Tuesday, July 2, 2013

Top 10 Clinical Endocrinology Research Abstracts Presented at the 2013 ACVIM Meeting

Last month, I spent a week in Seattle, Washington attending the the 2013 American College of Veterinary Internal Medicine Forum.  As part of that meeting, a number of research abstracts were presented (oral and poster presentations) that dealt with various aspects of canine and feline endocrinology. I plan to spend the next three blogs discussing some of the newest and best research findings featured at the ACVIM meeting.

Of all of the excellent endocrine research abstracts presented, I've selected a "top 10 list" of the ones that have the most potential to change what I do in my clinical practice.  To do this, I've enlisted the help of Dr. Rhett Nichols, a well-known expert in endocrinology and internal medicine whose day-job is senor member of the veterinarian consulting service for Antech Diagnostics, the world's largest laboratory dedicated to animal health.  However, since Rhett also serves as a consultant for the Animal Endocrine Clinic (my practice), it was not that difficult to get him involved in this project!

In this post, we will review 4 of these top 10 abstracts, followed by the remaining 6 in the upcoming 2 posts. We hope you agree with our selections, but if you don't, remember that you can always post a comment and add your opinion.

Niessen S, Scudder C, Forcada Y, et al. Pasireotide (SOM230) opens doors to medical management of feline hypersomatotropism. J Vet Intern Med 2013:685.

Feline hypersomatotropism (HS) appears to be a significant cause of feline diabetes mellitus. However, successful treatment of HS is currently challenging. Radiotherapy and hypophysectomy seem the only effective therapeutic modalities, yet come with significant disadvantages. Medical options would be desirable although somatostatin (sst) analogues and dopamine agonists have thus far proven largely ineffective. Pasireotide (SOM230), a novel multi-receptor ligand sst analogue with high binding affinity for sst receptor subtypes 1, 2, 3 and 5 has been shown to suppress growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in rodents as well as humans suðering from HS. Additionally, direct and indirect anti-tumor activity has been observed in vitro including sst receptor-mediated apoptosis and anti-angiogenesis. The current study aimed to assess the potential of SOM230 as a treatment modality for naturally occurring feline HS. Feline HS was diagnosed in eight diabetic cats by documenting serum IGF-1 concentration >1000 ng/ml (radioimmunoassay) and presence of a pituitary enlargement (computed tomography). On day 1 and 5, serum IGF-1 concentration was established and glycemic control assessed using a 12-hour blood glucose (BG) curve, measuring BG every 2 hours. On day 2, 3 and 4, the cats were injected with 0.03 mg/kg SOM230 s.c. BID. The initial insulin dose was dictated by the choice of the attending clinician, although was reduced according to regular BG measurements during the treatment period to avoid hypoglycemia. Pre- and post-treatment IGF-1, average 12-hour BG and insulin dose were compared using a paired t-test (significance at P < 0.05). All eight cats showed a significant decrease in serum IGF-1 (mean+/-SD day 1: 1884 + /-218 ng/ml; day 5: 1169 + /-395 ng/ ml, p = 0.001) and average 12-hour BG (day 1: 20 + /-5 mmol/l; day 5: 13 + /-4 mmol/l; p = 0.002). A significant insulin dose reduction was necessary in all cats (day 1: 10.8 + /-6 iu/injection; day 5: 3.1 + /-2 iu/injection; p = 0.015). No side effects were noticed during or after the 3 day treatment period, apart from hypoglycemia in one cat, which resolved after provision of food and reduction of insulin dose. The current study indicates that SOM230 is able to rapidly decrease GH and IGF-1 concentrations in feline HS. This, therefore, suggests that sst receptors are present in most feline somatotrophinomas, which has previously been unclear given the disappointing results during somatostatins and sst analogue therapy attempts. A return of insulin sensitivity was seen, enabling improved glycemic control to be established with reduced doses of exogenous insulin in all cats. In light of these results, a clinical trial with a longer-acting formulation of SOM230 is currently being conducted to establish long-term effects and potential for diabetic remission. 

Comments— Pasireotide (SOM230, trade name Signofor, Novartis) is an orphan drug approved for the treatment of Cushing’s disease in adult human patients when surgery has failed or is not an option (1). The drug is a somatostatin analog that targets multiple somatostatin receptors with high affinity. The result is apoptosis of those cells that produce ACTH, with significant lowering of plasma ACTH levels (2,3).

