Good afternoon everyone. It’s a pleasure to be here and I won’t – anyone a 7^th stretch if you need it.  No disclosures today and I’m going to be talking about three main categories of drugs, I’ve chosen to focus on the antipsychotics, antiretrovirals and the antirejection or immunosuppressive agents.  While other things may precipitate diabetes rarely I wanted to focus where there’s some significant clinical impact and also in areas where you can’t simply change the offending drugs so you sometimes need to know a bit about it and treat through it. 

For each of these categories I’m going to cover the risk of diabetes relative to other agents in that group, the mechanisms for hypoglycemia or diabetes where they are known and then some considerations for treatment focusing largely on drug interactions.

Thomas Willis is a founder, is the father of neuroscience but he also recognized the pathology of diabetes mellitus and coined that term in addition to describing the Circle of Willis and he seems to  have noted a link between neuropsychiatric disease and diabetes, the diabetes being the morbid disposition he was referring to here. 

There’s an increased prevalence of obesity in psychiatric illness.  This data is from a study that looked at 169 patients in an outpatient psychiatric care setting.  Forty-eight percent of those patients had schizophrenia and the remainder had a major mood disorder. 

So these patients were compared to a sample from the 1994 NHANES population.  So on the left the graph is looking at women and on the right men.  And we’re looking at the percentage of each subjects in the BMI categories, moving from underweight to healthy weight, overweight and then the classes of obesity.  And as you can see moving into the higher BMI categories there’s a large representation of the psychiatric patient group versus the population sample from the NHANES study. 

A nine study meta-analysis looking at diabetes in depressed patients showed a 37 percent increased risk.  Only one-third of the included studies had really strictly excluded pre-existing diabetes by using laboratory measurements rather than just self-report so that may have been a bit of an overestimate but still some increase was evident.  And schizophrenic patients have a two-fold increased risk of developing diabetes compared to the general population.  So it’s difficult to separate medication effects from looking at that. 

The relationship between antipsychotics and weight gain is much better established than that for diabetes.  So certainly there are case reports of very acute and severe hyperglycemia occurring with many of the atypical anti-psychotics but in general the strength of that data for diabetes and specific drugs is not terribly strong and it’s difficult to separate out what is simply due to weight gain. 

On this graph just to point out the Trazodone is third from the left and at the time of this study it had not yet been FDA approved nor was Quetiapine so it’s not included here.  What we’re looking at is data from 81 different studies and the weight change after ten weeks on standard does of some typical and atypical antipsychotics.   

So zooming in here you can see that haloperidol, risperidone, olanzapine and clozapine were all statistically associated with weight gain at ten weeks and for clozapine that weight change was approximately 5 kilograms at 10 weeks for the mean. 

Possible mechanisms of weight gain with the antipsychotics may include disorder regulation of ghrelin.  Ghrelin is an appetite stimulating hormone that’s released from cells in the gastric fundus and pancreas.  There is disordered regulation of leptin and  leptin is an appetite reducing adipokine.  Normally  higher  levels of leptin correlate with higher body mass index.  But as we’ve touched upon earlier today, leptin resistance is also involved in obesity. 

This study examined changes in weight, changes in ghrelin and in adipokine in patients who were initially drug naïve, treated for one year with antipsychotics for the first time. And they were using haloperidol here, olanzapine and risperidone.  In the top section you can see that weight and BMI both increased significantly in one year.  Ghrelin levels were significantly higher at one year.  And leptin also increased significantly. So probably there’s hypothalamic target cell resistance to leptin as in other obese patients.  It’s difficult to tell from the data out there and particularly in this study if the antipsychotic drug had any effect on that beyond simply the obesity.  But another study has shown that perhaps there’s an association of that BMI and leptin correlation with the use of antipsychotics hinting at some dysregulation.

Clozapine has also been shown to increase neuropeptide Y  levels from the arcuate nucleus in rat hypothalamus and neuropeptide Y is a very potent central stimulator of food intake. Another possible mechanism with both clozapine and olanzapine is antagonism of the serotonin 2C receptors with  potentiation of increased food intake via that antagonism.

