Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies.

Click on title for pdf download...

Should diabetes patients be on these new incretin drugs long term?

Gastroenterology. 2011 Jul;141(1):150-6. Epub 2011 Feb 18.


Abstract


BACKGROUND & AIMS: Glucagon-like peptide-1-based therapy is gaining widespread use for type 2 diabetes, although there are concerns about risks for pancreatitis and pancreatic and thyroid cancers. There are also concerns that dipeptidyl peptidase-4 inhibitors could cause cancer, given their effects on immune function.



METHODS:

• We examined the US Food and Drug Administration's database of reported adverse events for those associated with the dipeptidyl peptidase-4 inhibitor sitagliptin and the glucagon-like peptide-1 mimetic exenatide, from 2004-2009; data on adverse events associated with 4 other medications were compared as controls.
• The primary outcomes measures were rates of reported pancreatitis, pancreatic and thyroid cancer, and all cancers associated with sitagliptin or exenatide, compared with other therapies.

RESULTS:

• Use of sitagliptin or exenatide increased the odds ratio for reported pancreatitis 6-fold as compared with other therapies (P<2×10(-16)).
• Pancreatic cancer was more commonly reported among patients who took sitagliptin or exenatide as compared with other therapies (P<.008, P<9×10(-5)).
• All other cancers occurred similarly among patients who took sitagliptin compared with other therapies (P=.20).

CONCLUSIONS: These data are consistent with case reports and animal studies indicating an increased risk for pancreatitis with glucagon-like peptide-1-based therapy. The findings also raise caution about the potential long-term actions of these drugs to promote pancreatic cancer.

Weighing Risks and Benefits of Liraglutide — The FDA's Review of a New Antidiabetic Therapy

Weighing Risks and Benefits of Liraglutide — The FDA's Review of a New Antidiabetic Therapy
Published at www.nejm.org February 17, 2010 (10.1056/NEJMp1001578)

Worthwhile read not only for the interesting potential link between this medication and medullary thyroid cancer, but also a look at what goes into the approval process for new diabetic medications.

Lose more weight with bigger breakfast?

Interesting summary of a study presented at Endo Society Meeting by Dr. Daniela Jakubowicz. Also info about a book.

Breakfast of Champions--and thin people

Corned beef for breakfast

Pancreatic fat and diabetes

Noninvasive Quantification of Pancreatic Fat in Humans

The Journal of Clinical Endocrinology & Metabolism Vol. 94, No. 10 4070-4076
Ildiko Lingvay, Victoria Esser, Jaime L. Legendre, Angela L. Price, Kristen M. Wertz, Beverley Adams-Huet, Song Zhang, Roger H. Unger and Lidia S. Szczepaniak

Objective: To validate magnetic resonance spectroscopy (MRS) as a tool for non-invasive quantification of pancreatic triglyceride (TG) content and to measure the pancreatic TG content in a diverse human population with a wide range of body mass index (BMI) and glucose control.

Methods: To validate the MRS method, we measured TG content in the pancreatic tissue of 12 lean and 12 fatty ZDF rats (ages 5–14 weeks) both by MRS and the gold standard biochemical assay. We used MRS to measure pancreatic TG content in vivo in 79 human volunteers. Additionally, to assess the reproducibility of the method, in 33 volunteers we obtained duplicate MRS measurements 1–2 weeks apart.

Results: MRS quantifies pancreatic TG content with high reproducibility and concordance to the biochemical measurement (Spearman’s rank correlation coefficient = 0.91). In humans, median pancreatic TG content was as follows: (1) normal weight and normoglycemic group 0.46 f/w%, (2) overweight or obese but normoglycemic group 3.16 f/w%, (3) impaired fasting glucose or impaired glucose tolerance group (BMI matched with group 2) 5.64 f/w%, and (4) untreated type 2 diabetes group (BMI matched with group 2) 5.54 f/w% (Jonckheere-Terpstra trend test across groups p <>

Conclusions: Human pancreatic steatosis, as measured by MRS, increases with BMI and with impaired glycemia. MRS is a quantitative and reproducible non-invasive clinical research tool which will enable systematic studies of the relationship between ectopic fat accumulation in the pancreas and development of type 2 diabetes.



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Comments:
How is pancreatic fat related to diabetes/IFG and how is it related to fat deposition in other organs? This intriguing study examines both animal models and humans to help understand the pathophysiology of fat deposition and its relationship to diabetes.

