Successfully reported this slideshow.

Safety and Efficacy of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes Mellitus

717 views

Published on

Hyperglycemia leads to microvascular complications and
glucotoxicity, which results in metabolic abnormalities and
progression of the disease. Inspite of many drugs available,
managing hyperglycemia remains a challenge. We are still far from a molecule that will not cause hypoglycemia and weight gain and at the same time offer durable and optimum glycemic control. Inhibitors of renal sodiumeglucose cotransporter have recently been developed and this acts independent of beta cell and insulin resistance. This also causes weight loss and improves glycemic control without causing hypoglycemia.

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

Safety and Efficacy of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes Mellitus

  1. 1. Safety and Efficacy of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes Mellitus
  2. 2. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 1 6 e1 1 7 Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/apme Review Article Safety and efficacy of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus Tirthankar Chaudhury Senior Consultant, Diabetes and Endocrinology, Apollo Gleneagles Hospital, Kolkata, India article info Article history: Received 30 April 2013 Accepted 15 May 2013 Available online 6 June 2013 Keywords: Phlorizin Empagliflozin Glucosuria Hyperglycemia leads to microvascular complications and glucotoxicity, which results in metabolic abnormalities and progression of the disease. Inspite of many drugs available, managing hyperglycemia remains a challenge. We are still far from a molecule that will not cause hypoglycemia and weight gain and at the same time offer durable and optimum glycemic control. Inhibitors of renal sodiumeglucose cotransporter have recently been developed and this acts independent of beta cell and insulin resistance. This also causes weight loss and improves glycemic control without causing hypoglycemia. Many studies have shown that 1% reduction in HbA1c leads to 35% risk reduction in microvascular complications.1,2 Managing glucotoxicity leads to decreased insulin resistance and rate of beta cell failure.3,4 Hypoglycemia, weight gain and beta cell failure are the bigger obstacles in achieving HbA1c below 7%. A new molecule has been developed to reduce hyperglycemia by increasing glucosuria. 1. Physiology of glucose transport in kidney The maximum glucose transport capacity of the proximal tubule is 375 mg/min5 and almost all the glucose is absorbed in the S1 and S3 segment of proximal tubule by SGLT2 (sodiumeglucose transporter) and SGLT1 respectively. SGLT2 has low affinity and high capacity for glucose absorption responsible for 80e90% of the glucose absorption in the S1 segment of proximal tubule. SGLT1 has high affinity and low capacity for glucose absorption.6 Normally 180 L of plasma is filtered through the kidney and contains 162 g of glucose and all of which is reabsorbed. In diabetes the threshold of maximum glucose transport capacity (Tm) is increased. This is a maladaptive process happening due to excess glucose filtration and inherent function of the kidney to preserve glucose needed by the brain for neuronal nutrition. In diabetes, it is desired that the excess glucose is discarded to help achieve normoglycemia. SGLT2 E-mail address: tchaudhury67@yahoo.co.uk. 0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2013.05.011
  3. 3. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 1 6 e1 1 7 inhibitor is desired over SGLT1 inhibitor as the receptors of the later are also present in intestine. 