diabete indotto da psicofarmaci atipici

Rischio di diabete con i più recenti psicofarmaci antipsicotici, in particolare con la clozapina [Leponex] e la olanzapina [Zyprexa] !

[NEW YORK (Reuters) 17 settembre 003 - L' Ely Lilly casa farmaceutica annuncia che la U. S. Food and Drug Administration (l' Autorità Usa che esercita il controllo sui farmaci, ndt) ha avanzato la richiesta in data 17 settembre 2003 che sei dei più ampiamente usati psicofarmaci debbano recare una scritta di pericolo di aumentare il rischio di diabete e di elevare il livello di zuccheri nel sangue

La casa di Indianapolis (sede Usa dell'Ely Lilly), che produce il trattamento principe per la schizofrenia, lo Zyprexa, dichiara che la U. S Food and Drug ha anche richiesto che sia messa la stessa scritta per il prodotto rivale della Johnson & Johnson, il Risperdal (Risperidone), nonché il prodotto della Novartis il Clozaril (commercializzato in Italia come Leponex, ndt), il prodotto della Bristol-Myers Squibb detto Abilify, il Seroquel della Pfizer Geodon.

Tutti questi sei farmaci sono i cosiddetti antipsicotici atipici, la nuova generazione di medicine che non causano molti dei turbanti effetti collaterali, come tremito alle mani, rilevato con i vecchi trattamenti]

2) da Medscape september 25 2003 (testo originale in coda)

Antipsychotic-induced type 2 diabetes: evidence
from a large health plan database [Evidenza di diabete tipo 2 indotto da farmaci
antipsicotici, ricavata da un ampio database di casi medici]

J Clin Psychopharmacol 2003 Aug;23(4):328-35 (ISSN: 0271-0749)
Gianfrancesco F; White R; Wang RH; Nasrallah HA
*HECON Associates, Montgomery Village, MD.

L'evidenza dei casi suggerisce che alcuni antipsicotici possono indurre diabete
del tipo 2. L'obbiettivo di questi studi è stato di valutare la correlazione tra
i trattamenti antipsicotici e il diabete tipo 2 in un ampio database medico.
Dati rilevanti di pazienti con psicosi in un prospetto di circa 2 milioni di
casi, sono stati analizzati con il metodo della regressione logistica. Sono
state comparate le frequenze di diabete di tipo 2 in pazienti non prima trattati
per diabete in pazienti non trattati con antipsicotici e in pazienti trattati
con quietiapina, con risperidone, con olanzepina, con gli antipsicotici
tradizionali. Rispetto ad una esposizione di mesi di trattamento con
antipsicotici, i pazienti con quietiapina e risperidone risultano con una
probabilità di dover ricevere trattamento per diabete tipo 2 inferiore ai
pazienti non trattati con antipsicotici (ma differenza non statisticamente
significativa); i pazienti trattati con antipsicotici tradizionali risultano con
una probabilità virtualmente equivalente ai pazienti non trattati; i trattati
con solo olanzepina hanno invece un indice significativamente più alto dei
pazienti non trattati (P = 0.0247). Gli indici relativi facendo una
scrematura supponendo un preesistente diabete tipo 2 di otto mesi e assumendo un
trattamento di 12 mesi con antipsicotici sono: risperidone = 0660 (95% CI
0.311-1.408); olanzapina = 1.426 (95% CI 1.046-1.955); quetiapina = 0.976 (95%
CI 0.422-2.271); e convenzionali antipsicotici = 1.049 (95% CI 0.688-1.613. Casi
riportati nella letteratura scientifica, sperimentazioni di prospettiva e altri
studi retrospettivi hanno sempre di più implicato l'olanzapina e la clozapina
come causanti un esacerbato diabete di tipo 2. Pochi hanno implicato il
risperidone e la rilevanza della quietalpina è risultata limitata. Questo studio
reperisce quel che era già stato trovato circa il rapporto tra il risperidone e
l'olanzapina ma evidenzia anche la quietialpina. Studi aggiuntivi sono necessari
per valutare la correlazione tra trattamenti antipsicotici e il diabete tipo 2.