The figure above in A. shows glucose readings along with total pancreatic Triglycerides(pTG) as assessed by magnetic resonance spectroscopy. The pancreatic triglyceride measurements were correlated with a biochemical determination of TG for the rats - Fatty and Lean Zucker rats. There is a progressive increase in pTG along with glucose levels in the Fatty Zucker rats, but no change in either levels in the lean rats. Figure B shows the correlation between the MRS technique and biochemical determination.

Humans were divided into 4 groups and were scanned by MRS as well. The results are as in the abstract. Intereting findings included that blood glucose levels 2 hours after a glucose load were most closely correlated with pTG content. HBA1c, serum Tg, # of DM risk factors, age, BMI, fasting glucose, excercise, and dietary fat intake had either no or a weak relationship to pTG content.

Also of interest was the fact that there was little relationship between pancreatic and hepatic TG content (a previous report had shown a low correlation between hepatic and myocardial TG content).

What is not known is to what degree the TG deposition is related to Beta-cell damage/loss if at all? Also can medications, diet, weight loss or more severe caloric restriction reverse the pancreatic TG deposition and if so can this lead to a new B-cell production?

Is more of the right fat the answer?

A study in the journal Diabetes examined the role of butyric acid, a short-chain fatty acid formed by fermentation in the large intestine, in the regulation of insulin sensitivity in mice fed a high-fat diet.

The concluded that:

• Dietary supplementation of butyrate can prevent and treat diet-induced insulin resistance in mouse.
  
• The mechanism of butyrate action is related to promotion of energy expenditure and induction of mitochondria function.

to read more....

Hypogonadism and Diabetes

I recently had to review a paper on the topic of hypogonadism an diabetes and came across an entire topic that I was not aware of. There has been extensive research done looking at the association between testosterone (free and total), SHBG, and the development of diabetes.

A number of things affect both SHBG as well as testosterone. Age, exercise, obesity just to name a few. However, insulin also affects SHBG levels. Hyperinsulinemia is associated with a reduction in SHBG concentration and SHBG concentration is positively associated with insulin sensitivity. SHBG concentration is also negatively correlated with insulin resistance, insulin levels and glucose concentration. Both insulin and insulin-like growth factor 1 have inhibitory effects on SHBG secretion by Hep G2 cells in vitro. Insulin also suppresses hepatic SHBG synthesis.

Because of this relationship, many papers are studying whether SHBG levels can be predictive of the development of diabetes. Because SHBG binds to its receptor and actually has some actions through g-protein/cAMP pathway, there are studies also looking at whether low levels of SHBG may actually lead to diabetes. If this pans out, perhaps SHBG may be a target in the future for something else we have to raise.

Further Reading:

1. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care. 2000;23(4):490-494.

This article shows that there is a Odds ratio of 1.89 of developing diabetes with a 1SD reduction in SHBG concentration.

2. Nair KS, Rizza RA, O'Brien P, et al. DHEA in Elderly Women and DHEA or Testosterone in Elderly Men. N Engl J Med. 2006;355(16):1647-1659.

From the WFMC...this article shows what little effect treating the elderly with DHEA in women or testosterone in men had on inuslin sensitivity.

3. Betancourt-Albrecht M, Cunningham GR. Hypogonadism and diabetes. Int. J. Impot. Res. 2003;15 Suppl 4:S14-20.

A pretty good review article on the topic.

ADA Accord follow-up

Bromocriptine and diabetes

Diabetes Care. 2000 Aug;23(8):1154-61. Links

Bromocriptine: a novel approach to the treatment of type 2 diabetes.

OBJECTIVE:

• In vertebrates, body fat stores and insulin action are controlled by the temporal interaction of circadian neuroendocrine oscillations.
• Bromocriptine modulates neurotransmitter action in the brain and has been shown to improve glucose tolerance and insulin resistance in animal models of obesity and diabetes.
• We studied the effect of a quick-release bromocriptine formulation on glucose homeostasis and insulin sensitivity in obese type 2 diabetic subjects.

RESEARCH DESIGN AND METHODS:
There were 22 obese subjects with type 2 diabetes
randomized to receive a quick-release formulation of bromocriptine (n = 15) or placebo (n = 7) in a 16-week double-blind study.
Subjects were prescribed a weight-maintaining diet to exclude any effect of changes in body weight on the primary outcome measurements.
Fasting plasma glucose concentration and HbA(1c) were measured at 2- to 4-week intervals during treatment.
Body composition (underwater weighing), body fat distribution (magnetic resonance imaging), oral glucose tolerance (oral glucose tolerance test [OGTT]), insulin-mediated glucose disposal, and endogenous glucose production (2-step euglycemic insulin clamp, 40 and 160 mU x min(-1) x m(-2)) were measured before and after treatment.

