La Terapia Insulinica...Introduzione: obiettivi della terapia insulinica nel paziente diabetico...

Simposio

Nuove prospettive terapeutiche nella gestione del paziente diabetico anziano

30 Novembre 2017

La Terapia Insulinica

Vito Borzì

Outline

Introduzione: obiettivi della terapia insulinica nel paziente diabetico anziano

Associazione tra ipoglicemie, variabilità glicemica ed outcomes Importanza del controllo glicemico post-prandiale Approccio fisiopatologico alla PPG: insulina Faster Aspart Approccio fisiopatologico alla FPG: insulina Degludec Nuovi approcci terapeutici nel fallimento da BOT: IDegLira

Outline


Associazione tra ipoglicemie, variabilità glicemica ed outcomes Importanza del controllo glicemico post-prandiale Approccio fisiopatologico alla PPG: insulina Faster Aspart Approccio fisiopatologico alla FPG: insulina Degludec Nuovi approcci terapeutici nel fallimento da BOT:IDegLira

Il diabete in età geriatrica

Con il progredire dell’età si assiste ad un progressivo aumento del numero di persone affette da diabete di tipo 2.

Progressiva riduzione della secrezione insulinica e aumento dell’insulino-resistenza

Riduzione della massa magra

Aumento assoluto/relativo del tessuto adiposo

Riduzione dell’attività fisica (sedentarietà, disabilità)

Dieta povera in fibre e ricca di carboidrati e grassi

Cause iatrogene (Diuretici tiazidici, cortisonici)

Fattori neuro-ormonali

Osservatorio ARNO Diabete Anziani 2017

ipovedenza, sordità

comorbidità

polifarmacoterapia

Solitudine

istituzionalizzazione

disabilità

L’anziano diabetico

demenza

depressione

Gentle Giant – First Album - 1970

Outline



Diabetes Research and Clinical Practice 115; 2016; 24-30

According to multivariable logistic regression analysis, advanced age, cognitive dysfunction, and nephropathy were associated to occurrence of hypoglycemia

53 Italian Internal Medicine Units 3167 patients enrolled

IPOGLICEMIA nell’anziano

- Mortalità

- Ischemia

(miocardica e cerebrale)

- Aritmie

- Cadute

- Demenza

- Costi King Crimson – In the court of the Crimson King - 1969

Severe hypoglycaemia is associated with increased rates of MACE and

all-cause mortality across cardiovascular outcomes trials: VADT

ACCORD ADVANCE EXAMINE ORIGIN LEADER

Severe hypoglycaemia and outcomes

MACE, major adverse cardiovascular events ACCORD Study Group. N Engl J Med 2008;358:2545–59; Zinman et al. Diabetes 2017;66(Suppl. 1):A95; Duckworth et al. J Diabetes Complications 2011;25:355–61; Duckworth et al. N Engl J Med 2009;360:129–39; Goto et al. BMJ 2013;347:f4533; Bonds et al. BMJ 2010;340:b4909; Zoungas et al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group; Mellbin et al. Eur Heart J 2013;34:3137–44, for the ORIGIN Trial Investigators

No Hypo Hypo No Hypo Hypo

53 Italian Internal Medicine Units 3167 patients enrolled Diabetes Research and Clinical Practice 115; 2016; 24-30

Pathophysiological cardiovascular consequences of hypoglycaemia

CRP, C-reactive protein; IL-6, interleukin 6; VEGF, vascular endothelial growth factor; Adapted from Desouza et al. Diabetes Care 2010;33:1389; Frier et al. Diabetes Care 2011;34 (Suppl. 2):S132; 1. Wright et al. Diabetes Care 2010;33:1591; 2. Chow et al. Diabetologia 2013;56 (Suppl. 1):S243

VEGF IL-6 CRP

Neutrophil

activation

Platelet

activation Factor VIII

Blood

coagulation

abnormalities

Sympathoadrenal response

Epinephrine

Inflammation

Endothelial

dysfunction

Vasodilatation

Heart rate

variability

Rhythm

abnormalities

Haemodynamic changes

Heart workload

Contractility

Output

HYPOGLYCAEMIA

Persists for up to 48 hours1 Effects last up to 7 days2

• Abnormalities in: • Atrioventricular conduction

• Ventricular repolarisation

• Catecholamine release leads to: • K+

• R-wave amplification

• T-wave flattening

• Depression of ST segment

• Prolongation of QT interval

• Risk of cardiac arrhythmia

Hypoglycaemia is associated with ECG abnormalities

ECG, electrocardiogram Laitinen et al. Ann Noninvasive Electrocardiol 2008;13:97–1051

