953373115

1.63597179

1.7278576367

1.673008827

1.7888332464

1.7141610904

1.8904592627

1.7609286282

1.9433047912

1.7926527661

1.9718762197

1.821658291

1.9882027503

1.8437577385

2.0249374442

1.8741444789

2.0494272401

1.9224870203

2.0902435667

1.9722107772

2.1476206158

2.0206201825

2.204997665

2.0649415121

2.2459812716

2.0926423431

2.2828665175

2.130038465

2.3033583208

2.157739296

2.3279484847

2.2089858334

2.3812271732

2.2643874955

2.4429555683

2.3128639498

2.4717621526

2.3517528387

2.5046839633

2.3712514459

2.5378789841

2.4075136495

2.5669246272

2.4381970526

2.6084184032

2.4898009577

2.6540615567

2.5428735834

2.7038540878

2.6085160415

2.7536466189

2.6393283665

2.7785428845

2.6631712837

2.8202095512

2.6954746545

2.8452095512

2.7362622776

2.8868762178

2.7995534168

2.9452095512

2.8770182056

3.0452095512

2.927793946

3.1163392583

2.9561627404

3.1372597604

2.9703672858

3.1958371662

2.9902819373

3.23349407

3.0116190639

3.2962555763

3.0600521123

3.3757534842

3.1213930539

3.4678036934

3.1628216253

3.5224255422

3.1942951589

3.5476356262

3.2186504598

3.5602938541

3.2601977377

3.5940491283

3.2989351839

3.6320238119

3.3505851122

3.7290702254

3.4022350404

3.783922546

3.4482120519

3.8303360481

3.4856221239

3.872530141

3.5129996455

3.8851883688

3.5389362449

3.9147242338

3.5735183775

3.9569183266

3.6282734207

4.037087103

3.668619242

4.1045976515

3.7249776235

4.1552305629

3.7626042516

4.1847664279

3.7814448313

4.23117993

3.8003127558

4.2649352043

3.8380486049

4.3115453738

3.8801385904

4.3751046958

3.941185102

4.476799611

3.9993246369

4.5704166323

4.0414757997

4.6214804621

4.077813009

4.6810549302

4.1039757997

4.7150974834

4.128721069

4.761905994

4.1927676483

4.8087145047

4.262840641

4.8640336536

4.3226946556

4.9278634408

4.3577311519

4.9576506749

4.3796609765

4.9831825898

4.4176726724

5.0002038664

4.4425264736

5.0385017387

4.5024679941

5.1193528025

4.555099573

5.1834553666

4.6048071753

5.251831435

4.6457428479

5.2774724607

4.6735206256

5.3159339991

4.6925543006

5.3330280162

4.7218368775

5.3586690419

4.7790216282

5.4441391273

4.846668687

5.5125151957

4.8849602923

5.5811847236

4.9070516031

5.6242881719

4.9424498332

5.6589202065

4.9646064063

5.6935522411

5.0015340281

5.7368422844

5.050278489

5.7758033234

5.1168465363

5.849396397

5.1701009742

5.9186604662

5.2041750483

5.957790901

5.2382996774

5.9882256836

5.2665314753

6.005616988

5.2903056209

6.0360517706

5.351226869

6.0969213358

5.4032328126

6.1969213358

5.4478093356

6.2969213358

5.4760411335

6.3317039445

5.5102164678

6.3751822054

5.5354764976

6.4230082923

5.5696518319

6.4664865532

5.6097707026

6.5621387271

5.6796072554

6.6273561184

5.733099083

6.6882256836

5.7689199785

6.7012691619

5.7928005755

6.723103223

5.8166811726

6.7580377208

5.833099083

6.7973390309

5.8778752024

6.8410071532

5.9257077884

6.9196097732

5.9810142159

6.97201152

6.0199947256

6.9938455811

6.0470217526

7.0375137034

6.0755502812

7.0811818257

6.1085833142

7.1204831357

6.1567760853

7.1859853191

6.2185230732

7.2427538781

6.2757519889

7.3169896859

6.3225797835

7.3654478357

6.3391960977

7.3962848401

6.3664275651

7.4579588489

6.4012233291

7.4799852806

6.4556862641

7.5592804348

6.5056862641

7.62535973

6.549625658

7.7222760295

6.5890195974

7.7398971749

6.614816259

7.7707341793

6.643647822

7.7971658974

6.677031737

7.8412187608

6.7423812811

7.9249192013

6.8093523617

8.0350513599

6.8642304105

8.1231570868

6.8993449143

8.1672099502

6.9375128533

8.1849090653

6.969573922

8.1937586228

6.9863678151

8.2247320741

7.0092685785

8.2778294193

7.0321693418

8.3176524281

7.0504899525

8.357475437

7.073460856

8.3795993308

7.0903061853

8.4017232246

7.1071515145

8.4061480033

7.1285910245

8.4415462334

7.1484991409

8.4990683573

7.1867839801

8.5565904812

7.223593796

8.6052630476

7.255802385

8.6362364989

7.27880852

8.6583603927

7.2864772316

8.6760595078

7.2910784586

8.7026081803

7.3048821396

8.7291568529

7.3186858206

8.7557055255

7.3340232439

8.7778294193

7.3478269249

8.7999533131

7.3647240063

8.8220772069

7.3862293826

8.8487438735

7.4061986607

8.8842994291

7.45228161

8.9598549846

7.492220166

9.0442994291

7.5260663199

9.0800137148

7.5383740122

9.0889422862

7.5537586276

9.106879506