2. SGLT2 inhibitors Dapagliflozin Canagliflozin Ipragliflozin Empagliflozin LX4211 PF04971729 TS-071 Phlorizin was the first SGLT2 inhibitor but with very poor bioavailability.5,7,8 Phlorizin administration in 90% pancreatectomized rats caused reversal of hyperglycemia, reversed insulin resistance and caused glucosuria and provided proof of concept.9 Initial studies started with O-glucosides but later C-glucosides entered phase 3 trials. These are showing dose dependent glucosuria, increased IGF1 levels, HbA1c reduction equivalent to Metformin and better with higher baseline HbA1c. Causes weight loss due to loss of calories. Dapagliflozin is the most ahead among SGLT2 inhibitors in studies. Initial studies demonstrated Dapagliflozin in doses (5, 25,100 mg/day) produced glucosuria (37, 62, 80 g/24 h). Significant decrease in fasting and postprandial glucose levels. Highly protein bound and minimal renal excretion. Major metabolite is an inert glucuronide (M15).10,11 In a head to head comparison between Metformin þ Sulphonylurea and Metformin þ Dapagliflozin, the results of reduction in HbA1c were comparable but the subjects in the study had relatively low HbA1c at the baseline. (11) Other SGLT2 inhibitors are also in various stages of development with similar encouraging results. Decreased glucose and sodium absorption with SGLT2 inhibitors would lead to more sodium to the juxtaglomerular apparatus and this may inhibit renineangiotensin system leading to less glomerular pressure and decreased hyperfiltration. So some renoprotection is expected.12 Increased rate of urinary tract infection has been noted. Also the incidence of vulvovaginitis and balanitis was slightly higher. Some reports of breast and bladder cancer but these tissues do not express SGLT2 receptors and intensive study in animals do not reflect carcinogenic potential. 5. Conflicts of interest The author has none to declare. references 1. 2. 3. 4. 5. 6. 7. 8. 9. Nonglycemic benefits observed Weight loss. Reduction in BP due to more sodium filtering out and decreased activity of RAS due to more sodium at juxtaglomerular junction. Some reduction in uric acid. 4. Safety Since ‘Familial renal glucosuria’ is a benign condition without any problem, SGLT2 inhibitors should not pose a problem. Conclusion This is a new molecule with potential to decrease HbA1c by 0.8% and is not affected by progressive beta cell failure. Author is presently engaged in the phase 3 trial of one of the SGLT2 inhibitors. 10. 3. 117 11. 12. DCCT Research Group. N Engl J Med. 1993;329:977e986. UKPDS. Lancet. 1998;352:837e853. DeFranzo RA. Banting lecture. Diabetes. 2009;58:773e795. Rosseti L, Giacarri A, DeFranzo RA. Glucose toxicity. Diabetes Care. 1990;13:610e630. Li A, Zhang J, Greenberg J, Lee T, Liu J. Discovery of nonglucoside SGLT2 inhibitors. Bioorg Med Chem Lett. 2011;21:2472e2475. Valtin H. Tubular Reabsorption. Boston: Little Brown and Company; 1983. Vick HD, Deidrich DF. Reevaluation of renal tubular glucose transport inhibition by phlorizin analogs. Am J Physiol. 1973;224:552e557. Ehrenkranz JR, Lewis NG, Khan CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev. 2005;21:31e38. Rosseti L, Shulman GI, Zawalich W, DeFranzo RA. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rat. J Clin Invest. 1987;80:1037e1044. Hussey E, Clark R, Amin D, et al. Early clinical studies to assess safety, tolerability, pharmacokinetics and pharmacodynamics of single dose of sergliflozin, a novel inhibitor of renal glucose reabsorption in healthy volunteers and subjects with type 2 diabetes mellitus. Diabetes. 2007;56(suppl):A189. Hussey E, Dobbins R, Stolz R, et al. A double blind randomized repeat dose study to assess safety, tolerability, pharmacokinetics and pharmacodynamics of three times daily dosing of sergliflozin, a novel inhibitor of renal glucose reabsorption in healthy overweight and obese subjects. Diabetes. 2007;56(suppl):A491. Arakawa K, Ishihara T, Oku A, et al. Improved diabetic syndrome in C57BL/KsJ-db/db mice by oral administration of the Naþ glucose cotransporter inhibitor T-1095. Br J Pharmacol. 2001;132:578e586.
  4. 4. A o oh s i l ht:w wa o o o p a . m/ p l o p a : t / w .p l h s i lc l ts p / l ts o T ie: t s / ie. m/o p a A o o wt rht :t t r o H s i l p l t p /w t c ts l Y uu e ht:w wy uu ec m/p l h s i ln i o tb : t / w . tb . a o o o p a i a p/ o o l ts d F c b o : t :w wfc b o . m/h A o o o p a a e o k ht / w . e o k o T e p l H s i l p/ a c l ts Si s ae ht:w wsd s aen t p l _ o p a l e h r: t / w .i h r.e/ o o H s i l d p/ le A l ts L k d : t :w wl k d . m/ mp n /p l -o p a i e i ht / w . e i c c a y o oh s i l n n p/ i n no o a l ts Bo : t :w wl s l e l . / l ht / w . t a h a hi g p/ e tk t n

×