P

R

S

Q

ECG

(m

V)

Time (seconds)

3

2

1

0

–0.25 0.00 0.25 0.50 0.75

Baseline

Hypoglycaemic hyperinsulinaemia

T

Chow et al. Diabetes 2014;63:1738–47

Incidence rate of arrhythmias during hypoglycaemia vs euglycaemia

Day Night

IRR 95%

CI p IRR

95% CI

p

Bradycardia N/A N/A N/A 8.42 1.40-51.0

0.02

Atrial ectopic 1.35 0.92-1.98

0.13 3.98 1.10-14.40

0.04

VPB 1.31 1.10-1.57

<0.01 3.06 2.11-4.44

<0.01

Complex VPB

1.13 0.78-1.65

0.52 0.79 0.22-2.86

0.72

Table 2 Analysed using generalised estimated equations IRR, incident rate ratio; VPB, ventricular premature beat

Hypoglycaemia is associated with ECG abnormalities

Frier, B. M. Nat. Rev. Endocrinol. 10, 711–722 (2014)

Rachel A. Whitmer JAMA. 2009;301(15):1565-1572

A longitudinal cohort study from 1980-2007 of 16 667 patients with a mean age of 65 years and type 2 diabetes

Association between glycaemic variability, hypoglycaemia and outcomes

Desouza et al. Diabetes Care 2010;33:1389–94; Driesen et al. J Neurosci Res 2007;85:575–82; Mooradian. Brain Res Brain Res Rev 1997;23:210–8; Sanon et al. Clin Cardiol 2014;37:499–504; Dhalla et al. J Hypertens 2000;18:655–73

Presented at the 53rd Annual Meeting of the European Association for the Study of Diabetes (EASD), Session 33. 15 September 2017, Lisbon, Portugal

Outcomes Glycaemic variability

Hypoglycaemia

Hyperglycaemia

Glycaemic control: variability

BG, blood glucose Image adapted from Penckofer et al. Diabetes Technol Ther 2012;14:303–10; Vora & Heise. Diabetes Obes Metab 2013;15:701–12

Hypoglycaemia

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 23 24

0

6

2

4

10

12

14

16

18

22 Time (hours)

BG

(m

mol/

L)

Patient A

36

72

108

144

180

216

252

288

324

BG

(mg/d

L)

Mean BG ≈ HbA1c 7.8%

(61.7 mmol/mol)

Patient B

Low variability

High variability

8

0

Hyperglycaemia

Glycaemic control: similar HbA1c, different profile

Image adapted from Penckofer et al. Diabetes Technol Ther 2012;14:303–10; Vora & Heise. Diabetes Obes Metab 2013;15:701–12

Hypoglycaemia

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 23 24 22 Time (hours)

Mean BG ≈ HbA1c 7.8%

(61.7 mmol/mol)

Low variability

High variability

36

72

108

144

180

216

252

288

324

BG

(mg/d

L)

0 0

6

2

4

10

12

14

16

18

BG

(m

mol/

L)

8

Patient A Patient B

The relationship between glycaemic variability and hypoglycaemia is established

Bode et al. Diabetologia 2013;56(Suppl. 1):S423

Outline



Postprandial spikes in glucose are part of the normal physiological process…

PPG, postprandial glucose Schematic representation. Adapted from Monnier L & Colette C. Diabetes Metab 2015;41:179–182

Breakfast Lunch Dinner

Glycaemia (mmol/L; mg/dL)

Prep

ran

dia

l g

lycaem

ia F

PG

Postprandial glycaemia

Normal

4 h 4 h 4 h

Prep

ran

dia

l g

lycaem

ia

Prep

ran

dia

l g

lycaem

ia

Physiological exposure

…BUT in diabetes are greater and of longer duration

PPG, postprandial glucose Schematic representation. Adapted from Monnier L & Colette C. Diabetes Metab 2015;41:179–182

Breakfast Lunch Dinner

Glycaemia (mmol/L; mg/dL)