RESULTS:
No changes in body weight or body composition occurred during the study in either placebo- or bromocriptine-treated subjects.
Bromocriptine significantly reduced HbA(1c) (from 8.7 to 8.1%, P = 0.009) and fasting plasma glucose (from 190 to 172 mg/dl, P = 0.02) levels, whereas these variables increased during placebo treatment (from 8.5 to 9.1%, NS, and from 187 to 223 mg/dl, P = 0.02, respectively). The differences in HbA(1c) (delta = 1.2%, P = 0.01) and fasting glucose (delta = 54 mg/dl, P < 0.001) levels between the bromocriptine and placebo group at 16 weeks were highly significant.
The mean plasma glucose concentration during OGTT was significantly reduced by bromocriptine (from 294 to 272 mg/dl, P = 0.005), whereas it increased in the placebo group. No change in glucose disposal occurred during the first step of the insulin clamp in either the bromocriptine- or placebo-treated group.
During the second insulin clamp step, bromocriptine improved total glucose disposal from 6.8 to 8.4 mg x min(-1) kg(-1) fat-free mass (FFM) (P = 0.01) and nonoxidative glucose disposal from 3.3 to 4.3 mg min(-1) x kg(-1) FFM (P < 0.05), whereas both of these variables deteriorated significantly (P < or = 0.02) in the placebo group.

CONCLUSIONS: Bromocriptine improves glycemic control and glucose tolerance in obese type 2 diabetic patients. Both reductions in fasting and postprandial plasma glucose levels appear to contribute to the improvement in glucose tolerance. The bromocriptine-induced improvement in glycemic control is associated with enhanced maximally stimulated insulin-mediated glucose disposal.

New guidelines alert!

Let's get some opinions on the new guidelines.

Here is the rehash of the algorithm. It appears that most people are treated in the tiered pathyway.

NICE-SUGAR, Mean endocrinologist?

Intensive versus Conventional Glucose Control in Critically Ill Patients

The NICE-SUGAR Study Investigators

Abstract PDF Supplementary Material Editorial by Inzucchi, S. E. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited

ABSTRACT

Background

The optimal target range for blood glucose in critically ill patients remains unclear.

Methods

• Within 24 hours after admission to an intensive care unit (ICU), adults who were expected to require treatment in the ICU on 3 or more consecutive days were randomly assigned to undergo either intensive glucose control, with a target blood glucose range of 81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), or conventional glucose control, with a target of 180 mg or less per deciliter (10.0 mmol or less per liter).
• We defined the primary end point as death from any cause within 90 days after randomization.

Results

• Of the 6104 patients who underwent randomization,
  
• 3054 were assigned to undergo intensive control and
  
• 3050 to undergo conventional control; data with regard to the
  
• primary outcome at day 90 were available for 3010 and 3012 patients, respectively. The two groups had similar characteristics at baseline. A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group died (odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P=0.02). The treatment effect did not differ significantly between operative (surgical) patients and nonoperative (medical) patients (odds ratio for death in the intensive-control group, 1.31 and 1.07, respectively; P=0.10). Severe hypoglycemia (blood glucose level, 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control group (P<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU (P=0.84) or hospital (P=0.86) or the median number of days of mechanical ventilation (P=0.56) or renal-replacement therapy (P=0.39).

Conclusions
In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. (ClinicalTrials.gov number, NCT00220987 [ClinicalTrials.gov] .)

Diabetic foot exam - plantar fasciitis

I saw a 47 yo patient today with DM2. She was complaining of L heel pain for 1 month. She wakes up with pain and it is present all day long. There was no cracking, redness, warmth, etc. She had no history of trauma. She has had some minor symptoms of numbness in both feet. B DP 1+. Ankle reflexes 2+. LT and vibration intact B. I found a nice picture from uptodate submitted by Robert P Sheon, MD of a test to elicit plantar fasciitis pain. This maneuver - which involves grasping and dorsiflexing the toes with one hand while palpating the plantar foot with the other hand - did in fact elicit pain. I am also ordering plain films, but I thought that this was a nice and simple test to perform for diabetics with otherwise unexplained plantar or heel pain.

Diabetic Retinopathy and VEGF antibody

From NEJM Feb 26, 2009

Viva Hypoglycemia!