Testo oroginale:
Antipsychotic-induced type 2 diabetes: evidence from a large health plan
database [In Process Citation]

J Clin Psychopharmacol 2003 Aug;23(4):328-35 (ISSN: 0271-0749)

Gianfrancesco F; White R; Wang RH; Nasrallah HA
*HECON Associates, Montgomery Village, MD.

Case evidence suggests that some of the atypical antipsychotics may induce type
2 diabetes. The objective of this study was to evaluate the association of
antipsychotic treatment with type 2 diabetes in a large health plan database.
Claims data for patients with psychosis within a health plan of nearly 2 million
members were analyzed using logistic regression. Frequencies of newly treated
type 2 diabetes in patients untreated with antipsychotics and among patients
treated with quetiapine, risperidone, olanzapine, and conventional
antipsychotics were compared. Based on exposure measured in months of
antipsychotic treatment, quetiapine and risperidone patients had estimated odds
of receiving treatment for type 2 diabetes that were lower than those of
patients untreated with antipsychotics (not statistically significant); patients
treated with conventional antipsychotics had estimated odds that were virtually
equivalent to those of patients untreated with antipsychotics; olanzapine alone
had odds that were significantly greater than those of patients untreated with
antipsychotics (P = 0.0247). Odds ratios based on 8 months of screening for
pre-existing type 2 diabetes and assuming 12 months of antipsychotic treatment
were: risperidone = 0.660 (95% CI 0.311-1.408); olanzapine = 1.426 (95% CI
1.046-1.955); quetiapine = 0.976 (95% CI 0.422-2.271); and conventional
antipsychotics = 1.049 (95% CI 0.688-1.613). Case reports, prospective trials,
and other retrospective studies have increasingly implicated olanzapine and
clozapine as causing or exacerbating type 2 diabetes. Few have implicated
risperidone while evidence on quetiapine has been limited. This study supports
earlier findings on risperidone versus olanzapine and builds evidence on
quetiapine. Additional studies are needed to evaluate the association of
antipsychotic treatment with type 2 diabetes.

Language: English

MEDLINE Indexing Date: 200308

Publication Type: Owner: NLM; Status: In-Process

Publication Type: Journal Article

PreMedline Identifier: 0012920407

Unique NLM Identifier: 22800985

Journal Code: IM

New Insights in Diabetes and Psychiatric Illness: Integrating Management

Faculty: James R. Gavin III, MD, PhD; Peter J.Weiden, MD; F. Xavier Pi-Sunyer, MD; John W. Newcomer, MD

Release Date: December 10, 2002; Valid for credit through December 10, 2003

-------------------------------------------------------

John W. Newcomer, MD

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When antipsychotic medications were first introduced with chlorpromazine in 1954, we saw a series of reports describing how this low-potency phenothiazine could aggravate existing diabetes mellitus, and could produce new onset cases of type 2 diabetes. For example, the introduction of chlorpromazine increased prevalence in one clinical setting from approximately 4% to approximately 17%. Various groups reported these abnormalities in glucose control, including the National Diabetes Data Group, which added phenothiazines to the "bad" list, a list of medications that could disturb glucose metabolism. They added phenothiazines in the 1970s. The point I'm trying to make is that this is not a new story. This is actually an old story that we forgot to some degree.

The reason that we forgot this is not just bad memory. This is in part due to the fact that not all antipsychotic medications produce this association to the same degree. Some medications, for example high-potency drugs such as haloperidol, seem not to do this as much as low-potency phenothiazines. This helped us to forget this clinical problem in part as more and more haloperidol was used around the world. In addition, this was an early demonstration that not all drugs are created equal with regard to this particular adverse event.

With the introduction of newer antipsychotic medications, beginning with clozapine, we saw a resurgence of clinical reports describing this problem of new onset diabetes mellitus, exacerbations of existing diabetes, impaired glucose tolerance, and complications such as diabetic ketoacidosis (DKA).

This is a summary of the published case reports from a Medlinesearch conducted in March 2001, and what you see is an uneven frequency of distribution of reports across the different medications; and this is not explained by shear numbers of prescriptions or when medications came onto the market.