So this is a summary of the atypical antipsychotics in weight gain and the risk for diabetes roughly parallels weight gain in most studies.  So clozapine and olanzapine are most highly associated with weight gain, risperidone, quetiapine and paliperidone do cause weight gain but to a  lesser extent.  And in most studies Ziprasidone and Aripiprazole tend to cause minimal weight gain.  These are all second generation or atypical antipsychotics, among the typical agents Haldol causes relatively less weight gain while propamidine causes relatively more.  But of course in the selection of an agent weight gain can’t be the only factor that’s considered so of course psychiatric efficacy is an important point, extrapyramidal symptoms, hyperprolactinemia which endocrinologist think about quite a bit and prolongation of the QT interval are all important side effects to think about.

Some investigators have tried to look more specifically at the relationship between diabetes and antipsychotic medication.  In a retrospective record review looking at 436 patients receiving medication at a clinic in Rochester New York, those patients included were older than the age of 18, had a psychotic or a major mood disorder and we’re treated with a single anti-psychotic agent for 3 or more months.  Patients were excluded in this review if they had diabetes before the age of 18.  6.7 percent of the study population was diagnosed with diabetes while they were on their current antipsychotic drug and another 7.6 percent had previously been diagnosed before being on that current antipsychotic and only 8 of the patients examined in this review had had a diagnosis of diabetes prior to the initiation of any antipsychotic. 

In this study about a third of the patients receiving atypicals were taking clozapine and the authors saw a trend towards higher prevalence of diabetes for the atypical antipsychotic group as a whole compared to Haldol or fluphenazine decanoate but did not quite reach statistical significance and they did not control for BMI or for changes in BMI which tends to be a common weakness in many of these studies. 

A central Texas VA also retrospective review with about 3000 patients found discrepant results.  So in this case  patients were also older than 18, all included patients had records available 12 months before and 12 months after receiving an initial antipsychotic medication.  They had not had a prescription for an antipsychotic in the  prior 6 months and no prescription for diabetes medication or a diagnosis of diabetes in the proceeding year.

When they did intention to treat analysis which is the upper left table, they did not see any difference in the frequency of new onset diabetes for typical versus atypical agents.  And they were using Haldol as their typical agent and olanzapine, risperidone and quetiapine in the atypical group.  When  patients were crossed over between categories where its analyzed separately there was still no difference and when they  looked among those three atypical agents, still not difference in new onset diabetes and they concluded that there was no statistical difference for typical versus atypical agents in new onset diabetes.

There are some plausible biologic mechanisms separate from the insulin resistance induced by weight gain that could account for diabetes.  So clozapine can inhibit glucose dependent insulin release from the beta cells by membrane hyperpolarization, clozapine and olanzapine can also inhibit cholinergic stimulated insulin secretion.  And a final mechanism is muscarinic acetylcholine receptor antagonism in the pancreatic islets.  So the M3 receptors are involved in insulin release and our antagonized by both clozapine and olanzapine again.

In 2003 the ADA, the American Psychiatric Association and some other professional groups got together to examine the question of antipsychotic drugs, obesity and diabetes.  And in early 2004 they published a consensus statement of their findings. This is actually a pretty concise 3 or 4 page article. And based on the data available at that time, it determined that clozapine and olanzapine were highly associated with weight gain and did carry an increased risk of diabetes.   They determined that risperidone and quetiapine again had less weight gain and more discrepant data for diabetes risk.  And Aripiprazole and Ziprasidone both only had their clinical trial data available at this time, so no real world longitudinal data. And they thought that the data on weight gain was somewhat equivocal and that there was no increased risk of diabetes for these agents.

Based on the data available at that time, this consensus group recommended that nutrition and physical activity counseling be given to overweight or obese patients at the initiation of an antipsychotic drug, that those patients should also be educated about the signs and symptoms of diabetic decompensation including DKA and that those patients who were, seemed to be at higher risk for diabetes based on family history or other clinical factors may be considered by the clinician to receive a less weight gain producing or diabetogenic second generation medication among those antipsychotics. 