In addition, pasireotide has been shown to suppress GH and IGF -1 in rodents and human patients with acromegaly (4). Moreover, recent results of a phase III study of human patients with acromegaly treated with a long-acting release form of pasireotide show that this novel form of therapy is significantly more effective than the current standard therapy with octreotide (5).

This study by Niessen et al indicates that pasireotide is able to rapidly decrease GH and IGF-1 concentrations in feline acromegaly and suggests that somatostain receptors are present in most cats with pituitary tumors that produce excessive GH. In light of these results, a clinical trial with the long-acting release form of pasireotide is currently being conducted to establish long-term effects and potential for diabetic remission in cats with acromegaly.

The Bottom Line—It is great to finally have a medical treatment that may actually work for cats with acromegaly. Unfortunately, administration of pasireotide SC twice daily may not be a practical or affordable therapeutic option for many of our cat owners.

References:
  1. Signifor Official Site - Signifor® (pasireotide) Injection. Signifor.US‎. 
  2. Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med 2012;366:914-924. 
  3. McKeage K. Pasireotide: a review of its use in Cushing's disease. Drugs 2013;73:563-574. 
  4. Petersenn S, Farrall AJ, Block C, et al. Long-term efficacy and safety of subcutaneous pasireotide in acromegaly: results from an open-ended, multicenter, Phase II extension study. Pituitary 2013. DOI 10.1007/s11102-013-0478-0 
  5. Colao A, Bronstein M, Freda P, et al. Pasireotide LAR is significantly more effective than octreotide LAR at inducing biochemical control in patients with acromegaly: Results of a 12-month randomized, double-blind, multicenter, Phase III study. Joint 15th International Congress of Endocrinology and 14th European Congress of Endocrinology. Abstract #OC1.1. 2012 

De Marco V, Noronha KSM, Casado TC, et al. Therapy of canine hyperlipidemia with bezafibrate. J Vet Intern Med2013;27:694.

The primary and secondary hyperlipidemia are common in dogs and its treatment is necessary to prevent clinical complications such as pancreatitis, seizures, liver disease and diabetes. The therapy of mild hyperlipidemia comprising a fat restricted diet, but in more severe cases pharmacological treatment is necessary. Bezafibrate (BZF) is effective in the treatment of hypertriglyceridemia in humans, however there are no clinical studies in dogs. The objectives of this study were to assess the efficacy of BZF in reducing serum triglyceride (TG) and cholesterol (CHO) in hyperlipidemic dogs, identify a therapeutic protocol for this drug and assess possible side eðects such as muscle pain, emesis, diarrhea and elevated CK and TGP levels. Only animals with moderate to severe hypertriglyceridemia (TG> 350 mg/dL) were treated with BZF every 24 hours for 30 days before introduction of any other therapy according to the protocol: tablet 200 mg for dogs weighting less than 12 kg, tablet 200 mg for dogs weighing between 13 and 25 kg, 1 tablet 200 mg for dogs weighing over 25 kg. We studied 46 dogs (26 females and 20 males) with a mean age of 9 years. Fifteen dogs (32.6%) had primary hyperlipidemia and 31 (67.4%) secondary hyperlipidemia, which included hyperadrenocorticism (41.3%), hypothyroidism (15.2%) and chronic corticoideterapia (10.8%). All 46 (100%) dogs had hypertriglyceridaemia and 33 (71.7%) had both hypertriglyceridaemia and hypercholesterolemia. After 30 days using BZF, normalization of serum TG (TG <150 mg/dL) was observed in 91.3% of cases (n = 42/46) and of CHO (CHO < 270 mg/dL) in 66 7% (n = 22/33) of cases. Means and standard deviations of serum TG and COL before (752 ± 663 mg/dL and 428 ± 217 mg/dL) and after therapy (110 ± 82 and 244 ± 71 mg /dL) were significantly lower (p < 0.005, paired Student t test). The bezafibrate dose most used with a 95% confidence interval was 5.3 to 6.1 mg/kg (range: 4–10 mg/kg). No side effects were observed, and there was no statistical difference between the values of ALT and CK before and after therapy. It can be concluded that bezafibrate is a safe and effective drug for the canine hyperlipidemia therapy.
  
Comments—Bezafibrate is a fibrate drug used for the treatment of hyperlipidemia (1-3). In people, fibrates are used as an accessory drug in many forms of hypercholesterolemia, usually along with statins. Bezafibrate helps lower cholesterol and triglycerides in the blood and increase high density lipoproteins (HDL). The main toxicity is hepatic, myopathy, and rarely rhabomyolysis.

