Top Clinical Endocrinology Research Abstracts, 2014 ACVIM Forum: Diabetes Part 2

Following last week’s post, this is the next installment of my review of the "top 12 list" of clinical endocrinology research abstracts presented at this year's American College of Veterinary Internal Medicine Forum.

As with last week's post, I've enlisted the help of Dr. Rhett Nichols, a well-known expert in endocrinology and internal medicine whose day-job is senior member of the veterinarian consulting service for Antech Diagnostics, the world's largest laboratory dedicated to animal health.  Rhett also serves as a consultant for the Animal Endocrine Clinic, so I talk to him almost every day about the more difficult cases I see in my practice.

In this post, we will review 2 more of these "top 12" abstracts (both dealing with issues in diabetes), followed by the remaining 6 abstracts in the next 3 weeks' 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.

Claus P, Gimenes, AM, Castro, JR, Schwartz DS. Fructosamine Levels Do Not Agree with Clinical Classification Regarding Diabetic Compensation in Diabetic Dogs Under Treatment. J Vet Intern Med 2014;28:1034-1035.

Fructosamine levels are measured for diabetes management in veterinary medicine, but are rarely used in human clinical practice. A prospective, cross-sectional study was conducted between January 2010 and August 2012 to assess serum fructosamine levels of diabetic dogs under treatment in order to determine glycemic control compared to clinical classification of "compensated" versus "non-compensated," based on clinical signs and owner evaluation of the animal clinical status.
     The study population included 86 dogs: 25 were healthy, non-diabetic dogs (controls), 14 were diabetic dogs at diagnosis, 24 were diabetic under treatment (at least 30 days), and 23 had diabetic ketoacidosis (DKA).
     Compared to controls, serum fructosamine levels were significantly higher for all the diabetic groups, which were similar between each other. Considering all dogs, 8.3% were within the lower level (300–350 mg/dL), 11.9% had excellent glycemic control (350–400 mg/dL), 14.3% had good glycemic control (400–450 mg/dL), 14.3% had regular glycemic control (450–500 mg/dL) and 51.2% had poor control (> 500 mg/dL). Considering dogs under treatment, 95.8% were classified as having poor glycemic control and only 4.2% had a good control. Although 17/24 (70.8%) were clinically classified as "compensated," they all had fructosamine levels > 500 μmol/L; therefore, a poor glycemic control. Only one dog in this group had fructosamine levels indicating good glycemic control, but in this case, the owner had reported polyuria, polydipsia, polyphagia, and therefore, had been classified as non-compensated. Further studies must assess if insulin therapy adjustment based on fructosamine levels, and not only on clinical status, would lead to hypoglycemia episodes.

Study overview— Plasma fructosamine measurements are widely used as an indicator of glycemic control in diabetic dogs and cats (1-6). Because fructosamine is the product of an irreversible reaction between glucose and the amino groups of plasma proteins, it is assumed that its concentration reflects the mean blood glucose concentration of the preceding 1 to 2 weeks. Circulating fructosamine concentrations increase when glycemic control worsens and decrease when glycemic control improves.

In this abstract, the investigators determined that the vast majority (95.8%) of the 24 treated diabetic dogs would have been classified as having poor control, based on their high fructosamine levels (> 500 µmol/L). However, 17 of these 24 poorly-controlled dogs (based on the fructosamine level) were classified as well controlled or "compensated” diabetics based upon the history (i.e., no polyuria, polydipsia, or polyphagia). In contrast, 1 of the treated diabetic dogs was classified as having good control based on the fructosamine concentration, yet was classified clinically as an “uncompensated diabetic” because of owner complaints of continued polyuria, polydipsia and polyphagia. This discordancy between the clinical signs of diabetes and plasma fructosamine levels raised the question whether insulin dose adjustments could be based on fructosamine concentrations alone.

Comments—The discordancy between the clinical status of a treated diabetic patient (compensated versus uncompensated diabetes) and fructosamine levels that indicated poor control was somewhat surprising compared to the results of other published studies (1-4). However, there are several explanations that may account for these findings. These include the following:

1. The fructosamine reference interval “cut-off values” are too low.
2. Plasma Fructosamine is a “rear-view mirror” assessment of glycemic control.
3. Circulating fructosamine concentrations can be quite variable.

Reference interval cut-offs: Reference ranges for plasma fructosamine concentrations differ slightly between laboratories (5). This difference is often due to the commercially-available fructosamine test kit, and the reagents used by each laboratory. Claus et al. adopted a fructosamine reference range where the cut-off for poor regulation is > 500 µmol/L, while others have adopted a wider reference range where the cut-off for poor regulation is defined as a fructosamine > 600 µmol/L (5,6). If the reference range cut-off in this study was raised, many of the dogs categorized as having poor regulation would likely be reclassified as having moderate control.