7.5629893968

9.1203324208

7.5706817045

9.1562068602

7.5937586276

9.1920812997

7.6076047814

9.2100185194

7.6399124737

9.236924349

7.6568355506

9.2683144835

7.6737586276

9.2952203131

7.6845278583

9.3266104477

7.6983740122

9.371453497

7.7352970891

9.4073279365

7.7815220506

9.4656239006

7.8231887173

9.5284041696

7.8463726431

9.568762914

7.8587374035

9.5911844387

7.8711213044

7.8896971558

9.6001530486

7.8958891063

9.6270588782

7.9036290444

9.6405723917

7.9144649577

9.6675994187

7.9299688336

9.6856174367

7.9470230972

9.7081399592

7.9640773608

9.7216534728

7.9702789112

9.7441759953

8.0105889887

9.7982300493

8.055550229

9.8477795989

8.0943099189

9.8973291484

8.1129434593

9.9243561755

8.1331297947

9.955887707

8.1517633351

9.973905725

8.1595273102

9.9964282475

8.1766080556

10.009941761

8.1936888009

10.0369687881

8.2138751363

10.0414732926

8.2402726518

10.0504823016

8.2511422171

10.0820138331

8.2713285525

10.1225543737

8.2899620928

10.1585904097

8.3210179935

10.2171489682

8.3614534522

10.2531850043

8.4003942622

10.3342660854

8.4144129538

10.3612931124

8.4331045426

10.3793111304

8.4518545426

10.4109853386

8.4643545426

10.4336097729

8.4784170426

10.4517093205

8.4971670426

10.4788586417

8.5096670426

10.5105328499

8.5268545426

10.5286323974

8.5362295426

10.5557817186

8.5612295426

10.5829310399

8.5940933923

10.5965057005

8.6364131416

10.6734287775

8.6677611039

10.7367771938

8.7007281369

10.7731408301

8.7195960614

10.7958681029

8.738463986

10.8185953756

8.7573616238

10.8322317392

8.7825584742

10.8595044665

8.8030309151

10.8776862847

8.8156293403

10.9095044665

8.8376765844

10.9185953756

8.8534246159

10.9322317392

8.8738970568

10.9504135574

8.8959443009

10.964049921

8.9195663482

10.9958681029

8.9542120175

11.0867771938

9.0077553246

11.1458681029

9.0502750096

11.1825653506

9.0771737438

11.255959846

9.100907921

11.3064185616

9.1151484273

11.3431158093

9.1325534906

11.3568772772

9.1499585539

11.3660515891

9.1673636172

11.379813057

9.1768572881

11.4027488368

9.1910977944

11.4165103047

9.2053383007

11.4348589285

9.222743364

11.4577947084

9.2369838703

11.4944919561

9.2828699463

11.5220148918

9.3319205792

11.5770607634

9.3604015919

11.6458681029

9.3857180476

11.6779781946

9.4062876678

11.6871947845

9.4268572881

11.7102362591

9.4379507904

11.719452849

9.453798651

11.7378860287

9.4680617255

11.7609275034

9.4775704418

11.7748163922

9.5092661629

11.7794460219

9.5314531676

11.7933349108

9.5488858142

11.8303719478

9.5679032469

11.8488904663

9.6091076843

11.8998163922

9.6518969077

11.9368534293

9.688346987

11.9694115688

9.7105692092

11.9973185456

9.7169184155

12.0112720339

9.7423152409

12.0205743595

9.7645374632

12.0484813363

9.7835850822

12.0577836618

9.7915215901

12.076388313

9.8058073044

12.0903418014

9.8248549235

12.0949929642

9.8407279393

12.1463948333

9.8470771457

12.1604793404

9.8725143476

12.1745638474

9.9091385514

12.2449863826

9.9441703986

12.3013244108

9.9728328189

12.3482727676

9.9887563858

12.357662439

10.0078646661

12.385831453

10.0142442514

12.3999159601

10.0301932147

12.4046107958

10.0541166597

12.4140004671

10.0732554157

12.4515591526

10.0860145863

12.4703384953

10.0971788606

12.4938126737

10.1147227203

12.5125920164

10.1290767873

12.5266765235

10.1450257506

12.5548455375

10.1625696102

12.5970990587

10.2008471222

12.6299629084

10.2375297378

12.6771327198

10.2599297378

12.7101515877

10.2807297378

12.7337364933

10.2887297378

12.7667553613

10.3095297378

12.7997742292

10.3191297378

12.8375100782

10.3447297378

12.8422270594

10.3527297378

12.8516610216

10.3655708293

12.8610949839

10.3784325657

12.8893968707

10.3977562372

12.9176987575

10.4219108265

12.9460006443

10.4525066397

12.9931704556

10.4831024529

13.0309063047

10.5249704079

13.0733591349

10.5507353032

13.0969440405

10.5717030451

13.1063780028

10.5942836903

13.1252459273

10.6200901419

13.1393968707

10.6378320774

13.1582647952

10.6523482064

13.1771327198

10.6700901419

13.2055687387

10.6879763208

13.2340047577

10.6994329492

13.2582766023

10.7208850945

13.282548447

10.7459268307

13.3168621725

10.8020492797

13.3618621725

10.8556207082

13.4194537955

10.9129977574

13.4697682609

Conf. hypo

weekIDeg_ODIGlar_ODIDeg OD (n=753)IGlar OD (n=251)