Hyperlipidemia is a relatively commonly recognized disorder in dogs but management can be frustrating (4). In this study, 46 dogs with primary or secondary hyperlipidemia (diabetes mellitus, Cushing’s syndrome. hypothyroidism) were treated with bezafibrate once a day over a 30-day period; triglycerides and cholesterol were significantly lowered in the majority of dogs. In addition, there was no evidence of untoward side effects (e.g., no clinical issues and ALT and CK levels were not altered).

There are 2 preparations of bezafibrate available: 200 mg tablets and 400 mg sustained-release tablets. The sustained-release preparation is taken once a day; the non-sustained release tablets are taken with each meal. For dogs, the average dose used in this study was 5 to 6 mg/kg once a day. The dosing protocol was ¼ of a 200 mg tablet for dogs < 12 kg, ½ of a 200 mg tablet for dogs weighing between 12 and 25 kg, and one 200 mg tablet for dogs > 25 kg.

The Bottom Line—Bezafibrate given once a day appears to be a safe and effective drug for the treatment of hyperlipidemia in the dog.

References:
  1. Goa KL, Barradell LB, Plosker GL. Bezafibrate. An update of its pharmacology and use in the management of dyslipidaemia. Drugs 1996;52:725-753.  
  2. Goldenberg I, Benderly M, Goldbourt U. Update on the use of fibrates: focus on bezafibrate. Vasc Health Risk Manag 2008;4:131-141.  
  3. Teramoto T, Shirai K, Daida H, et al. Effects of bezafibrate on lipid and glucose metabolism in dyslipidemic patients with diabetes: the J-BENEFIT study. Cardiovasc Diabetol 2012;11:29. 
  4. Xenoulis PG, Steiner JM. Lipid metabolism and hyperlipidemia in dogs. Vet J 2010;183:12-21.

Salesov E, Boretti FS, Sieber-Ruckstuhl NS, et al. Urinary and plasma catecholamine and metanephrine in dogs with pheochromocytoma, hyperadrenocorticism and in healthy dogs. J Vet Intern Med 2013 27:688-689.

Pheochromocytoma (PHEO) is a rare malignant catecholamine-secreting tumor of the adrenal medulla. Catecholamines and metanephrines in plasma and in 24-h urine are approved biomarkers for the detection of the disease in humans, however, the question which of the tests is best is controversial. We previously demonstrated that measurement of urinary catecholamine and metanephrine to creatinine ratios is helpful for the diagnosis of PHEO in dogs and that urinary normetanephrine to creatinine ratio may be the best test to discriminate between PHEO and hypercortisolism (HC). Knowledge on plasma catecholamines and metanephrines in dogs is scarce and no comparison between urinary and plasma parameters has been performed. The objective of the study was to measure urinary as well as plasma catecholamines and metanephrines in dogs with PHEO, HC and in healthy dogs and to determine the test with the least overlap between the group. Six dogs with PHEO, 9 dogs with HC (6 with ATH, 3 with PDH) and 10 healthy dogs were included. Urine samples were collected into HCL containing tubes to ensure a pH 2, blood samples were collected on ice, centrifuged at 4°C and immediately snap frozen in liquid nitrogen. All samples were stored at – 80°C. Urinary epinephrine (U-Epi), norepinephrine (U-Norepi), metanephrine (U-Meta) and normetanephrine (U-Normeta), and epinephrine (P-Epi), norepinephrine (P-Norepi), free and total metanephrine (PF-Meta and PT-Meta) and free and total normetanephrine (PF-Normeta and PT-Meta) were analysed by HPLC. Urinary catecholamines and metanephrines were expressed as ratios to urine creatinine concentrations. Data were analysed by non-parametric tests (P < 0,05). Similar to our previous findings U-Epi, U-Norepi, U-Meta and U-Normeta were significantly higher in dogs with PHEO and U-Norepi and U-Normeta were significantly higher in dogs with HC compared to healthy dogs. Comparison between dogs with HC and dogs with PHEO revealed significantly higher U-Meta and U-Normeta in the latter group. U-Normeta was the only parameter with no overlap. In dogs with PHEO P-Norepi, PF-Meta, PT-Meta, PF-Normeta, PT-Normeta were significantly higher and in dogs with HC P-Norepi, PF- Normeta and PT-Normeta were significantly higher than in healthy dogs. Comparison between dogs with HC and dogs with PHEO showed significant higher PF-Meta, PT-Meta, PF- Normeta, PT-Normeta in the PHEO group. Overlap was present with all 4 parameters, but was least with PF-Normeta and PT-Normeta. According to our results U-Normeta, PF- Normeta and PT-Normeta are valuable parameters for the diagnosis of PHEO, so far U-Normeta performed better than the plasma parameters. 