Postprandial glycaemia

Diabetes

Normal

4 h 4 h 4 h

Prep

ran

dia

l g

lycaem

ia

Prep

ran

dia

l g

lycaem

ia

Physiological exposure

Overall glucose exposure in people with diabetes • Basal hyperglycaemia • Postprandial

hyperglycaemia

Postprandial hyperglycaemia

PPG increment: PPG peak–preprandial glycaemia

Prep

ran

dia

l g

lycaem

ia F

PG

Basal hyperglycaemia

The association between postprandial blood glucose and cardiovascular mortality

CVD, cardiovascular disease; PPG, postprandial blood glucose 1. DECODE Study Group. Lancet 1999;354:617–621; 2. Cavalot F et al. J Clin Endocrinol Metabol 2006;91:813–819; 3. Shaw JE et al. Diabetologia 1999;42:1050–1054; 4. Tominaga M et al. Diabetes Care 1999;22:920–924; 5. Balkau B et al. Diabetes Care 1998;21:360–367; 6. Hanefeld M et al. Diabetologia 1996;39:1577–1583; 7. Barrett-Connor E et al. Diabetes Care 1998;21:1236–1239; 8. Donahue RP et al. Diabetes 1987;36:689–692

DECODE 19991

Pacific and Indian Ocean

19993

Funagata Diabetes Study

19994

Whitehall, Paris and

Helsinki Study 19985

Diabetes Intervention Study 19966

The Rancho-Bernardo

Study 19987

PPG

Honolulu Heart Program

19878

CVD death

San Luigi Gonzaga

Study 20062

1. Cavalot F et al. J Clin Endocrinol Metabol 2006;91:813–819; 2. Cavalot F et al. Diabetes Care 2011;34:2237–2243

• 529 (284 men and 245 women) consecutive type 2 diabetic patients1

• 77 events over 5 years1

• Multivariate analysis including HbA1c, pre- and postprandial glucose showed only post-lunch glucose to be predictive1

• Long-term follow up (14 years) confirms this evidence2

aMay lead to diabetic complications; bMay predispose to future CV events CV, cardiovascular; OGTT, oral glucose tolerance test; PPG, postprandial plasma glucose Ceriello A. Diabetes Technol Ther 2017 DOI: 10.1089/dia.2017.0135

“Recent evidences, however, suggest that the value of glycaemia at 1 h during an OGTT

is a stronger predictor for developing diabetes than the value at 2 h and that it is an

independent risk factor for CV disease.”

Outline



Approaching the physiological insulin profile could improve PPG control

Promoted signal

+

-

Stimulatory

Inhibitory

Suppressed signal

Postprandial state

Rate of glucose

appearance

Rate of glucose

disappearance

PG

Endogenous insulin

Glucagon

+

-

-

+

Fat Muscle

Tissues

Liver

Glucose is primarily derived from the gut

Gut

Time (h)

Insulin a

ction (

at

mealtim

e)*

Exogenous insulin

-

Under-insulinisation of hepatic tissue results in insufficient

suppression of EGP

Fast-acting insulin

From the normal pancreas

‘Ultra-fast’ insulin

Regular human insulin

Ultra-fast insulin should:

• Better approach physiological insulin secretion

• Provide greater early suppression of EGP

Less suppression of EGP

EGP, endogenous glucose production; PG, plasma glucose; PPG, postprandial plasma glucose Adapted from: Aronoff et al. Diabetes Spectr 2004;17:183–90; Gerich et al. Diabet Med 2010;27:136–42; Home. Diabetes Obes Metab 2015;17:1011–20

La prima insulina Ultra-fast: Faster Aspart

*also known as nicotinamide – the amide form of vitamin B3 Adapted from Brange J et al. Diabetes Care 1990;13:923–954

Asp

Asp

Niacinamide*: modificatore dell’assorbimento

Responsabile dell’assorbimento più veloce

Arginina: potenziatore di stabilità

Aumenta la stabilità molecolare

Faster aspart vs. insulin aspart via sc injection

Twice as fast onset of appearance in the bloodstream

Two-fold higher insulin exposure within the first 30 min

74% greater insulin action within the first 30 min

Compared with insulin aspart, faster aspart has:

Pooled analysis of NN1218 trials 3887, 3888, 3889, 3891, 3921, 3978. Faster aspart, fast-acting insulin aspart; GIR, glucose infusion rate; IAsp, insulin aspart; sc, subcutaneous

Faster aspart Insulin aspart

0 30 60 Time (min)

0

50

100

150

200

250

300

IAsp s

eru

m c

onc.