00000

0.14285714290.01460823370.01992031871.46082337321.9920318725

0.28571428570.02790610610.03984063752.79061060723.984063745

0.42857142860.04388480110.04780876494.38848011454.780876494

0.57142857140.06119505410.06772908376.11950541416.7729083665

0.71428571430.08915777050.10358565748.91577705210.3585657371

0.85714285710.13443073990.123585657413.443073989412.3585657371

10.17837215130.143585657417.837215134514.3585657371

1.14285714290.20766642560.175714171420.766642564617.5714171427

1.28571428570.22364512070.19981055722.364512071919.9810556969

1.42857142860.246342050.223906942524.634204995822.3906942511

1.57142857140.26636875220.248003328126.636875222824.8003328053

1.71428571430.29841147590.272099713629.841147585927.2099713595

1.85714285710.32778397250.328324613232.778397252232.8324613194

20.35991248660.368485255835.991248657836.8485255764

2.14285714290.3826701840.404629834138.267018403440.4629834077

2.28571428570.40414669410.412694350240.414669410241.2694350206

2.42857142860.42025407670.424791124442.025407665242.47911244

2.57142857140.44307286860.444952414744.307286859844.4952414723

2.71428571430.48736817060.477210479248.736817061247.7210479239

2.85714285710.54374400950.545758866354.374400953854.5758866335

30.58277496510.594145963158.277496512359.414596311

3.14285714290.61103876050.618339511561.103876054761.8339511497

3.28571428570.62990668510.65059757662.990668507665.0597576013

3.42857142860.64877460960.682855640564.877460960468.2855640529

3.57142857140.66764253410.707049188966.764253413270.7049188916

3.71428571430.7202031810.759468543872.020318103275.9468543755

3.85714285710.76467757460.799791124476.467757456379.97911244

40.81461009820.856242737381.46100981885.6242737303

4.14285714290.84171036920.864307253484.171036918386.4307253432

4.28571428570.86881064020.888500801886.881064018688.8500801819

4.42857142860.88375629240.904695133888.375629235990.4695133803

4.57142857140.89600119030.937083797889.600119031993.7083797771

4.71428571430.94089914950.973521044794.089914950297.3521044734

4.85714285710.98443656451.030201206798.4436564468103.0201206678

51.03885833321.0706870366103.8858333176107.0687036637

5.14285714291.07423248281.0909299516107.4232482836109.0929951617

5.28571428571.09328010191.1314157816109.3280101883113.1415781576

5.42857142861.11232772091.1516586966111.2327720931115.1658696556

5.57142857141.13821327951.1799987775113.8213279514117.9998777528

5.71428571431.18044761191.2407275225118.0447611939124.0727522467

5.85714285711.2403931161.2933591014124.0393116026129.3359101414

61.29905614471.3581364293129.9056144676135.813642935

6.14285714291.33594139061.3824279273133.5941390577138.2427927325

6.28571428571.35916543431.4067194253135.9165434293140.6719425301

6.42857142861.37831728111.4270446286137.8317281078142.7044628553

6.57142857141.40982413041.4595649538140.9824130393145.9564953756

6.71428571431.44818029481.4880202383144.8180294777148.8020238309

6.85714285711.50708440441.56119097150.7084404366156.1190970017

71.54818029481.6018413765154.8180294777160.1841376521

7.14285714291.56875642651.6302966611156.8756426464163.0296661073

7.28571428571.58384558971.6587519456158.3845589702165.8751945626

7.42857142861.6112804321.6953373115161.1280431951169.533731148

7.57142857141.635971791.7278576367163.5971789976172.7857636683

7.71428571431.6730088271.7888332464167.3008827013178.8833246439

7.85714285711.71416109041.8904592627171.4161090387189.0459262699

81.76092862821.9433047912176.0928628214194.3304791155

8.14285714291.79265276611.9718762197179.2652766145197.1876219726

8.28571428571.8216582911.9882027503182.1658291007198.8202750338

8.42857142861.84375773852.0249374442184.3757738521202.4937444216

8.57142857141.87414447892.0494272401187.4144478852204.9427240134

8.71428571431.92248702032.0902435667192.2487020289209.0243566665

8.85714285711.97221077722.1476206158197.2210777195214.7620615845

92.02062018252.204997665202.0620182451220.4997665026

9.14285714292.06494151212.2459812716206.4941512091224.5981271583

9.28571428572.09264234312.2828665175209.2642343116228.2866517485

9.42857142862.1300384652.3033583208213.0038464999230.3358320763

9.57142857142.1577392962.3279484847215.7739296024232.7948484698

9.71428571432.20898583342.3812271732220.898583342238.1227173222

9.85714285712.26438749552.4429555683226.438749547244.2955568284

102.31286394982.4717621526231.2863949764247.1762152646

10.14285714292.35175283872.5046839633235.1752838653250.4683963346

10.28571428572.37125144592.5378789841237.1251445895253.7878984093

10.42857142862.40751364952.5669246272240.7513649521256.6924627246

10.57142857142.43819705262.6084184032243.819705259260.841840318

10.71428571432.48980095772.6540615567248.980095775265.4061556707

10.85714285712.54287358342.7038540878254.2873583448270.3854087827

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46.857142857110.073255415712.45155915261007.32554156721245.1559152567