Rear-view mirror assessment: Many dogs require at least 8 weeks or more to establish adequate glycemic control (6). Fructosamine determinations at 30-60 days may be too early to accurately assess the status of diabetic regulation. In other words, the finding of high plasma fructosamine concentrations, when sampled at 30-60 days after the start on insulin therapy, may be misleading, since fructosamine concentrations reflect the mean blood glucose levels over the preceding 1 to 2 weeks.

Variability: The range of plasma fructosamine concentrations associated with a given blood glucose concentration can be quite wide, even after the fructosamine concentration has plateaued (4). For example in one study, fructosamine concentrations ranged from 400 to 633 µmol/L, with a blood glucose concentration of 523 mg/d (4). Given the large range of plasma fructosamine concentrations for a given glucose concentration, the range of fructosamine concentrations from well controlled and poorly-controlled diabetics will likely overlap.

The Bottom Line—Fructosamine is far from a perfect test, but despite its shortcomings, it remains a valuable adjunct parameter to monitor glycemic control. However, it should always be interpreted in conjunction with the history, physical exam findings and body weight and never used alone to adjust an insulin dose (1,5-7).

References:

1. Reusch CE, Liehs MR, Hoyer M, et al. Fructosamine. A new parameter for diagnosis and metabolic control in diabetic dogs and cats. J Vet Intern Med 1993;7:177-182.
2. Thoresen SI, Bredal WP. Clinical usefulness of fructosamine measurements in diagnosing and monitoring feline diabetes mellitus. J Small Anim Pract 1996:37;64-68.
3. Crenshaw KL, Peterson ME, Heeb LA, et al. Serum fructosamine concentration as an index of glycemia in cats with diabetes mellitus and stress hyperglycemia. J Vet Intern Med1996:10:360-364.
4. Link KR, Rand JS. Changes in blood glucose concentration are associated with relatively rapid changes in circulating fructosamine concentrations in cats. J Fel Med Surg 2008;10;583-592
5. Reusch CE. Diabetic monitoring. In: Kirk’s Current Veterinary Therapy XV. Elsevier, St Louis, 2014; 193-199.
6. Feldman EC, Nelson RW. Canine diabetes mellitus. In: Canine and Feline Endocrinology and Reproduction. 3rd ed, Elsevier, St Louis, 2004; 510.
7. Briggs CE, Nelson RW, Feldman EC, et al. Reliability of history and physical examination findings for assessing control of glycemia in dogs with diabetes mellitus: 53 cases (1995-1998). J Am Vet Med Assoc 2000;217; 48-53.

Gostelow R, Scudder C, Keyte S, Forcada Y, Fowkes RC; Schmid HA, Church DB, Niessen SJM. Pasireotide (SOM230) Long-Acting Release Treatment for Feline Hypersomatotropism: A Proof of Concept Trial.  J Vet Intern Med 2014;28:1030.

Hypersomatotropism (HS) is a relatively common cause of feline diabetes mellitus. Attempts at its long-term medical management with somatostatin (sst) analogues have previously proven unrewarding. However, pasireotide (SOM230, Novartis, Basel, Switzerland), a novel sst analogue with binding affinity for sst receptor subtypes 1, 2, 3 and 5, was recently shown capable of decreasing serum insulin-like growth factor 1 (IGF-1) and improving insulin sensitivity in cats with HS when administered for 3 days as a short-acting, BID subcutaneous (SC) preparation. A long-acting release formulation (LAR) has been developed to allow convenient, once-monthly dosing and has led to successful biochemical control of human HS. The current study aimed to assess the potential of once-monthly pasireotide LAR as a treatment for feline HS.
      Feline HS was diagnosed in 12 diabetic cats based on increased serum IGF-1 (> 1000 ng/ml) and pituitary enlargement on computed tomography. Cats received 8 mg/kg SC pasireotide LAR once monthly for 6 months. Fructosamine concentration, IGF-1 concentration, and a 12-hour blood glucose curve (BGC) were performed at baseline and once monthly thereafter to monitor treatment response. A repeat CT-scan was performed at the end of the trial. A mixed-effects model was used to assess significance of changes in fructosamine, IGF-1 concentration, mean blood glucose (MBG) of BGCs, and insulin dose (U/kg).
       Seven of 12 cats completed the trial; 3 of 12 cats entered diabetic remission. Trial withdrawal occurred after a median of 2 months (range 1–4.5 months) due to persistence of uncontrolled diabetes mellitus (n = 1), diarrhoea (n = 2), a hypoglycemic event (n = 1), and an episode of diabetic ketoacidosis (n = 1). A significant decrease in IGF-1 (p < 0.001), insulin dose (p < 0.001), fructosamine (p = 0.04), though not MBG (p = 0.71) was documented. Adverse events included soft stools (9/12), worsening polyphagia (3/12), hypoglycaemia (4/12), and delayed hair regrowth (1/12). Maximum pituitary mass height had increased in 2/7, decreased in 4/7 and remained the same in 1/7 cats.
      In summary, pasireotide LAR is the first drug that shows potential to cause long-term biochemical and clinical improvement in cats with HS. In a proportion of cases, diabetic remission can even be achieved. Further work should focus on dose optimisation to enable higher success and lower withdrawal rates, specifically by trying to reduce adverse gastrointestinal events. The observed decrease in pituitary tumor size in some cats further establishes this as a useful primary, long-term treatment modality, although its preoperative use, enabling glycemic stabilization and tumor shrinkage before hypophysectomy, may also be of benefit.