(pm

ol/

L)

9 4

0 30 60

GIR

(m

g/k

g/m

in)

0

2

4

6

8

Time (min) Heise et al. Clin Pharmacokinet 2017;56:551–9

PPG control with mealtime faster aspart Standardised meal test: mealtime comparison

Faster aspart (mealtime) Insulin aspart (mealtime)

*p<0.0001; P-values are 2-sided. ETD represents PPG changes from baseline estimates. Changes from baseline in PPG increments were analysed based on an ANOVA model.

0

18

36

54

72

90

108

126

0

1

2

3

4

5

6

7

0

Week 26

PPG

incre

ment

(mg/d

L)

Time (min) Bolus dose 0.1 U/kg

PPG

incre

ment

(mm

ol/

L)

0 60 120 180 240

108

126

72

90

36

54

18

0

6

7

4

5

2

3

1

0

PPG

incre

ment (m

g/d

L)

2-h ETD**: –0.67 mmol/L [95% CI: –1.29; –0.04] –12.0 mg/dL [95% CI: –23.3; –0.7]

**

1-h ETD*: –1.18 mmol/L [95% CI: –1.65; –0.71] –21.2 mg/dL [95% CI –29.7; –12.8]

*

**p=0.0375.

aCompared with mealtime insulin aspart. ANOVA, analysis of variance; CI, confidence interval; ETD, estimated treatment difference (faster aspart–insulin aspart); PPG, postprandial plasma glucose

Error bars: ± standard error (mean). *p<0.0001; **p=0.0375.

Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771

0

10

20

30

40

50

60

70

80

Week 26 Week 52

Severe

or

BG

-confirm

ed h

ypogly

caem

ic

epis

odes p

er

patient-

year

of exposure

NS

NS

Week 261 Week 522

Estimated ratio

95% CI Estimated

ratio 95% CI

Faster aspart (mealtime)/ insulin aspart (mealtime)

1.01 0.88;1.15 1.01 0.88;1.15

Faster aspart (post-meal)/ insulin aspart (mealtime)

0.92 0.81;1.06 n/a n/a

The analysis was based on a negative binomial regression model. Treatment-emergent was defined as an event that has onset up to 1 day after last day of randomised treatment and excluding the events occurring in the run-in period. Estimated treatment ratios (faster aspart/insulin aspart) are presented with 95% CIs BG-confirmed: PG value <3.1 mmol/L (56 mg/dL) BG, blood glucose; CI, confidence interval; faster aspart, fast-acting insulin aspart; PG, plasma glucose; NS, non-significant

Treatment-emergent hypoglycaemia

Faster aspart (mealtime)

Insulin aspart (mealtime)

Faster aspart (post-meal)

1. Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771; 2. Mathieu et al. ADA 2017. Poster 992-P

NS

No difference in the overall rates of severe or BG-confirmed hypoglycaemia between treatment arms

SCHEDA TECNICA

Si può somministrare da 2 minuti prima del pasto a 20 minuti dopo

36

Early exposure glucose-lowering effect

Randomised, double-blind, two-period crossover

trial, 30 elderly (>65 years) and 37 younger adults

(18–35 years) with T1DM received single subcutaneous

faster aspart or IAsp dosing (0.2 U/kg) and underwent an

euglycaemic clamp (target 5.5 mmol/L) for up to 12 h

Faster aspart

Faster aspart, fast-acting insulin aspart; PPG, postprandial plasma glucose; T1D, type 1 diabetes

Effectively improved glycaemic control

No statistically significant difference in the overall rate of hypoglycaemia

Similar overall safety profiles, and as expected for insulin aspart

Has the potential to improve postprandial glucose control over current rapid-acting insulin analogues in elderly patients with diabetes

Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771; Mathieu et al. ADA 2017. Poster 992-P