4710.086014586312.47033849531008.60145863261247.0338495291

47.142857142910.097178860612.49381267371009.71788606481249.3812673694

47.285714285710.114722720312.51259201641011.47227202971251.2592016417

47.428571428610.129076787312.52667652351012.90767872831252.667652346

47.571428571410.145025750612.55484553751014.502575061255.4845537544

47.714285714310.162569610212.59709905871016.2569610251259.7099058671

47.857142857110.200847122212.62996290841020.08471222111262.9962908436

4810.237529737812.67713271981023.75297378411267.7132719757

48.142857142910.259929737812.71015158771025.99297378411271.0151587681

48.285714285710.280729737812.73373649331028.07297378411273.3736493342

48.428571428610.288729737812.76675536131028.87297378411276.6755361266

48.571428571410.309529737812.79977422921030.95297378411279.9774229191

48.714285714310.319129737812.83751007821031.91297378411283.7510078247

48.857142857110.344729737812.84222705941034.47297378411284.2227059379

4910.352729737812.85166102161035.27297378411285.1661021644

49.142857142910.365570829312.86109498391036.55708293341286.1094983908

49.285714285710.378432565712.88939687071037.84325656681288.93968707

49.428571428610.397756237212.91769875751039.77562371661291.7698757493

49.571428571410.421910826512.94600064431042.19108265381294.6000644285

49.714285714310.452506639712.99317045561045.25066397431299.3170455606

49.857142857110.483102452913.03090630471048.31024529471303.0906304663

5010.524970407913.07335913491052.49704078591307.3359134851

50.142857142910.550735303213.09694404051055.07353031891309.6944040512

50.285714285710.571703045113.10637800281057.17030451241310.6378002776

50.428571428610.594283690313.12524592731059.42836902851312.5245927304

50.571428571410.620090141913.13939687071062.00901418981313.93968707

50.714285714310.637832077413.15826479521063.78320773821315.8264795228

50.857142857110.652348206413.17713271981065.23482064141317.7132719757

5110.670090141913.20556873871067.00901418981320.5568738714

51.142857142910.687976320813.23400475771068.7976320761323.4004757672

51.285714285710.699432949213.25827660231069.94329492381325.8276602332

51.428571428610.720885094513.2825484471072.08850944531328.2548446992

51.571428571410.745926830713.31686217251074.5926830681331.6862172482

51.714285714310.802049279713.36186217251080.20492796591336.1862172482

51.857142857110.855620708213.41945379551085.5620708231341.9453795519

5210.912997757413.46976826091091.29977574111346.9768260928

Conf. hypo

IDeg OD (n=753)

IGlar OD (n=251)

Time (weeks)

Confirmed hypoglycaemia (cumulative events per 100 PYE)

Nocturnal confirmed hypoglycaemia

SASComparisons: Estimates adjusted for multiple covariates

25% risk reduction, p=0.04

Noc

turn

al c

onfir

med

hyp

ogly

caem

ia

(cum

ulat

ive

even

ts p

er 1

00 p

atie

nts)

Time (weeks)

IDeg OD (n=753)IGlar OD (n=251)

