L’Iperglicemia da Stress

Iatrogena

Paolo Di Bartolo

Francesca Pellicano

U.O di Diabetologia Prov di Ravenna

Dip. Chirurgico

A.U.sl della Romagna

Prevalenza del Diabete in Ospedale

UK: 15-28 %

USA:14-25 %

Italia: 6-21 %

ER 21 %

DM

Standard di Cura Italinai per il DM: www.infodiabete.it K Dathariya: Diab Med 2012; 10: 1463

Review of medical records

of 2030 consecutive adult

patients admitted

to Georgia Baptist Medical

Center, a . hospital in Atlanta,

GA, from July 1,

1998, to October 20, 1998. Our results indicate that in-hospital hyperglycemia is a common finding and represents an important marker of poor clinical outcome and mortality in patients with and without

a history of diabetes. Patients with newly diagnosed hyperglycemia

had a significantly higher mortality rate and a lower functional outcome than patients with a known history of

diabetes or normoglycemia

Levels of Evidence Treatment of Glucocorticoids Induced Hyperglycemia

HTA

Metanalysis

Natural History of Type 2 DiabetesSeverity of Glucose Intolerance

Normal Blood

Glucose

IGT Frank DiabetesNGT

Macrovascular Complications

Insulin Resistance

Years to

Decades

Insulin Secretion

Postprandial Blood Glucose

Microvascular Complications

Progressive ß-cell

Dysfunction

Typical Diagnosis of Diabetes

Fasting Blood Glucose

HOMA=homeostasis model assessment.

UKPDS Group. Diabetes 1995;44:1249―58.

Adattata da Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21―5.

Il declino della funzione della -cellula determina la natura progressiva del DMT2

Funzio

ne

della-c

ellula

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ale

con H

OM

A)

Tempo (anni)

0

20

40

60

80

100

―10 ―8 ―6 ―4 ―2 0 2 4 6

Momento della diagnosi

?

Funzione pancreatica

= 50% del normale

Stress hormones such as glucocorticoids, growth hormone, and catecholamines induce insulin resistance

Glucocorticoids also increase hepatic glucose production by stimulating gluconeogenesis.

Glucocorticoids have an inhibitory effect on insulin release from Beta cells

Delaunay F,et al. J. Clin. Invest 1997; 100: 2094-209

Glucocorticoids Diabetogenic Effects

Steroid-Induced Diabetes Mellitus (SDM)

Glucose production

Liver

Insulin release

Muscle

Insulin

sensitivity

Pancreas

-cells

Adapted from Delaunay F,et al. J. Clin. Invest 1997; 100: 2094-209

GlucocorticoidsHyperglycemia

Glucagon uptake

Glucocorticoids mediate their effects through a specific intracellular

receptor present in almost all cell types, including Pancreatic beta cells.

The glucocorticoid receptor (GR) belongs to the superfamily of nuclear hormone receptors….

We have data suggesting that GR overexpression

level is a major factor determining beta cells sensitivity towards

Glucocorticoids.

“What proportion of incident diabetic cases in a population is associated

with prescribed glucocorticoid drugs?”

The adjusted OR of diabetes associated with a cumulative

oral dose equivalent to 2.5 g hydrocortisone was 1.25 (1.01–1.54), .. The median equivalent

dose of hydrocortisone for subjects in this category was 9.9 g (interquartile

range 4.7–22.0).

The estimated number needed

to harm for continuous useof corticosteroids

relative to PPIs over 1, 2 and 3 years of use

were 41, 23 , 16 respectively

Steroid-Induced Diabetes Mellitus (SDM)

Approximately 5–25% of patients receiving glucocorticoids exhibit overt diabetes

Hirsch IB et al. Diabetes management in special situations.

Endocrinol. Metab Clin North Am 26:631–645, 1997

Prevalence and predictors of corticosteroid-related

hyperglycemia in hospitalized patients.

Donihi AC, Raval D, Saul M, Korytkowski MT, DeVita MA.

OBJECTIVE: To investigate the prevalence of and risk factors for

hyperglycemia in hospitalized patients receiving corticosteroids, which have been identified as an independent predictor of hyperglycemia

Methods

Retrospective review of electronic medical records of patients admitted to the general medicine service at a university hospital during a 1-month period. Pharmacy charges were used to identify patients receiving high doses (> or = 40 mg/day of prednisone or the equivalent) of corticosteroids for at least 2 days. Occurrence of hyperglycemia and the presence of risk factors, including history of diabetes, duration of corticosteroid therapy, …were determined

During the 1-month study period, 66 of 617 patients received high doses of corticosteroids..