However these recommendations were really somewhat controversial and so other experts in the field really questioned the data about the diabetes promotion. They were concerned about a recommendation that was also made to change agents or consider a change in agents for metabolic side effects perhaps before the full psychiatric benefit had been realized, and looking at the same data at about the same period of time, the FDA determined in 2003 that the entire class of atypical antipsychotics should include a warning about hyperglycemia.

Subsequently a very large Danish study was published looking at over 300,000 patients, and this paper was published in 2010 but the data was collected between 1996 and 2005.  In that population they actually saw a larger increased risk of incident diabetes for Ziprasidone with a relative risk of about 3, this was compared to the general population not on the drug, and then a milder risk for Risperidone, Clozapine or Olanzapine, and no increased risk for Quetiapine.  So I think on the balance the jury is still out on some of these agents. 

The other thing that could have played a role in this particular study is that since a lot of the papers had begun to be published in the early 2000s looking at risk of diabetes there may have been some selection bias with clinicians choosing something like Ziprasidone for those patients that they thought were at higher risk already. 

I wanted to touch briefly on antidepressants and weight gain and diabetes.  So certainly among the classes of antidepressants the selective serotonin reuptake inhibitors as well as the tricyclics are more likely to cause weight gain in the short term and the long term than some other agents, but there are within class differences as well.  Among the SSRIs Paroxetine is more likely to cause weight gain.

A study of the UK General Practice Database found that those patients on tricyclics or SSRIs for greater than 2 years had an increased risk of diabetes if they were taking moderate to high doses and they saw that larger risk correlated with a larger baseline body mass index. 

A Finnish study also found a roughly doubled relative risk of diabetes with longer term use of the tricyclics and SSRIs, but their absolute risk increase was small, so the 5 year absolute risk for diabetes was 1.1% for nonusers of antidepressants versus 1.8% for all users of antidepressants taken together with some dose effect seen in their other sub-analyses.  So in treating this group there is really no published data, and that will be a common theme for the three groups of drugs I’m discussing, there is not a lot of solid guidance out there that really differs from the general diabetic population, so diet and exercise to mitigate weight gain ideally from the initiation of psychotropics with weight effects is prudent.

Just as a reminder Bromocriptine actually does now carry an FDA approved indication for diabetes, not that I’ve seen anyone using it for that but you don’t want to use this Dopamine agonist in conjunction with a drug that as a Dopamine antagonist effect lightly as you can interfere with the psychiatric effect of the other drug.   SSRIs given with sulfonylureas may increase the risk of hyponatremia and SIADH and certainly in the setting of acute severe hyperglycemia you may need to initiate insulin.  Lesser, less severe cases may be appropriate to treat with orals and as in any patient with diabetes and excess weight if there are no contraindications to Metformin then it can be a great choice to help mitigate weight effects.

I’m now going to move on and talk about immunosuppressive medications that are used post-transplant for either stem cell transplantation or solid organ, but I’m going to start with glucocorticoids just because they have such broad clinical utility.  So normally glucocorticoids increase insulin resistance through very well described postreceptor effects.  So when insulin binds to the insulin receptor a cascade of events is triggered that starts with autophosphorylation of the internal portion of that receptor, that’s followed by activation of insulin receptor substrate I, phosphatidylinositol 3- kinase, protein kinase B and then ultimately translocation of the GLUT4 glucose transporter to the cell surface, allowing increased glucose uptake.  And glucocorticoids interfere at a variety of these steps as shown here. And they also inhibit various downstream steps so that their net effect is to decrease glucose uptake, decrease glycogen synthesis, increase protein degradation and decrease protein synthesis.