Garber A et al. Lancet 2012;379:1498-507

Chart1

00

0.14285714290.1428571429

0.28571428570.2857142857

0.57142857140.5714285714

0.71428571430.7142857143

0.85714285710.8571428571

11

1.14285714291.1428571429

1.28571428571.2857142857

1.42857142861.4285714286

1.57142857141.5714285714

1.71428571431.7142857143

1.85714285711.8571428571

22

2.14285714292.1428571429

2.28571428572.2857142857

2.42857142862.4285714286

2.57142857142.5714285714

2.71428571432.7142857143

2.85714285712.8571428571

33

3.14285714293.1428571429

3.28571428573.2857142857

3.42857142863.4285714286

3.57142857143.5714285714

3.71428571433.7142857143

3.85714285713.8571428571

44

4.14285714294.1428571429

4.28571428574.2857142857

4.42857142864.4285714286

4.57142857144.5714285714

4.71428571434.7142857143

4.85714285714.8571428571

55

5.14285714295.1428571429

5.28571428575.2857142857

5.42857142865.4285714286

5.57142857145.5714285714

5.71428571435.7142857143

5.85714285715.8571428571

66

6.14285714296.1428571429

6.28571428576.2857142857

6.42857142866.4285714286

6.57142857146.5714285714

6.71428571436.7142857143

6.85714285716.8571428571

77

7.14285714297.1428571429

7.28571428577.2857142857

7.42857142867.4285714286

7.57142857147.5714285714

7.71428571437.7142857143

7.85714285717.8571428571

88

8.14285714298.1428571429

8.28571428578.2857142857

8.42857142868.4285714286

8.57142857148.5714285714

8.71428571438.7142857143

8.85714285718.8571428571

99

9.14285714299.1428571429

9.28571428579.2857142857

9.42857142869.4285714286

9.57142857149.5714285714

9.71428571439.7142857143

9.85714285719.8571428571

1010

10.142857142910.1428571429

10.285714285710.2857142857

10.428571428610.4285714286

10.571428571410.5714285714

10.714285714310.7142857143

10.857142857110.8571428571

1111

11.142857142911.1428571429

11.285714285711.2857142857

11.428571428611.4285714286

11.571428571411.5714285714

11.714285714311.7142857143

11.857142857111.8571428571

1212

12.142857142912.1428571429

12.285714285712.2857142857

12.428571428612.4285714286

12.571428571412.5714285714

12.714285714312.7142857143

12.857142857112.8571428571

1313

13.142857142913.1428571429

13.285714285713.2857142857

13.428571428613.4285714286

13.571428571413.5714285714

13.714285714313.7142857143

13.857142857113.8571428571

1414

14.142857142914.1428571429

14.285714285714.2857142857

14.428571428614.4285714286

14.571428571414.5714285714

14.714285714314.7142857143

14.857142857114.8571428571

1515

15.142857142915.1428571429

15.285714285715.2857142857

15.428571428615.4285714286

15.571428571415.5714285714

15.714285714315.7142857143

15.857142857115.8571428571

1616

16.142857142916.1428571429

16.285714285716.2857142857

16.428571428616.4285714286

16.571428571416.5714285714

16.714285714316.7142857143

16.857142857116.8571428571

1717

17.142857142917.1428571429

17.428571428617.4285714286

17.571428571417.5714285714

17.714285714317.7142857143

17.857142857117.8571428571

1818

18.142857142918.1428571429

18.285714285718.2857142857

18.428571428618.4285714286

18.571428571418.5714285714

18.714285714318.7142857143

18.857142857118.8571428571

1919

19.142857142919.1428571429

19.285714285719.2857142857

19.428571428619.4285714286

19.571428571419.5714285714

19.714285714319.7142857143

19.857142857119.8571428571

2020

20.142857142920.1428571429

20.285714285720.2857142857

20.428571428620.4285714286

20.571428571420.5714285714

20.714285714320.7142857143

20.857142857120.8571428571

2121

21.142857142921.1428571429

21.285714285721.2857142857

21.428571428621.4285714286

21.571428571421.5714285714

21.714285714321.7142857143

21.857142857121.8571428571

2222

22.142857142922.1428571429

22.285714285722.2857142857

22.428571428622.4285714286

22.571428571422.5714285714

22.714285714322.7142857143

22.857142857122.8571428571

2323

23.142857142923.1428571429

23.285714285723.2857142857

23.428571428623.4285714286

23.571428571423.5714285714

23.714285714323.7142857143

23.857142857123.8571428571

2424

24.142857142924.1428571429

24.285714285724.2857142857

24.428571428624.4285714286

24.571428571424.5714285714

24.714285714324.7142857143

24.857142857124.8571428571

2525

25.142857142925.1428571429

25.285714285725.2857142857

25.428571428625.4285714286

25.571428571425.5714285714

25.714285714325.7142857143

25.857142857125.8571428571

2626

26.142857142926.1428571429

26.285714285726.2857142857

26.428571428626.4285714286

26.571428571426.5714285714

26.714285714326.7142857143

2727

27.142857142927.1428571429

27.285714285727.2857142857

27.428571428627.4285714286

27.571428571427.5714285714

27.714285714327.7142857143

27.857142857127.8571428571

2828

28.142857142928.1428571429

28.285714285728.2857142857

28.428571428628.4285714286

28.714285714328.7142857143

28.857142857128.8571428571

2929

29.142857142929.1428571429

29.285714285729.2857142857

29.428571428629.4285714286

29.571428571429.5714285714

29.714285714329.7142857143

29.857142857129.8571428571

3030

30.285714285730.2857142857

30.428571428630.4285714286

30.571428571430.5714285714

30.714285714330.7142857143

30.857142857130.8571428571

3131

31.142857142931.1428571429

31.285714285731.2857142857

31.428571428631.4285714286

31.571428571431.5714285714

31.714285714331.7142857143

31.857142857131.8571428571

3232

32.142857142932.1428571429

32.285714285732.2857142857

32.571428571432.5714285714

32.714285714332.7142857143

32.857142857132.8571428571

3333

33.142857142933.1428571429

33.285714285733.2857142857

33.428571428633.4285714286

33.571428571433.5714285714

33.714285714333.7142857143

33.857142857133.8571428571

3434

34.142857142934.1428571429

34.285714285734.2857142857

34.428571428634.4285714286

34.571428571434.5714285714

34.714285714334.7142857143

3535

35.142857142935.1428571429

35.285714285735.2857142857

35.428571428635.4285714286

35.571428571435.5714285714

35.714285714335.7142857143

35.857142857135.8571428571

3636

36.142857142936.1428571429

36.285714285736.2857142857

36.428571428636.4285714286

36.571428571436.5714285714

36.714285714336.7142857143

36.857142857136.8571428571

3737

37.142857142937.1428571429

37.285714285737.2857142857

37.428571428637.4285714286

37.571428571437.5714285714

37.714285714337.7142857143

37.857142857137.8571428571

3838

38.142857142938.1428571429

38.285714285738.2857142857

38.428571428638.4285714286

38.571428571438.5714285714

38.714285714338.7142857143

38.857142857138.8571428571

3939

39.142857142939.1428571429

39.285714285739.2857142857

39.428571428639.4285714286

39.571428571439.5714285714

39.714285714339.7142857143

39.857142857139.8571428571

4040

40.142857142940.1428571429

40.285714285740.2857142857

40.428571428640.4285714286

40.571428571440.5714285714

40.857142857140.8571428571

4141

41.142857142941.1428571429

41.285714285741.2857142857

41.428571428641.4285714286

41.571428571441.5714285714

41.714285714341.7142857143

41.857142857141.8571428571

4242

42.142857142942.1428571429

42.285714285742.2857142857

42.428571428642.4285714286

42.714285714342.7142857143

42.857142857142.8571428571

4343

43.142857142943.1428571429

43.285714285743.2857142857

43.428571428643.4285714286

43.571428571443.5714285714

43.714285714343.7142857143

43.857142857143.8571428571

4444

44.142857142944.1428571429

44.428571428644.4285714286

44.571428571444.5714285714

44.714285714344.7142857143

44.857142857144.8571428571

4545

45.142857142945.1428571429

45.285714285745.2857142857

45.428571428645.4285714286

45.571428571445.5714285714

45.714285714345.7142857143

45.857142857145.8571428571

4646

46.142857142946.1428571429

46.285714285746.2857142857

46.428571428646.4285714286

46.571428571446.5714285714

46.714285714346.7142857143

46.857142857146.8571428571

4747

47.142857142947.1428571429

47.285714285747.2857142857

47.428571428647.4285714286

47.571428571447.5714285714

47.714285714347.7142857143

47.857142857147.8571428571

4848

48.142857142948.1428571429

48.285714285748.2857142857

48.571428571448.5714285714

48.714285714348.7142857143

48.857142857148.8571428571

4949

49.142857142949.1428571429

49.285714285749.2857142857

49.428571428649.4285714286

49.571428571449.5714285714

49.714285714349.7142857143

49.857142857149.8571428571

5050

50.142857142950.1428571429

50.285714285750.2857142857

50.428571428650.4285714286

50.571428571450.5714285714

50.714285714350.7142857143

50.857142857150.8571428571

5151

51.142857142951.1428571429

51.285714285751.2857142857

51.571428571451.5714285714

51.714285714351.7142857143

51.857142857151.8571428571

5252

IDeg OD (n=753)