Comments—In some recent studies, up to one in five adrenal tumors has been a pheochromocytoma. In the past, a presumptive diagnosis of a pheochromocytoma was based on history which was often a vague, sometimes episodic description of illness, documentation of hypertension, an adrenal mass noted on abdominal ultrasound, and ruling out adrenal-dependent Cushing’s syndrome with an endogenous ACTH level or the results of dexamethasone suppression testing. This current research adds additional data to the idea that measurement of urinary and plasma catecholamine and metanephrine can also be used to aid in diagnosis.

The Bottom Line—Currently, a urine normetaphrine/creatinine level, appears to be the most sensitive and specific test to document a pheochromocytoma.  This test requires that the urine sample is acidified at the time of collection and a control urine sample from a normal dog (also acidified) is submitted. A urine normetaphrine/creatinine level at least 4-times the control is consistent with pheochromocytoma.

In the US, the test for urine normetaphrine/creatinine can be performed at Marshfield Labs (www.marshfieldlabs.com). Acid pellets for urinary acidification are available from the laboratory.

References:
  1. Quante S, Boretti FS, Kook PH, et al. Urinary catecholamine and metanephrine to creatinine ratios in dogs with hyperadrenocorticism or pheochromocytoma, and in healthy dogs. J Vet Intern Med 2010;24:1093-1097. 
  2. Kook PH, Grest P, Quante S, et al. Urinary catecholamine and metadrenaline to creatinine ratios in dogs with a phaeochromocytoma. Vet Rec2010;166:169-174. 
  3. Kook PH, Boretti FS, Hersberger M, et al. Urinary catecholamine and metanephrine to creatinine ratios in healthy dogs at home and in a hospital environment and in 2 dogs with pheochromocytoma. J Vet Intern Med2007;21:388-393. 

Sangster K, Panciera JL, Abbott A, et al. Cardiac biomarkers in hyperthyroid cats. J Vet Intern Med 2013:637. 

Differentiation of hyperthyroid heart disease from primary myocardial disease is challenging. The cardiac biomarkers NT- proBNP and troponin I (cTNI) have proven useful in identifying cats with myocardial disease and may provide a method by which hypertrophic cardiomyopathy (HCM) and hyperthyroid heart disease can be discriminated. The primary purpose of this study was to compare plasma concentrations of NT-proBNP and cTNI in three groups of cats: cats with naturally occurring hyperthyroidism, cats with primary cardiomyopathy, and healthy older cats to determine if biomarkers differ between groups and if bio-marker concentrations in hyperthyroid cats change after resolution of the thyroid disease. We prospectively evaluated 61 client-owned cats: 23 hyperthyroid cats, 19 cats with HCM without congestive heart failure, and 19 euthyroid, normotensive healthy cats eight years of age or older. Fourteen of the hyperthyroid cats were re-evaluated three months after administration of I-131. A complete history, physical examination, CBC, serum biochemistries, urinalysis, blood pressure measurement, serum T4 concentration, plasma concentrations of NT-proBNP and cardiac troponin I, and echocardiography was obtained for each cat. Hyperthyroid and HCM cats had plasma NT-proBNP and cTNI concentrations that were significantly greater than healthy older cats, but there was no significant difference between hyperthyroid and HCM cats with respect to concentration of either biomarker. Plasma NT-proBNP and cTNI concentrations decreased in each cat that was examined three months after I-131 treatment. Plasma cTNI was within the reference interval for all cats at the three month recheck. Severely thickened myocardium persisted in one formerly hyperthyroid cat at the three month recheck, and this cat’s plasma NT-proBNP remained elevated. Although there may be a role for NT-proBNP in monitoring the cardiac response to treatment of hyperthyroidism, neither NT-proBNP nor cTNI can be used to distinguish hyperthyroid cats from cats with HCM. Therefore, the thyroid status of older cats should be ascertained prior to interpreting results of cardiac biomarker testing.
  