For example olanzapine, on the market some years after risperidone, has had a higher frequency of reports of these adverse events. We also can see from this that there is going to be the potential perhaps to see this adverse event with any medication. Again, it's a question of frequency whether this will be a common event or a rare or infrequent event.

The problem with DKA is that this has some potential mortality associated with it. In the MedWatch, which is the Food and Drug Administration (FDA) postmarketing surveillance database, in 1999 there were already something like 8 deaths that had been reported due to DKA. There is 1 death listed here, published in the German literature, during a DKA episode in a patient receiving olanzapine treatment.

Antipsychotic Medication Effects

This study used modified oral glucose tolerance tests. This study was funded by the National Institute of Mental Health and the National Alliance for Research in Schizophrenia and Depression (NARSD); and the results are currently in press at the Archives of General Psychiatry.

This study used nondiabetic patients with schizophrenia who were receiving treatment with either typical antipsychotics (primarily haloperidol and fluphenazine), risperidone, olanzapine, or clozapine. We also had healthy control subjects.

All groups in this study were matched for adiposity. All groups were matched for age and balanced for ethnicity. The reason it's important to match for factors such as adiposity is that increasing abdominal adiposity would increase insulin resistance and potentially produce a much worse picture of glucose metabolism. The question we're asking in this study is: When the levels of adiposity are the same, can you still see differences in the level of glucose control across different medication treatments?

In this study, we see plasma glucose levels on the left, plasma insulin levels on the right, and a fasting baseline followed by an oral glucose tolerance challenge with 50 g of dextrose.

On the left, at every time point, it matters what group you're in. At every time point, olanzapine-treated subjects had higher mean glucose levels than patients taking typical antipsychotics.

Clozapine-treated subjects at the fasting and final time point had higher mean glucose levels than the patients taking typical antipsychotics. And both clozapine- and olanzapine-treated subjects at all those same time points had elevated plasma glucose levels in comparison with the healthy control subjects. It's relatively easy to be higher than healthy controls because they don't have psychiatric disease or any medications on board.

Risperidone-treated subjects did not have a perfect picture. At 3 time points, risperidone-treated subjects had elevated glucose levels in comparison with the untreated healthy controls only. At no time point in this study were the risperidone-treated subjects' plasma glucose levels higher than the patients taking typical antipsychotics.

Three points I'd like to make. Notice on the right, plasma insulin levels are still rising at the final time point in the clozapine- and olanzapine-treated subjects. This is a picture of the pancreas working overtime, if you will, to put out more insulin, to try to get those higher glucose levels to come down. It's just not working very well, and this is a picture consistent with insulin resistance.

Notice also that, on the glucose side, at the highest final plasma glucose mean level, olanzapine-treated subjects are about 50 mg/dL higher than the healthy control mean. We said that 21 mg/dL increases in postprandial glucose are independently associated with a 1.6 times elevated chance of myocardial infarction. The point that we wanted to make with this study is that these results seem to be potentially clinically, as well as statistically, significant

This analysis is from that same data set looking at a calculation of insulin resistance in these matched groups of patients and controls showing, again, olanzapine-treated subjects having higher levels of insulin resistance than patients taking typical antipsychotics.

This is a meta-analysis done by Allison and colleagues looking at estimated weight gain at 10 weeks of treatment. On the Y axis is weight gain in kg estimated at 10 weeks. It looks like a staircase, so there are different estimated weight gains depending on the medication used.

On the right are the drugs that cause the most weight gain on average, and on the left are the drugs that cause the least weight gain.

On the right of this graph you'll see more drugs in blue. Blue are the medicines that are newer atypical antipsychotics, and white are the older, conventional antipsychotics, and you see more white on the left.

There are some exceptions to this, but in general, the take-home message is that the class of atypical antipsychotics cause more weight gain than the class of high-potency conventionals.

However, there's a big exception to this in terms of the atypicals, and that is ziprasidone, which is towards the left. You can't even see the bar because it does not cause weight gain or weight loss on average after 10 weeks of treatment.