IGlar OD (n=251)

0

0

0.0013280212

0.0079681275

0.0039875957

0.0119521912

0.0066507116

0.0106453853

0.015936255

0.015971617

0.023936255

0.0226294066

0.0279556383

0.0319683835

0.0292871962

0.0359844478

0.0319574232

0.040000512

0.0346276502

0.0372978772

0.0413032176

0.0520487048

0.04665797

0.0600808333

0.0533514104

0.0640968976

0.057378256

0.0600628198

0.0721614137

0.0614051017

0.0761936717

0.0654319473

0.0842581879

0.0721433567

0.092322704

0.0761810418

0.1003872201

0.0815646218

0.1044194782

0.0842600396

0.1124839943

0.0869554574

0.1165162524

0.0909985841

0.1286130266

0.0950417108

0.1366775427

0.1058233819

0.1085224373

0.1447420588

0.1139424915

0.1180075321

0.1487743169

0.1568714829

0.1193680763

0.1609200659

0.1207286206

0.1248102532

0.1649686489

0.1302524301

0.1730658149

0.1397762396

0.1811629809

0.1852115639

0.1438578723

0.1892601469

0.1493074635

0.1933087299

0.1547570548

0.2014058959

0.1588442483

0.2054544788

0.1670297872

0.2135516448

0.1711281478

0.2176002278

0.1738603883

0.2216488108

0.2257138515

0.1779699773

0.1793398403

0.2297788921

0.1807097033

0.2460390547

0.1861891554

0.1889326396

0.2501040954

0.1916761238

0.1944196081

0.1971630923

0.254169136

0.1999065765

0.2622992173

0.2012783186

0.2785593799

0.2067803819

0.2826244206

0.2122976233

0.2907876859

0.2178224851

0.2948693185

0.2192037006

0.2989509512

0.223347347

0.2302534244

0.2343970708

0.3071476725

0.2413127001

0.3194427545

0.2482379079

0.2551631156

0.3235411151

0.2593182403

0.2620883234

0.266243448

0.3317378364

0.2745536973

0.2814789051

0.3399682891

0.2856455718

0.3481987418

0.2898238447

0.356497497

0.292613245

0.3606468746

0.2954026453

0.3037708461

0.3647962522

0.3135473824

0.3730950074

0.3191339746

0.3772443849

0.3247440728

0.3814110516

0.3317665447

0.3373924238

0.3430183028

0.3980777183

0.3486521056

0.3542938546

0.41481412

0.3628044929

0.4189982204

0.3642249474

0.4231823208

0.3670698976

0.3684923727

0.435734622

0.3741985068

0.4482869233

0.381341364

0.4566902846

0.3884944398

0.4608919653

0.392792434

0.4693307839

0.3942250988

0.4028334202

0.4071375809

0.4186153427

0.4243624691

0.4819890117

0.4258013181

0.4904278303

0.4301240846

0.4315650068

0.4358877734

0.4459742287

0.4488560731

0.4988666489

0.4546364199

0.4575307759

0.461878602

0.5115248767

0.4662327385

0.5199636953

0.4734896325

0.4763923901

0.5369128478

0.4851133204

0.5538620004

0.495287739

0.570883277

0.5054621576

0.5751385961

0.5083691343

0.5793939153

0.5127295994

0.5836492344

0.5141852035

0.5185520157

0.5243914318

0.5316907019

0.5921598727

0.5375301179

0.5433780711

0.547764036

0.5964151919

0.5536119893

0.5565359659

0.6220562175

0.5623839191

0.630603226

0.5638459074

0.566769884

0.6348767303

0.5711622705

0.5740905282

0.6391502346

0.5799556309

0.6562442517

0.5887791603

0.660517756

0.5917246684

0.6691014469

0.5990884386

0.6820324814

0.6035132174

0.607944532

0.6863614858

0.6108987417

0.6950194944

0.6168071612

0.7036775031

0.6271621908

0.7080065074

0.6345586405

0.7123355117

0.6434475294

0.7166833378

0.6464148885

0.7210311639

0.6523584249

0.6568160772

0.6612737295

0.7384224683

0.6657313818

0.7558137726

0.6716749182

0.7688572509

0.6761325705

0.777552903

0.6805902228

0.7819007291

0.683561991

0.7905963813

0.6909914115

0.7992920335

0.6954490638

0.7028784843

0.8036398596

0.7117937889

0.7192564755

0.7222415501

0.7237340874

0.8080066718

0.7267191621

0.731196774

0.812373484

0.7356810789

0.8254739207

0.7446496888

0.7506466903

0.7566526963

0.8342075451

0.7611572008

0.8429411696

0.8516747941

0.7656752731

0.8604084185

0.7747114177

0.8735088552

0.7777234659

0.8953429163

0.7822551879

0.9129640617

0.7837657619

0.9261799207

0.7883043398

0.9305852071

0.7913300585

0.9438010661

0.9482063524