Cyclosporin is a calcineurin inhibitor often used as an immunosuppressant post-transplant and it’s associated with impaired glucose tolerance in up to 35% of renal transplant recipients who take it. Cyclosporin has been shown to decrease insulin secretion and inhibits insulin release from human islets in vitro and causes morphologic changes in the islet visible at biopsy that include cytoplasmic swelling, vacuolization and loss of secretory granules.  It also decreases the metabolism of prednisolone through cytochrome P450 effects.

Cyclosporin has been studied in hyperglycemic glucose clamp studies and in this technique subjects have glucose infused to raise their blood sugar to an elevated and constant level.  And by doing that the infusion rate of the glucose becomes a surrogate that can be used to calculate insulin secretion and glucose clearance. 

The subjects in this study were all non-diabetic patients with renal failure awaiting renal transplant, they were all on hemodialysis.  They underwent one hyperglycemic glucose clamp at baseline and then were treated with Cyclosporin for three weeks at doses meant to approximate what they would be achieving post-transplant.  And subsequently had a second glucose clamp study.  So comparing study to study between the subjects there was no change in the first phase of insulin secretion but after Cyclosporin which is the line with the open circles, there was a decrement in the second phase insulin secretion but had not seen any change in glucose clearance or insulin sensitivity index.

Tacrolimus is another calcineurin inhibitor also known as FK506 and similarly has beta cell effects like cyclosporin but there’s actually a greater incidence of post-transplant diabetes with tacrolimus compared to cyclosporin.  If you look across transplant populations there is about a 1.7 fold increase risk with tacro compared to cyclosporin. And it’s been demonstrated that some patients will have improvement in their diabetes if cyclosporin is able to be substituted for tacrolimus.

This graph is from a Medicare database study with over 11,000 renal transplant patients and almost everyone in this study was on a steroid so they didn’t try to separate that effect out.  But the upper curve is those treated without tacrolimus, the lower curve is those with tacrolimus and what we’re looking at is months post-transplant with survival free of diabetes.   And you can see the difference in these curves appears quite early and persists.  At 36 months post-transplant those patients on tacrolimus have accumulative incidence of diabetes of about 32 percent. 

Tacrolimus also decreases insulin secretion from islet cells in vitro and IV Glucose tolerance studies have been shown to also have an issue with secretion rather than sensitivity.  This beta cell toxicity appears to be reversible at least in animal models within  two weeks of drug discontinuation.  Other immunosuppressants including sirolimus  have some conflicting data so depending on what cell type you look at in vitro there appears to be a decrement in insulin sensitivity for skeletal muscle cells but improvement in insulin sensitivity for some other types of  cells and their beta cell effects are also conflicting.  Mycophenolate similarly has conflicting in vitro data but depending on what species of cell is used.  No effects on glucose metabolism is noted in the clinical trials of mycophenolate but there are no human in vivo studies with clamps or IV glucose tolerance tests to my  knowledge using this agent.

So in summary of this section glucocorticoids certainly have a prominent effect on hyperglycemia and promotion of diabetes, glucose intolerance.  Cyclosporin and tacrolimus neuroinhibitors both also can have a negative impact on glycemia.   Azathioprine which we’ve not discussed, sirolimus and mycophenolate all appear to be fairly neutral.

There’s also a consensus group looking at this issue in about the same time in 2003 and you can consider manipulating the immunosuppressives in this group as possible and in conjunction with the prescribing physician.  So  reducing steroids when it’s clinically appropriate certainly can help with     diabetes control.  Changing tacrolimus to cyclosporin actually does have evidence behind it if it’s clinically appropriate for that patient.

And this consensus group recommended a stepwise approach to therapy starting first with diet and exercise, moving on to oral agents, oral combinations and then finally insulin.  There are a few specific drug-drug interactions to consider here.  So metformin and cyclosporin if given together and you end up having a decrease in renal function for the cyclosporin you’ll  have an increased risk of lactic acidosis side effect from metformin.  Sitagliptin and mycophenolate have a theoretical risk of competing for excretion at the renal tubule but it’s not clear if that’s a clinically significant effect or not.  And in any patient you want to think about the consistency of their oral intake before you prescribe a sulfonylurea so in a patient who’s recently post-transplant or otherwise in a period of significant clinical flux, they’re not taking PO, their risk for hypoglycemia is going to be higher.  Practically speaking in the post-transplant period or during acute changes, insulin is often going to be the safest and kind of the most tailorable agent.