Fascinating tidbit about an "outbreak" of hypoglycemia related to sexual performance enhancing drugs tainted with glyburide with tragic consequences from the NEJM.

(The tragic results are nothing to laugh about, but some of the names of these names of the drugs ought to automatically steer one clear: Power 1 Walnut, Santi Bovine Penis Erecting Capsule.)

Should we put all of our overweight/obese at risk for diabetes patients on anti-inflammatories?
I actually found this article after my husband gave me an article from the Wall Street Journal commenting on an 1876 (!) German journal article that noted that Salsalate improved "diabetics ability to control blood sugars". For those who strongly believe that inflammation 2/2 to obesityin leads to insulin resistance and ultimately diabetes, this is more support for this hypothesis. Based on this study, Shoelson got funding for a much larger NIH funded study that just started.
Keep your eyes and ears open for more to come and don't forget to take your daily Advil.

Diabetes Care. 2008 Feb;31(2):289-94. Epub 2007 Oct 24.
Links

Salsalate improves glycemia and inflammatory parameters in obese young adults.
Fleischman A, Shoelson SE, Bernier R, Goldfine AB.
Harvard Medical School, Boston, Massachusetts, USA.
OBJECTIVE: Sedentary lifestyle and a western diet promote subacute-chronic inflammation, obesity, and subsequently dysglycemia. The aim of the current study was to evaluate the efficacy of the anti-inflammatory drug salsalate to improve glycemia by reducing systemic inflammation in obese adults at risk for the development of type 2 diabetes. RESEARCH DESIGN AND METHODS: In a double-masked, placebo controlled trial, we evaluated 20 obese nondiabetic adults at baseline and after 1 month of salsalate or placebo. RESULTS: Compared with placebo, salsalate reduced fasting glucose 13% (P < 0.002), glycemic response after an oral glucose challenge 20% (P < 0.004), and glycated albumin 17% (P < 0.0003). Although insulin levels were unchanged, fasting and oral glucose tolerance test C-peptide levels decreased in the salsalate-treated subjects compared with placebo (P < 0.03), consistent with improved insulin sensitivity and a known effect of salicylates to inhibit insulin clearance. Adiponectin increased 57% after salsalate compared with placebo (P < 0.003). Additionally, within the group of salsalate-treated subjects, circulating levels of C-reactive protein were reduced by 34% (P < 0.05). CONCLUSIONS: This proof-of-principle study demonstrates that salsalate reduces glycemia and may improve inflammatory cardiovascular risk indexes in overweight individuals. These data support the hypothesis that subacute-chronic inflammation contributes to the pathogenesis of obesity-related dysglycemia and that targeting inflammation may provide a therapeutic route for diabetes prevention.
PMID: 17959861 [PubMed - indexed for MEDLINE]

Is there a wolf underneath that sheep?

Looks like they are out to help right?

Check this out.

NEW ADA Guidelines update

Recent article in diabetes care published an update to the ADA diabetes guidelines. Here are some of the updates (great source of board questions)...

• In patients with coronary heart failure (CHF), thiazolidinedione use is contraindicated. (C)
• For all patients with diabetes, perform an annual comprehensive foot examination to identify risk factors predictive of ulcers and amputations. The foot examination should include inspection, assessment of foot pulses, and testing for loss of protective sensation (10-g monofilament plus testing any one of: vibration using 128-Hz tuning fork, pinprick sensation, ankle reflexes, or vibration perception threshold). (B)

click here for a complete list of the updates...
A link to the complete guidelines...(click here)

Who is Richard Bergman?

Ever wonder who this guy is?

What was so important about his work that he won the Banting award?

Here are two good links:

1. USC article explaining the significance.

2. Webcast from the man him self.

Fellows curriculum.

New tailored goals for type 2 diabetes patients?

In treating patients with type 2 diabetes, our goal had been to reduce the HBA1C to the near normal range(<6%).>

hypoglycemia was in 20% treatement vs 8.8% control

There were 29 cardiovascular deaths in the standard-treatment vs. 36 in the intensive-treatment group.

with sudden death in 4 vs. 11 patients, respectively, accounting for all of the excess mortality.

Predictors of sudden death were a prior macrovascular event, BMI, A1C at baseline, weight gained during the study, and low HDL cholesterol.

Recent severe hypoglycemia was a predictor of cardiovascular death and of the primary outcome and, in the standard-treatment group, of all-cause mortality.

From the VADT trial, it appears that there can be harm from intense glucose control. They looked at the benefit in relationship to duration of type 2 diabetes.