 Comments—Although it is well established that hyperthyroid cats will commonly develop secondary heart disease (1), it can sometimes be difficult to distinguish thyroid-induced cardiac disease from primary myocardial disease (cardiomyopathy). Over the last few years, a number of studies have confirmed the usefulness of plasma cardiac biomarkers (especially N-terminal pro-brain natriuretic peptide or NT-proBNP) to help detect hypertrophic cardiomyopathy in cats and to distinguish primary cardiac from non-cardiac causes of dyspnea in cats (2-5). Previous studies have found that hyperthyroid cats can have high circulaing levels of either troponin I or NT-proBNP; both biomarkers fall after successful treatment of the hyperthyroid state (6,7).

This research study confirmed that hyperthyroid cats can have high plasma NT-proBNP and troponin I (cTNI) concentrations, which decreased after I-131 treatment. However, there was no significant difference between hyperthyroid and HCM cats with respect to concentration of either biomarker.

The Bottom Line— Although hyperthyroid cats can have high plasma NT-proBNP and cTNI concentrations, there was no significant difference between hyperthyroid and HCM cats with respect to concentration of either biomarker. Therefore, neither of these cardiac biomarkers can be used to distinguish hyperthyroid cats from cats with HCM. Since hyperthyroidism can result in high levels of both biomarkers (6,7), the thyroid status of older cats should always be ascertained prior to interpreting results of cardiac biomarker testing.

References:
  1. Syme HM. Cardiovascular and renal manifestations of hyperthyroidism. Vet Clin North Am Small Anim Pract 2007;37:723-743, vi. 
  2. Wells SM, Sleeper M. Cardiac troponins. J Vet Emerg Crit Care 2008;18:235–245. 
  3. Boswood A. Biomarkers in cardiovascular disease: beyond natriuretic peptides. J Vet Cardiol 2009;11 Suppl 1:S23-32. 
  4. Fox PR, Oyama MA, Reynolds C, et al. Utility of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) to distinguish between congestive heart failure and non-cardiac causes of acute dyspnea in cats. J Vet Cardiol 2009;11 Suppl 1:S51-61. 
  5. Wess G, Daisenberger P, Mahling M, et al. Utility of measuring plasma N-terminal pro-brain natriuretic peptide in detecting hypertrophic cardiomyopathy and differentiating grades of severity in cats. Vet Clin Pathol 2011;40:237-244. 
  6. Connolly DJ, Guitian J, Boswood A, et al. Serum troponin I levels in hyperthyroid cats before and after treatment with radioactive iodine. J Feline Med Surg 2005;7:289-300. 
  7. Menaut P, Connolly DJ, Volk A, et al. Circulating natriuretic peptide concentrations in hyperthyroid cats. J Small Anim Pract 2012;53:673-678.  

7 comments:

Viviani De Marco said...

Dr Peterson, thank you very much for commenting my abstract about bezafibrate. It's a great honor to hear that from you!

King regards
Viviani de Marco (Brazil)

Dr. Mark E. Peterson said...

Hi Viviani,

You are welcome... your group did some nice work to enhance our knowledge on treatment of hyperlipidemia. Keep up the good work!

Roger Wilkinson said...

I also really liked that paper. Over the years we have tried treating a couple of hyperTG Mini Schnauzers with gemfibrozil (one with seizures, one with recurrent pancreatitis). i wondered if either yourself or Dr Peterson have a view on when it would now be appropriate to treat with bezafibrate? Any hyperTG dog? Specific clinical circumstances? None of the above (yet)? Any thoughts much appreciated.

Roger Wilkinson, Leeds, Uk

Dr. Mark E. Peterson said...

I would try the drug in any dog with undefined or idiopathic hyperlipidemia, especially if they failed dietary therapy.

Dr. Mark E. Peterson said...

I would try the drug in any dog with undefined or idiopathic hyperlipidemia, especially if they failed dietary therapy.

PoppiPoodle said...

My dog will soon be taking bezofibrate to control her triglyceride levels. Has Dr. De Marco's full study been published in the journal of Veterinary Internal Medicine, or was the abstract the only document published? I would like to read the full study if it is available (J Vet Intern Med2013;27:694).

Dr. Mark E. Peterson said...

I have not seen the final paper. I just did a medline search and nothing came up. Unfortunately, it generally takes a year to get a paper published once it's accepted, so it's not surprising that the paper has not yet come out.