0.795875513

0.9526116388

0.798905816

0.8019361191

0.9570169251

0.8049710204

0.9614222115

0.8095233725

0.9658274978

0.8125582738

0.9746380705

0.8171175444

0.9834486432

0.8232058244

0.9878539295

0.8308277756

1.0010697886

0.8354079283

1.0098803613

0.839988081

0.8460949512

0.8476216688

1.01430514

0.8491483863

1.0275794763

0.853728539

0.8583227197

1.0320042551

0.8598541133

0.8629169004

0.8659796875

0.8690424747

0.875168049

0.8828367606

1.0408538126

0.8889717299

1.0452785913

0.8905054723

0.8920392146

0.8935729569

1.0497033701

0.8966404416

1.0541281489

0.8997079263

0.9012416686

0.9043138652

0.9058499635

1.0630170378

0.9073860618

0.9150665534

0.9196748483

1.0763503711

0.9227517714

1.0808146568

0.9242902329

0.9258286945

0.9289056175

1.0852989617

0.9350594637

0.9381363868

0.9396748483

0.9412133098

1.0987518765

1.1032361815

1.1077204864

0.9442902329

1.1166890963

0.947367156

1.1211734012

0.9489079881

1.1256577061

0.9519944078

1.1301420111

0.956631193

1.1391106209

0.9628135732

1.1480792308

0.9705535113

1.1525635357

1.1615321456

0.9721014989

0.9736494865

0.9767502617

1.1660366501

0.9783006493

1.1705411546

0.9798510369

1.1795501636

1.1930636771

1.1975681816

0.9814014245

1.2020726861

0.9829542195

0.9845070145

1.2110816951

0.9891653996

1.2200907042

0.9907181947

1.2290997132

0.9922709897

0.9938237847

0.9984821698

1.2381087222

1.0015877599

1.2426132267

1.0046933499

1.2471177312

1.00779894

1.2606312447

1.0155749898

1.2921627762

1.0186902546

1.020247887

1.2966672807

1.023372887

1.026497887

1.3011921676

1.029622887

1.031185387

1.3057170545

1.034310387

1.035872887

1.323816602

1.040560387

1.3328663758

1.0515150036

1.3419161495

1.0546497998

1.3509659233

1.0562171979

1.360015697

1.0624966328

1.3691066061

1.0640689598

1.3736520607

1.0672136139

1.0719380233

1.3781975152

1.0735128265

1.3918338788

1.0766624328

1.0782372359

1.4009247879

1.0813868422

1.410015697

1.0845364485

1.4145611516

1.0924104643

1.0939852674

1.4191066061

1.0955600706

1.10028448

1.4372884243

1.1034340863

1.4509247879

1.1144577084

1.4555119439

1.1255336578

1.4876220356

1.1286982147

1.5013835035

1.1302804932

1.5105578155

1.1334450502

1.5151449714

1.1350273286

1.1381918856

1.5197321274

1.1413564426

1.5243192833

1.142938721

1.5334935953

1.1445209995

1.5380807512

1.5426679072

1.1476855565

1.1524323919

1.5518422191

1.561016531

1.1571792274

1.565603687

1.1603437843

1.1635083413

1.1650931274

1.1714322716

1.5702119819

1.5794712412

1.1761866297

1.1793562018

1.5933601301

1.1825257739

1.1856953461

1.5979897597

1.1888649182

1.1952040624

1.6026409225

1.1983786656

1.6072920853

1.2015532687

1.2063151735

1.6165944109

1.2126643798

1.2142516814

1.6212455737

1.6258967365

1.2190135862

1.6305478993

1.2237754909

1.6445665908

1.2253627925

1.2269526177

1.6492614265

1.2333220444

1.2365067578

1.6586510979

1.2428761845

1.2444685412

1.6633459336

1.2476532546

1.6680407692

1.6727356049

1.2508430473

1.6774304406

1.2588175289

1.2636022179

1.6821252763

1.2651971142

1.686820112

1.2683869069

1.2699818032

1.6915149476

1.2715766996

1.2763613886

1.6962097833

1.2827409739

1.2843358702

1.7009267645

1.2875358702

1.7056437456

1.2907358702

1.2939358702

1.7103607267

1.2955358702

1.719794689

1.2971358702

1.7245116701

1.2987358702

1.7292286513

1.3003410067

1.7339456324

1.7386626135

1.3083925365

1.7433795947

1.3100028424

1.3132234543

1.7480965758

1.3148337603

1.7528135569

1.3196646782

1.757530538

1.324495596

1.3309472089

1.3357859186

1.3406246283

1.3422375315

1.7669645003

1.7717038368

1.345489564

1.7906611828

1.8003699206

1.8052718814

1.3522922851

1.8102718814

1.357649428

1.8259786877

1.363796969

1.8322679959

Noct. conf. hypo

trl_idweekIDeg_ODIGlar_ODIDeg OD (n=753)IGlar OD (n=251)