Outline



Terapia insulinica basale

Borzì V, Il giornale AMD 2013: 16; 287-293

Insulin degludec IGlar U100

Type of insulin New-generation long-acting basal insulin analogue

First-generation basal insulin analogue

Mode of protraction

Forms soluble multihexamers Precipitates as microcrystals

Half-life ~25 hours ~12 hours

Day-to-day variability (AUCGIR,0–24h)

Coefficient of variation 20% Coefficient of variation 80%

AUCGIR, area under the curve for glucose infusion rate; IGlar U100, insulin glargine U100 Insulin glargine image data on file; Jonassen et al. Pharm Res 2012;29:2104–14; Heise et al. Expert Opin Drug Metab Toxicol 2015;11:1193–201; Heise et al. Diabetes Obes Metab 2012;14:859–64

Insulin degludec injected

Long multi-hexamers assemble

[ Phenol; Zn2+]

Insulin degludec from injection to depot

Phenol from the vehicle diffuses quickly, and degludec links up via

single side-chain contacts

L’insulina degludec un nuovo analogo, realizzato mediante la delezione del residuo Thr30

della catena B e l’aggiunta di una catena di acido grasso a 16 atomi di carbonio a livello di LysB29

Insulin degludec: slow release following injection

[Zn2+ ]

Insulin degludec

multi-hexamers

Zinc diffuses slowly causing individual hexamers to disassemble, releasing

monomers

Subcutaneous depot

Monomers are absorbed from the depot into the circulation

10

20

0

Gla-300 is a new long-acting basal insulin with a more even and prolonged PK/PD profile vs Gla-100®

Gla-300 Gla-100

Reduction of volume by 2/3

Reduction of depot surface by

1/2

Gla-300

Same amount of units

3

0

2

1

Gla-100

0 6 30 36

Insulin concentration, µU/mL

24 18 12

Gla-300

Gla-100

0 6 30 36

Glucose infusion rate (GIR), mg/kg/min

24 18 12

Gla-300

160

100

140

120

Gla-100

0 6 30 36

Time, h

Blood glucose, mg/dL

24 18 12

Gla-300

More even and prolonged

PK/PD profile

Gla-100

25

15

5

Steinstraesser A et al. Diabetes Obes Metab. 2014;16:873-6; Becker RHA et al. Diabetes Care. 2014 Aug 22. pii: DC_140006. [Epub ahead of print]

35% ipoglicemia grave

11% ipoglicemia totale

36% ipoglicemia notturna

46% ipoglicemia grave

30% ipoglicemia totale

42% ipoglicemia notturna

Ipoglicemia

51% nell’intero

periodo

RCP Degludec

7637 patients with type 2 diabetes

at high risk for cardiovascular events

Significant reduction of hypo and FPG with insulin degludec compared with IGlar U100

-40% -53%

-7.2 mg/dl

Impact of glycaemic variability on outcomes

in DEVOTE

Outcomes

Glycaemic variability

Hypoglycaemia

DEVOTE 2 Outcomes by variability tertile

0

1

2

3

4

5

6

Severe hypoglycaemia MACE All-cause mortality

Rate

(events

/100 P

YO

)

Zinman et al. Diabetologia 2017; doi:10.1007/s00125-017-4423-z

Low variability Medium variability High variability

DEVOTE 3 Explore the associations of severe hypoglycaemia with cardiovascular outcomes and mortality Risk of MACE and all-cause mortality following a severe hypoglycaemic event

Pieber et al. Diabetologia 2017; doi:10.1007/s00125-017-4422-0

Hazard ratio [95% CI]

Prior severe hypoglycaemia

No prior severe hypoglycaemia

N R N R

First 3-point MACE 1.38 [0.96; 1.96] 32 6.34 649 4.57

First 4-point MACE 1.37 [0.99; 1.91] 37 7.44 768 5.47

Individual components

Non-fatal myocardial infarction 0.74 [0.36; 1.49] 8 1.57 305 2.13

Non-fatal stroke 1.81 [0.92; 3.57] 9 1.76 141 0.97

Cardiovascular death (including unknown) 2.14 [1.37; 3.35] 21 4.05 257 1.76

Unstable angina requiring hospitalisation 1.34 [0.59; 3.04] 6 1.18 139 0.96

All-cause mortality 2.51 [1.79; 3.50] 38 7.32 385 2.64

Hazard ratio [95% CI]