Comments— Pasireotide (SOM230, trade name Signifor, 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, as well as in human patients with acromegaly (4). Moreover, recent results of a phase III study of human patients treated with a long-acting release (LAR) form of pasireotide (Pasireotide LAR) showed that this novel form of therapy is significantly more effective than the current standard therapy with octreotide LAR or landreotide autogel (ATG) (5,6).

This study by Niessen's group showed that a once monthly injection of Pasireotide LAR to cats with acromegaly has the potential to cause a significant decrease in IGF-1 and GH levels, shrinkage of the GH-secreting pituitary tumor, and diabetic remission in cats with acromegaly.

The Bottom Line— To date, the only effectve treatment options for cats with acromegaly are transsphenoidal surgery or radiation therapy. Both of these treatments are quite costly and not widely available; in addition, they are associated with modest risk for patient morbidity and mortality and can have variable efficacy (7,8).

The idea that medical therapy for acromegaly is now a viable option is great news, but any new treatment that may change the therapeutic landscape for any disorder should be met with cautious optimism. In other words, it is important to remember that cats with acromegaly, just like in people with the same disorder, may have a variable response to medical therapy (9-12). For example, 5 of 12 cats in the current clinical trial had to be withdrawn from the study; 3 because of issues related to poor diabetes management and 2 because of diarrhea, which is a common adverse effect associated with somatostatin analogs. In addition, pituitary tumor shrinkage, which is a function of tumor size, tumor type (well differentiated versus poorly differentiated tumor cells), and the density and expression of specific somatostatin receptors, should not be expected to occur in all cases (9-12). Moreover, even if circulating GH values fall, diabetic remission or improved glycemic control may not occur for multiple reasons; for example, hyperglycemia is seen in a significant proportion of human patients treated with pasireotide, presumably because the drug inhibits insulin release (2-6).

And lastly, especially for cats, another drawback to use of pasireotide LAR is its high cost, which is estimated at $2000 per cat per year. However, it may be possible to use this agent at lower doses or at less frequent intervals, with obvious cost implications (13). Further research is obviously needed to determine these issues.

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. http://www.ncbi.nlm.nih.gov/pubmed/23605695
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. 2014;17:132-140. 
5. Colao A, Bronstein MD, Freda P, et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab 2014;99:791-799. 
6. Gadalha M, Bronstein M, Brue T, et al. Pasireotide LAR demonstrates superior efficacy versus Octreotide LAR and landreotide ATG in patients with inadequately controlled acromegaly: Results from a Phase III, multicenter, randomized study. 16th European Congress of Endocrinology. 2014; 35: P907. 
7. Melmed S, Colao A, Barkan A, et al. Guidelines for acromegaly management: an update. J Clin Endocrinol Metab 2009;94:1509-1517. 
8. Gittoes NJ, Sheppard MC, Johnson AP, et al. Outcome of surgery for acromegaly--the experience of a dedicated pituitary surgeon. QJM 1999;92:741-745. 
9. Casarini AP, Jallad RS, Pinto EM, et al. Acromegaly: correlation between expression of somatostatin receptor subtypes and response to octreotide-lar treatment. Pituitary 2009;12:297-303. 
10. Casarini AP, Pinto EM, Jallad RS, et al. Dissociation between tumor shrinkage and hormonal response during somatostatin analog treatment in an acromegalic patient: preferential expression of somatostatin receptor subtype 3. J Endocrinol Invest 2006;29:826-830. 
11. Ezzat S, Kontogeorgos G, Redelmeier DA, et al. In vivo responsiveness of morphological variants of growth hormone-producing pituitary adenomas to octreotide. Eur J Endocrinol 1995;133:686-690. 
12. Bhayana S, Booth GL, Asa SL, et al. The implication of somatotroph adenoma phenotype to somatostatin analog responsiveness in acromegaly. J Clin Endocrinol Metab 2005;90:6290-6295. 
13. Turner HE, Thornton-Jones VA, Wass JA. Systematic dose-extension of octreotide LAR: the importance of individual tailoring of treatment in patients with acromegaly. Clin Endocrinol (Oxf) 2004;61:224-231.