Hyperglycemia was documented in 32 of these 50 patients (64%),

and multiple hyperglycemic episodes occurred in 26 (52%). A history of diabetes was documented

in 12 of 26 patients who experienced multiple episodes... Among patients without a history of diabetes,

19 of 34 (56%) had hyperglycemia at least once. Patients with multiple episodes of hyperglycemia

had more comorbid diseases, longer duration of corticosteroid

therapy, and longer duration of hospital stay.

Endocr Pract 2006; 12 :358-62

Glucose monitoring should be initiated in any patient not known to be diabetic who receives therapy associated with high-risk for hyperglycemia, including high-dose glucocorticoid therapy, …..

Glucose monitoring should be started within 48 hours;

Glucose monitoring must be performed also for a low-dose glucocorticoid treatement when therapy should be continued for more than 2 weeks;

Patients should be required to check mainly their post-prandial glucose level;

If hyperglycemia is documented and persistent, consider treating such patients to the same glycemic goals as patients with known diabetes.

Twenty-five patients with neurologic diseases who received prednisolone 30-60 mg/day orally after breakfast for more than 2 weeks

Plasma glucose concentrations were determined immediately before and 2 hours after each meal. The patients were divided into two groups on the basis of whether SDM had developed (13 patients) or not (12 patients). Thirteen of the 25 patients were identified with SDM, and all of them had plasma glucose concentrations of 200 mg/dl or greater 2 hours after lunch.

http://www.medscape.com/viewarticle/473201

A close relationship among postprandial hyperglycemia,

advanced age, and hypercholesterolemia is a characteristic of SDM in patients with neurologic diseases.

Therefore, monitoring the plasma glucose concentration 2 hours after lunch

may be useful to detect SDM in these patients

16 mg methylprednisolone effect on glycemic

control in a patients with T2DM

Methilprdnisolone 16 mg

La gestione ottimale di iperglicemia nei pazienti trattati con gli steroidi non è ben definità per la eterogeneità degli agenti steroidei utilizzati e per i diversi modi in cui vengono utilizzati nella pratica.

Note da tenere in considerazione nell’approccio clinico:

le proprietà farmacologiche del farmaco steroide utilizzato, in particolare la durata d'azione, i tempi e la frequenza delle dosi, la durata prevista della terapia.

la durata dell'effetto iperglicemico dipende dalla durata d'azione di glucocorticoidi: breve come nel caso del prednisone, lunga d'azione nel caso del desametasone.

Inoltre, un farmaco steroideo a breve durata d'azione somministrato una volta al giorno al mattino avrà un effetto diverso sulla glicemia rispetto allo stesso farmaco dato in dosi frazionate, per esempio ogni sei ore.

Trattamento della Iperglicemia indotta da Steroidi

Efficacy of Glimepiride for the Treatment of Diabetes

Occurring During Glucocorticoid Therapy

Glimepiride is a sulfonylurea that lowers blood glucose levels by stimulating insulin secretion from pancreatic Beta-cells and secondarily by increasing glucose uptake in peripheral tissues.

Such action mechanisms might be suitable for the treatment of glucocorticoid- induced diabetes

Three Japanese female patients who had been taking oral glucocorticoids (prednisolone 5–10 mg/day) were newly diagnosed with diabetes

Fasting blood glucose declined 4 weeks after the glimepiride (1-3 mg/die) administration

and was kept below 7 mmol/l (126 mg/dl) until 24 weeks. HbA1c significantly decreased 4 weeks after the treatment, decreasing to

6.7+ 0.6 % after 8 weeks and maintaining that level until 24 weeks.

HOMA Beta Index increased to the control levels 8 weeks after the treatment, remaining

within the control ranges at 24 we

S. Kasyama et al Diabetes Care 2002; 25: 2359-60

Troglitazone Efficacy in a Subject with

Glucocorticoid -Induced Diabetes

Troglitazone is an oral antidiabetic agent that ameliorates insulin resistance in both peripheral tissues and liver

Glucocorticoid administration, along with obesity, is one of the most common insulin-resistant conditions that we encounter in clinical settings

66-year-old female in whom diabetes was induced by glucocorticoid (Prednisolone 7.5 mg/day)

K. FUJIBAYASHIet al Diabetes Care 1999; 22: 2088

400 mg/day of troglitazone without sulfonylureas stabilized

her HbA1 c levels at ,6%

Insulin is the preferred therapy for

hyperglycemia in the hospital setting

Each of the major classes of oral antidiabetic agents has significant limitations for inpatient use and, therefore, is frequently discontinued upon hospital admission

Metformin has a propensity to result in lactic acidosis: renal insufficiency,

unstable hemodynamic status,

need for an imaging study that requires a radio-contrast dye

Sulfonylureas are associated with hypoglycemia in patients not consuming their normal nutrition;

Thiazolidinediones exacerbate fluid retention increasing intravascular volume, a particular concern in patients with congestive heart failure.