Higher risk of MACE/all-cause mortality any time following severe hypoglycaemia

0,25 0,5 1 2 4

DEVOTE Conclusions:

• DEVOTE confirmed the cardiovascular safety of insulin degludec in comparison with insulin glargine (both U100)

• The rate of severe hypoglycaemia was significantly reduced with insulin degludec versus IGlar U100 in DEVOTE

• DEVOTE supports a clinical benefit of a basal insulin that has low day-to-day variability and therefore provides consistent fasting glycaemia

• DEVOTE is consistent with data demonstrating an association between severe hypoglycaemia and mortality

Marso et al. N Engl J Med 2017;377:723–32

N. Simioni. Diabetes Ther April 12, 2017

52 subjects (48.1% >75 years)

At discharge, 28.9% had BG at target(140-180 mg/dl), while

50.0% had lower levels (average 119.0 ± 14.4 mg/dl). The

incidence rate of hypoglycemia was 0.07 (0.05; 0.11) episodes

per person-day; 1 out of 27 episodes occurred during the night.

Outline



ADA 2017 Guidelines

EMA e IDegLira

AIFA e IDeGlira

Categoria farmacoterapeutica: farmaci usati per il diabete.

Insuline e analoghi per iniezione, ad azione prolungata.

Codice ATC: A10AE56.

Combining therapies offers opportunities to enhance efficacy and diminish side effects

HbA1c FPG PPG Weight Hypoglycaemia

Basal insulin GLP-1 RA monotherapy

0

+

–

GLP-1 RA/insulin combined

Nausea

For illustrative purposes only, not drawn to scale FPG, fasting plasma glucose; PPG, postprandial glucose

• Subcutaneous injection

• 3-mL pre-filled pen

• Fixed ratio of insulin degludec (100 U/mL) and liraglutide (3.6 mg/mL)

1 U insulin degludec + 0.036 mg liraglutide

1 dose step


10 dose steps


50 dose steps

Insulin titration to achieve glycaemic control

One product with multiple mode of action or two products in one

Uncontrolled on basal insulin

IDegLira clinical development programme

• ext., extension; GLP-1 RA, glucagon-like peptide-1 receptor agonist; IDeg, insulin degludec; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine U100; OAD, oral antidiabetic drug; SU, sulphonylurea; SGLT2i, sodium glucose co-transporter-2 inhibitor

• www.clinicaltrials.gov. Last accessed April 2017

Uncontrolled on OADs Uncontrolled on GLP-1 RA

DUAL VIII Durability of IDegLira vs. IGlar U100 as add-on to OAD

Completed trials

DUAL II

IDegLira compared with IDeg in patients previously treated with basal insulin

DUAL V IDegLira vs. basal insulin optimisation

DUAL IX IDegLira add-on to SGLT2i vs. IGlar U100

DUAL I and ext.

IDegLira compared with its mono- components, added on to OAD(s)

DUAL IV IDegLira add-on to SU vs. placebo

DUAL III Switch to IDegLira from (daily) GLP-1 RA therapy vs. unchanged therapy

DUAL VI Easy titration Once- vs. twice-weekly titration

DUAL VII IDegLira vs. basal–bolus

Ongoing

The DUAL clinical programme Summary of key clinical findings

Across all seven studies, IDegLira decreased mean HbA1c to below 7% (6.0–6.9%)

IDegLira resulted in weight loss after basal insulin and was either weight neutral (±0.5 kg) or resulted in weight loss after OAD(s)

IDegLira resulted in a low risk of hypoglycaemia (0.16–3.5 events/PYE)

These results were achieved with once daily injection of IDegLira

IDegLira, insulin degludec/liraglutide; OAD, oral antidiabetic drug; PYE, patient-year of exposure Gough S et al. Diabetes Obes Metab 2015;17:965–73; Buse J et al. Diabetes Care 2014;37:2926–33. Linjawi et al. Diabetes Ther 2017;8:101-114. Rodbard HW et al. Diabet Med. 2017 Feb;34(2):189-196. Lingvay et al. JAMA 2016;315:898-907. Harris et al. Diabetes Obes Metab. 2017 Jun;19(6):858-865. Billings et al. ADA 2017;136-OR

HbA1c

La Terapia Insulinica...Introduzione: obiettivi della terapia insulinica nel paziente diabetico...

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