NN1250-358200000

NN1250-35820.14285714290.00132802120.00796812750.13280212480.796812749

NN1250-35820.28571428570.00398759570.01195219120.39875957161.1952191235

NN1250-35820.57142857140.00665071160.6650711562

NN1250-35820.71428571430.01064538530.0159362551.0645385331.593625498

NN1250-35820.85714285710.0159716170.0239362551.59716170212.393625498

NN1250-358210.02262940662.2629406635

NN1250-35821.14285714290.02795563830.03196838352.79556383263.1968383494

NN1250-35821.28571428570.02928719620.03598444782.92871962493.5984447751

NN1250-35821.42857142860.03195742320.0400005123.19574232184.0000512008

NN1250-35821.57142857140.03462765023.4627650188

NN1250-35821.71428571430.03729787723.7297877157

NN1250-35821.85714285710.04130321760.05204870484.13032176115.2048704779

NN1250-358220.046657970.06008083334.66579699546.0080833293

NN1250-35822.14285714290.05335141040.06409689765.33514103826.409689755

NN1250-35822.28571428570.0573782565.737825602

NN1250-35822.42857142860.06006281980.07216141376.00628197787.2161413679

NN1250-35822.57142857140.06140510170.07619367176.14051016577.6193671744

NN1250-35822.71428571430.06543194730.08425818796.54319472958.4258187873

NN1250-35822.85714285710.07214335670.0923227047.21433566919.2322704002

NN1250-358230.07618104180.10038722017.618104175110.0387220131

NN1250-35823.14285714290.08156462180.10441947828.156462183210.4419478196

NN1250-35823.28571428570.08426003960.11248399438.426003962211.2483994325

NN1250-35823.42857142860.08695545740.11651625248.695545741211.6516252389

NN1250-35823.57142857140.09099858410.12861302669.099858409612.8613026583

NN1250-35823.71428571430.09504171080.13667754279.504171078113.6677542712

NN1250-35823.85714285710.105823381910.582338194

NN1250-358240.10852243730.144742058810.85224372714.4742058841

NN1250-35824.14285714290.113942491511.3942491471

NN1250-35824.28571428570.11800753210.148774316911.800753212114.8774316905

NN1250-35824.42857142860.156871482915.6871482897

NN1250-35824.57142857140.11936807630.160920065911.936807633916.0920065893

NN1250-35824.71428571430.120728620612.0728620557

NN1250-35824.85714285710.12481025320.164968648912.48102532116.4968648889

NN1250-358250.13025243010.173065814913.025243008117.3065814881

NN1250-35825.14285714290.13977623960.181162980913.977623960418.1162980873

NN1250-35825.28571428570.185211563918.5211563869

NN1250-35825.42857142860.14385787230.189260146914.385787225718.9260146865

NN1250-35825.57142857140.14930746350.193308729914.930746353819.3308729861

NN1250-35825.71428571430.15475705480.201405895915.475705481920.1405895853

NN1250-35825.85714285710.15884424830.205454478815.884424827920.5454478849

NN1250-358260.16702978720.213551644816.702978716121.355164484

NN1250-35826.14285714290.17112814780.217600227817.112814781621.7600227836

NN1250-35826.28571428570.17386038830.221648810817.386038825322.1648810832

NN1250-35826.42857142860.225713851522.5713851483

NN1250-35826.57142857140.177969977317.7969977295

NN1250-35826.71428571430.17933984030.229778892117.933984030822.9778892133

NN1250-35826.85714285710.18070970330.246039054718.070970332224.6039054735

NN1250-358270.186189155418.6189155377

NN1250-35827.14285714290.18893263960.250104095418.893263960225.0104095385

NN1250-35827.28571428570.191676123819.1676123827

NN1250-35827.42857142860.194419608119.4419608052

NN1250-35827.57142857140.19716309230.25416913619.716309227725.4169136036

NN1250-35827.71428571430.19990657650.262299217319.990657650226.2299217336

NN1250-35827.85714285710.20127831860.278559379920.127831861427.8559379938

NN1250-358280.20678038190.282624420620.678038188828.2624420588

NN1250-35828.14285714290.21229762330.290787685921.229762326729.0787685895

NN1250-35828.28571428570.21782248510.294869318521.782248514629.4869318548

NN1250-35828.42857142860.21920370060.298950951221.920370061529.8950951201

NN1250-35828.57142857140.22334734722.3347347024

NN1250-35828.71428571430.230253424423.0253424372

NN1250-35828.85714285710.23439707080.307147672523.439707078130.7147672512

NN1250-358290.24131270010.319442754524.131270010331.9442754479

NN1250-35829.14285714290.248237907924.8237907859

NN1250-35829.28571428570.25516311560.323541115125.516311561632.3541115135

NN1250-35829.42857142860.259318240325.9318240269

NN1250-35829.57142857140.262088323426.2088323372

NN1250-35829.71428571430.2662434480.331737836426.624344802633.1737836447

NN1250-35829.85714285710.274553697327.4553697333

NN1250-3582100.28147890510.339968289128.147890508933.9968289121

NN1250-358210.14285714290.28564557180.348198741828.564557175634.8198741796

NN1250-358210.28571428570.28982384470.35649749728.982384473635.6497496983

NN1250-358210.42857142860.2926132450.360646874629.261324501536.0646874576

NN1250-358210.57142857140.295402645329.5402645294

NN1250-358210.71428571430.30377084610.364796252230.377084613136.479625217

NN1250-358210.85714285710.31354738240.373095007431.354738244437.3095007357

NN1250-3582110.319133974631.9133974623

NN1250-358211.14285714290.377244384937.724438495

NN1250-358211.28571428570.32474407280.381411051632.4744072838.1411051617

NN1250-358211.42857142860.331766544733.176654471

NN1250-358211.57142857140.337392423833.7392423753

NN1250-358211.71428571430.34301830280.398077718334.301830279739.8077718283

NN1250-358211.85714285710.348652105634.8652105614

NN1250-3582120.35429385460.4148141235.429385455641.4814119957

NN1250-358212.14285714290.36280449290.418998220436.280449285441.8998220375

NN1250-358212.28571428570.36422494740.423182320836.422494739942.3182320794

NN1250-358212.42857142860.367069897636.7069897613

NN1250-358212.57142857140.368492372736.8492372719

NN1250-358212.71428571430.43573462243.5734622049

NN1250-358212.85714285710.37419850680.448286923337.419850681344.8286923304

NN1250-3582130.3813413640.456690284638.134136395645.6690284649

NN1250-358213.14285714290.38849443980.460891965338.849443977946.0891965321

NN1250-358213.28571428570.3927924340.469330783939.279243404846.9330783886

NN1250-358213.42857142860.394225098839.4225098805

NN1250-358213.57142857140.402833420240.2833420182

NN1250-358213.71428571430.407137580940.7137580871

NN1250-358213.85714285710.418615342741.8615342707

NN1250-3582140.42436246910.481989011742.436246914448.1989011734

NN1250-358214.14285714290.42580131810.490427830342.580131806549.04278303

NN1250-358214.28571428570.430124084643.0124084635

NN1250-35

L’evoluzione della terapia del diabete tipo 2 - Marchesini Giulio - L... · L’evoluzione della...

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