1. "Duration was a significant predictor of the primary end point and showed a highly significant interaction with the treatment effect in the intensive-treatment group, suggesting that intensive treatment might be protective during the first decade of diabetes but that late intensive treatment in the fashion used in the VADT might be harmful. "
2. "The CAC score was independent of standard cardiovascular risk factors and was an even stronger risk factor than having a prior event. Furthermore, Reaven showed evidence that the effect of the treatment assignment was modified by the baseline CAC score: the participants with a baseline CAC score <100>100. "

read more.......

Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes

In summary, the microvascular benefits were not promising

There were no significant differences between the two study groups in the number of new eye procedures.

1. The cumulative rates of events in all patients, including those who had undergone eye procedures at baseline, did not differ significantly.
   
2. Fundus photographs showed no significant differences in progression to proliferative diabetic retinopathy (P=0.27) or in progression to clinically important macular edema (P=0.31).
   
3. There was a nonsignificant trend toward a beneficial effect in the intensive-therapy group with respect to diabetic retinopathy, with an increased incidence of at least two steps in severity in the standard-therapy group (P=0.07).
   
4. The between-group difference in new onset of retinopathy was not significant (P=0.27)

The GFR declined to 76 ml per minute by year 6 (P<0.001) with no difference between the two study groups (P=0.36).

1. Severe renal changes were unaffected by treatment (P=0.35).
   
2. Any worsening of albumin excretion was greater in the standard-therapy group (P=0.05).

There was a nonsignificant increase in autonomic neuropathy in the intensive-therapy group (P=0.07). No other significant changes in neuropathy were seen.

Since Andy did such a great job of hitting all of the main points, I will just raise some questions I had when reading it...perhaps you guys can enlighten me about some of them:

• The study reports that a sample size of 1700 patients provided a power of 86% to detect a relative difference of 21% in primary outcome. --> is 86% sufficient or underpowered?
• Mean duration of diabetes was 11.5 years and 40% of subjects had already had a cardiovascular event. --> if almost half of the subjects already have a CV event, isn’t the study now have two additional groups, those with CV disease and those without. Should these groups be studied separately?
• The lack of difference in microvascular disease was also very surprising because of the amount of data available to show that tight control dramatically improves this.
• Overall, my big criticism is the inclusion of the subjects with and without CV disease into one large group. This really is an issue of primary prevention vs. secondary prevention and the groups don't belong together. Without this combined group the study is under-powered to detect a difference. They found a slight decrease in the primary outcome in intense therapy vs. standard and I really think with adequate power, this difference is statistically significant.
  

Click here to read further....

Insulin begets more insulin, when do we stop?

Insulin Resistance and Hyperinsulinemia

Is hyperinsulinemia the cart or the horse?

Michael H. Shanik, MD¹, Yuping Xu, MD², Jan krha, MD, DSC³, Rachel Dankner, MD, MPH⁴, Yehiel Zick, PHD⁵ and Jesse Roth, MD^2,6

Diabetes Care 31:S262-S268, 2008 DOI: 10.2337/dc08-s264 © 2008

Insulin resistance, recently recognized as a strong predictor of disease in adults, has become the leading element of the metabolic syndrome and renewed as a focus of research. The condition exists when insulin levels are higher than expected relative to the level of glucose. Thus, insulin resistance is by definition tethered to hyperinsulinemia. The rising prevalence of medical conditions where insulin resistance is common has energized research into the causes. Many causes and consequences have been identified, but the direct contributions of insulin itself in causing or sustaining insulin resistance have received little sustained attention. We examine situations where insulin itself appears to be a proximate and important quantitative contributor to insulin resistance.

1) Mice transfected with extra copies of the insulin gene produce basal and stimulated insulin levels that are two to four times elevated. The mice are of normal weight but show insulin resistance, hyperglycemia, and hypertriglyceridemia.
2) Somogyi described patients with unusually high doses of insulin and hyperglycemia. Episodes of hypoglycemia with release of glucose-raising hormones, postulated as the culprits in early studies, have largely been excluded by studies including continuous glucose monitoring.
3) Rats and humans treated with escalating doses of insulin show both hyperinsulinemia and insulin resistance.
4) The pulsatile administration of insulin (rather than continuous) results in reduced requirements for insulin.
5) Many patients with insulinoma who have elevated basal levels of insulin have reduced (but not absent) responsiveness to administered insulin.
In summary, hyperinsulinemia is often both a result and a driver of insulin resistance.