Finally I’m going to talk a bit about antiretroviral therapy. So glucose intolerance and diabetes have been associated with both protease inhibitors and nucleoside reverse transcriptase inhibitors though they’re are significant within class differences.  So you can’t really say that glucose intolerance as a class effected either of these but I’m showing them separately here because their mechanisms vary. So the protease inhibitors particularly the older agents indinavir and ritonavir can have direct inhibition of insulin sensitivity by interfering with a GLUT 4 transporter.  The reverse transcriptase inhibitors have more indirect effects so they tend to increase the central and visceral adipose tissue mass at the expense of subcutaneous  tissue mass and those two effects together tend to  promote insulin resistance.  They also can cause mitochondrial toxicity within muscle and adipose tissue.  It’s also an important part of the HIV lipodystrophy syndrome. 

So these drugs given particularly in a background of a patient who’s predisposed by genetics or obesity can promote insulin resistance.  HIV and HCV hepatitis C virus coinfection also raises the risk of insulin resistance.  And interestingly patients who have clinically significant insulin resistance have a harder eradicating a Hepatitis C virus with treatment.

This chart does not  have every retroviral out there but I wanted to summarize those that have the most data available for their diabetes effects. So on the left these agents do have evidence that they decrease insulin sensitivity. Those on the right have had no significant effects on insulin resistance demonstrated.  Indinavir is not really used  much any  more and ritonavir is not used much as a single agent but is often used to  boost other protease inhibitors so it interferes with cytochrome P450  metabolism and thereby raises the level of the other protease inhibitor.

There aren’t good numbers on the prevalence of insulin resistance or diabetes in this population but when they look at mechanistic studies with protease inhibitors that do cause problems with insulin resistance in either  patients or in healthy volunteers the decrease in insulin sensitivity is in the range or 20 to 35 percent. 

Among the nucleoside reverse transcriptase inhibitors the older agents stavudine and zidovudine do tend to cause  problems with insulin resistance, tenofovir and abacavir do not.  And the data is somewhat mixed on efavirenz, nevirapine does not appear to cause much insulin resistance.

The drug-drug interactions do become more significant in patients on antiretrovirals.  So those taking protease inhibitors and pioglitazone can have altered hepatic metabolism of the pioglitazone in either raise or lower is levels.  Protease inhibitors given with nateglinide tend to increase the concentration of nateglinide.  Ritonavir or lopinavir and sulfonylureas actually increase the risk of a disulfiram-like reaction and can alter the sulfonylurea levels.

Metformin with either tenofovir or lopinavir has a similar concern as with cyclosporin.  So if your renal function is altered by those drugs which may have increased of then your metformin toxicity becomes more of a problem.  And tenofovir or lopinavir can again compete with sitagliptin for active renal tubular transport.

Nevirapine and nateglinide can induce hepatic metabolism and in doing so reduce the nateglinide levels.  In the European AIDS Society has recommended metformin be considered in those patients with HIV and diabetes but has not gone so far as to recommend its use in prediabetes or in insulin resistance.  And the HIV lipodystrophy syndrome is really beyond the scope of our talk today but thiazolidinediones have been tried as a specific  therapy in that condition and there’s actually mixed data there as well.

So finally, several medications that are used chronically for  complex medical conditions can either increase the risk of diabetes or worsen existing diabetes and promote hyperglycemia.  But there’s really little data on optimal treatment for these specific populations and what is out there is generally from expert consensus  statements.  You might consider altering medications in conjunction with the  other members of the treatment team but in general I would say let safety be your first guide, be wary about the potential for drug-drug interactions and  that’s all.  I thank you.