Moreover, these agents provide little flexibility or opportunity for titration in a setting that necessitates acute changes

Moghissi ES et al AACE and ADA Consensus Statement . Diabetes Care 32: 119- 131, 2009 Medscape J Med. 2008; 10(9): 216.

Se la durata prevista della terapia è di una o due settimane, può essere sufficiente utilizzare iniezioni di analoghi di insulina.

Evitare insuline basali durante il giorno: l’ effetto e il fabbisogno di insulina basale sarà difficile o impossibile da valutare quando è previsto un cambiamento della dose dello steroide (aumento o riduzione).

In alcuni casi, specialmente in un paziente ospedalizzato, una infusione di insulina per via endovenosa può essere il modo più efficiente e più rapido per ripristinare la normoglicemia.

L’insulina nel Trattamento della Iperglicemia Indotta

da Steroidi

Varia da paziente a paziente e dipende dalle dosi dello steroide impiegato.

Un paziente con diabete, anche ben controllato, può avere dal 50 al 100 per cento di aumento del fabbisogno di insulina quando la dose di steroidi è superiore a 20 mg al giorno di prednisone o equivalente.

A causa della variabilità degli effetti di un glucocorticoide sul fabbisogno insulinico, iniziare con cautela, con un incremento del 20 per cento della dose di insulina e aggiustamenti continui della dose, anche su base giornaliera per diversi giorni.

In molti pazienti la terapia steroidea potrebbe non richiedere terapia insulinica, o un incremento della dose di insulina.

Il fabbisogno di insulina, quando necessaria

L’insulina nel Trattamento della Iperglicemia Indotta

da Steroidi

NO ICU Setting Updated American Association of Clinical Endocrinologists-American Diabetes

Association guidelines for inpatient management of diabetes

RISS, Regular Insulin Sliding Scale; SQ, subcutaneous

Lleva RR et al. Current Opinion in Endocrinology, Diabetes & Obesity 2011, 18:110–118

What?

Which target?

(10 mmol/ L)

(7.8 mmol/ L)

NO ICU Setting The custom of delivering insulin therapy “as

required” (sliding scale) with regular or rapid acting insulin analogues injections at established intervals only if blood sugar exceeds an established threshold is still widespread, in Italy

too, though it is currently deemed an inappropriate and ineffective method

Basal insulinisation is lacking

It does not prevent hyperglycaemic episodes

High risk of hypoglycaemia.

Nutr Metab Cardiovasc Dis. 2011 Apr;21(4):302-14

What About Sliding Scale

Insulin Treatment??

Sliding Scale Vs Basal Bolus

Slidind Scale Only

Basal Bolus Therapy

LR Schmeltz LabMed 2011

Sample Order for Subcutaneous Insulin in a

Hospitalized Patient

Vasudev Magaji et al. Clinical Diabetes Volume 29, Number 1, 2011

INSULIN ALGORITHM: INTERVENTION GROUP

Prandial Dose Adjustment With Supplemental Insulin Supplemental insulin will be administered in addition to the prandial insulin according to the

following table

Guerra et al. Endocr Pract. 2011:17:737-746

Conclusioni L’insorgenza del diabete mellito nei pazienti sottoposti

a terapia steroidea risulta essere uno degli effetti indesiderati più frequenti associati a tale trattamento, in particolare quando le dosi di cortisone siano elevate o quando il trattamento sia in cronico.

Un elevato livello di vigilanza dovrà, quindi, essere attuato in questi pazienti per la pronta diagnosi e l’inizio di un adeguato approccio terapeutico.

Una diagnosi e una proposta terapeutica pronta appare importante per la presenza delle importanti comorbosità per il quale lo steroide viene prescritto e per evitare che il deragliamento metabolico secondario ad un diabete in stato di non adeguato compenso glicemico comprometta ulteriormente la qualità della vita, la durata della ospedalizzazione ed infine la prognosi in pazienti già caratterizzati da livelli molto elevati di fragilità.