MD Conference Express ADA 2013 - (Page 5)

Bernard Zinman, CM, MD, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada, discussed targeting mechanisms of glucose absorption and excretion in the treatment of T2DM. The alpha-glucosidase inhibitors [AGI] are a drug class that modifies glucose absorption by inhibiting the breakdown of carbohydrates in the upper intestine. Interestingly the AGIs also modify the secretion of gastrointestinal (GI) peptides like GLP1 but have modest efficacy. However, the tolerability of AGI is a major problem and their widespread acceptance in the United States has been limited by frequent GI side effects, such as diarrhea, flatulence, and abdominal distention. A new strategy focuses on targeting the sodium glucose cotransporter-2 (SGLT-2), which is an important mechanism responsible for the filtered glucose to be reabsorbed in the proximal tuble of the kidney. Nonetheless the capacity of the two transporters, SGLT-1 [high-affinity, low-capacity] and SGLT2 [low-affinity, high-capacity] to reabsorb glucose is limited; therefore, excess blood glucose levels above ~180 mg/dL causes glucose to remain in the urine filtrate [Gerich JE et al. Diabetic Med 2010]. However, in patients with poorly controlled diabetes there is an adaptive response whereby SGLT-2 is upregulated so that reabsorption of glucose is increased. Thus SGLT-2 inhibitors reduce glucose reabsorption in the kidney and with resultant glucosuria [increased urinary glucose]. Several SGLT-2 inhibitors that have shown promising results in clinical trials include empagliflozin [Hach T et al. Diabetes 2013], canagliflozin (Figure 2) [Schernthaner G et al. Diabetes Care 2013], and dapagliflozin [FDA. Dapagliflozin Advisory Committee Meeting. http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ EndocrinologicandMetabolicDrugsAdvisoryCommittee/ UCM264314.pdf. Published July 19, 2011]. Figure 2. Effect of Canagliflozin Versus Sitagliptin on HbA1C Levels Sitagliptin 100 mg Canagliflozin 300 mg 8.2 8.0 Mean (±SE) HbA1C (%) of phosphatidylinositol-3 kinase [Croze ML et al. Biochimie 2013], inositol metabolites, inhibition of PTEN [Pal A et al. N Engl J Med 2012], and inhibition of inositol phosphatases. Prof. Tahrani pointed out that nonpharmacologic interventions, such as weight loss, adequate sleep, and obstructive sleep apnea are also important to consider. For example, patients who were sleep restricted in a laboratory study had a significant decrease in glucose tolerance, acute insulin response to glucose, glucose effectiveness, and insulin sensitivity as compared with a well-rested state [Leproult R, Van Cauter E. Endocr Dev 2010]. Robert R. Henry, MD, University of California, San Diego, La Jolla, California, USA, presented information on treating inflammation in adipose and skeletal tissues. Individuals that tend to accumulate adipose tissue in the visceral region are more likely to have inflammation in their adipose tissue. In addition, patients with T2DM have greater fat deposition in the visceral versus subcutaneous region, as compared with patients without diabetes. Dr. Henry highlighted that adipose tissue produces chemicals called adipokines, which can have autocrine, paracrine, or endocrine signaling effects [Blüher M. Diabetes Metab J 2012]. As adiposity increases, the adipokines that are secreted become predominantly proinflammatory. A prevailing theory of a mechanism underlying insulin resistance in obesity is lipotoxicity [Johnson AM, Olefalsy JM. Cell 2013]. Excessive caloric intake can result in cellular stress and tissue inflammation, which can lead to insulin resistance [Odegaard JI, Chawla A. Science 2013]. Ultimately, inflamed adipose tissue with some level of metabolic dysfunction demonstrates an altered milieu as compared with lean adipose tissue with normal metabolic function [Ouchi N et al. Nat Rev Immunol 2011]. Adipocytes that live in an inflamed tissue have reduced insulin action [Odegaard JI, Chawla A et al. Science 2013]. A recent study demonstrated that treatment with salsalate, a tumor necrosis factor-a inhibitor, resulted in a significant decrease in white blood cell count, neutrophil count, and lymphocyte count over a 48-week period [Goldfine AB et al. Diabetalogia 2013]. In addition, salsalate treatment caused a reduction in nuclear factor kappalight chain enhancer (NF-kB) activity in visceral adipose tissue, compared with placebo, after 12 weeks of treatment. Importantly, NF-kB is a major player in inflammatory signaling pathways [Reilly SM et al. Nat Med 2013]. Inflammation of skeletal muscle is increased in obese patients compared with lean patients, as measured by macrophage infiltration and, as body mass index increases, so does the macrophage content of skeletal muscle [Varma V et al. Am J Physiol Endocrinol Metab 2009]. However, other studies have suggested that this finding may be due to cross-contamination by adipose tissue that is found within skeletal tissue [Tam CS et al. Obesity 2012]. 7.8 7.6 7.4 7.2 7.0 6.8 0 6 12 18 26 Weeks 34 42 52 Reproduced from Schernthaner G et al. Canagliflozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea: A 52-week randomized trial. Diabetes Care 2013;36(4):908-913. With permission from the American Diabetes Association. Official Peer-Reviewed Highlights From the American Diabetes Association 73rd Scientific Sessions 2013 5  http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM264314.pdf http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM264314.pdf http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM264314.pdf http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM264314.pdf

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MD Conference Express ADA 2013

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