Overview of New Strategy for Treatment of T2DM: SGLT2 Inhibiting Oral Antidiabetic Agents
Author and Curator: Aviral Vatsa, PhD, MBBS
Type 2 diabetes mellitus (T2DM) is a chronic disease, which is affecting widespread populations in epidemic proportions across the globe 1. It is characterised by hyperglycemia, which if not controlled adequately, eventually leads to microvascular and metabolic complications (Fig 1). Traditionally, T2DM management includes alteration in lifestyle, oral hypoglycemic agents and/or insulin. The present pharmacological approaches predominantly target glucose metabolism by compensating for reduction in insulin secretion and/or insulin action. However, these approaches are often limited by inadequate glucose control and the the possibility of severe adverse effects such as hypoglycemia, weight gain, nausea, and sometimes lactic acidosis 2–4 (Fig 1). Hence the search for new drugs with different mechanism of action and with little side affects is key in providing better glycemic control in T2DM patients and hence offering better prognosis with reduced morbidity and mortality.
Figure 1 (credit: aviral vatsa): Short overview of Type 2 diabetes mellitus (T2DM): complications, present therapeutic approaches and their limitations.
Along with pancreas, our kidneys play a vital role in regulating glucose levels in the plasma. Under physiological conditions, kidneys absorb 99% of the plasma glucose filtered through the renal glomeruli tubules. Majority i.e. 80-90% of this renal glucose resorbtion is mediated via the sodium glucose co-transporter 2 (SGLT2) 5,6. SGLT2 is a high-capacity low-affinity transporter that is mainly located in the proximal segment S1 of the proximal convoluted tubule 6. Inhibition of SGLT2 activity can thus induce glucosuria which inturn can lower blood glucose levels without targeting insulin resistance and insulin secretion pathways of glucose modulation (Fig 2).
Figure 2 (credit: aviral vatsa): Schematic overview of regulation of plasma glucose by sodium glucose co-transporter (SGLT).
Thus inhibition of SGLT2 provides a novel way to modulate blood glucose levels and consequently limit long term complications of hyperglycemia 7,8. Moreover, SGLT2 inhibitors will selectively target the renal glucose transportation and spare the counter regulatory hormones involved in glucose metabolism because SGLT2 is almost exclusively located in the kidneys. This novel way of glucose modulation will likely avoid severe side affects, e.g. hypoglycemia and weight gain, that are seen with present antidiabetic pharmacological agents.
Agents currently under development
Table below gives an overview of the SGLT2 inhibotors in development.
(Credit: Chao et al 2010)
In summary, increasing urinary glucose excretion represents a new approach to addressing the challenge of hyperglycaemia. SGLT2 inhibitors may have indications both in the prevention and treatment of T2DM, and perhaps T1DM, with a possible application in obesity. Further studies in large numbers of human subjects are necessary to delineate efficacy, safety and how to most effectively use these agents in the treatment of diabetes.
Bibliography
- Diabetes Atlas. International Diabetes Federation, (2009) at <www.diabetesatlas.org>
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 837–853 (1998).
- Buse, J. B. et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27, 2628–2635 (2004).
- Inzucchi, S. E. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 287, 360–372 (2002).
- Brown, G. K. Glucose transporters: Structure, function and consequences of deficiency. Journal of Inherited Metabolic Disease 23, 237–246 (2000).
- Wright, E. M. Renal Na+-glucose cotransporters. Am J Physiol Renal Physiol 280, F10–F18 (2001).
- Chao, E. C. & Henry, R. R. SGLT2 inhibition — a novel strategy for diabetes treatment. Nature Reviews Drug Discovery 9, 551–559 (2010).
- Ferrannini, E. & Solini, A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nature Reviews Endocrinology 8, 495–502 (2012).
Dr. Aviral
I like very much the credit for the Figures.
This post will go to Metabolic e-Book under the Editorial of Larry and Ritu.
Please design similar Figures for the Nitric Oxide e-Book. the Introduction to the book should have a figure about the flow among the chapters.
You and Larry have to complete the Table of Contents, Introduction and Book Title proposal for last week in December.
Please have all November posts before 12/1/2012.
Thank you
Thanks Aviva, I am thinking of making such figures for the book as i guess these figures are quite helpful in understanding the concepts. I ll dedicate more time to the book from first week onwards and will aim to achieve the targets you mentioned.
Nice read! Thanks for the post..
SGLT-2 inhibitors also have benefits of blood pressure lowering too. Since their mechanism is insulin-independant (urinary glucose excretion) they could work best if combined with other antidiabetic medications (metformin, DPP-4 inhibitors etc.) that increase glucose absorption or enhance insulin production.
Dapagliflozin has recently been approved for use in the European Union. It would be interesting to see how this drug class is going to grow.
Thanks Neethu for your comments. Indeed it will be very interesting how these SGLT2 inhibitors perform with other drugs and it is always exciting that some promising drugs are brought to bedside. And as you said, since they are insulin independent they bypass the ‘standard’ metabolic pathways in glucose maintenance.
I’ll have to consider being in contact with Aviral Vatsa using Skype as well as our current method.
I have an assignment to clean up before December 1.
When we have the book in order, then I can give attention to the Metabolism.
I have been interested in Type2DM for years, but I was in a position to contribute to the downstream effects.
I think that the complexity of this disease is as challenging as cancer. I can only hope with reservations that this new approach will succeed. If it succeeds, then the measurement of glucosuria by strip glucose oxidase or glucose dehydrogenase will become a thing of the past. I have to read up on this. I am to assume that the glucose transporter sets the glucose threshold.
When I was excited about DM as a medical student, my lecturer in endocrinology, then a new field, was a brilliant physician who died in a lecture of ruptured aortic aneurysm (Marfan’s).
I saw one of the very first cases of non-ketotic hyperglycemic lactic acidosis at Detroit Receiving Hospital with no history of DM. I also saw the only case of pheochromocytoma of the Organ of Zuckerkandl in the experience of the Surgery Chairman.
I don’t know what the effect of this is expected have on microalbuminuria. The metabolic evolution of diabetic crisis, seen commonly in type I DM in children in the past, but also seen with Type 2 DM, is very much like the evolution of sepsis—MOF—shock and CV collapse.
Thanks Larry for your comments and indeed we should catch up over skype. I ll get in touch with you after 2nd december and I ll have relatively more time to dedicate to the NO book. I agree with you on the intricasies involved in DM. Besides the etiopathological challanges it poses immense challanges in its multi systemic effects and it is exciting that after a substantial period of trying similar approaches there is a new target, which hopefully will not interfere with the insulin dependent interventions.
I enjoy your recollections of past events and stories pertaining to the posts…please keep them coming.
It is interesting idea, however I have a question.
The SGLTs are known as symporters or cotransporters, since both sodium and glucose are transported in the same direction across the membrane. Sodium is one of the electrochemical driving forces in the transport through the membrane, it’s also requires ATP to support transport of glucose across the apical membrane against an uphill glucose gradient.
How does inhibition of SGLT by the suggested medication avoids the sodium gradient disturbances?
Thanks for your comments Irina. It remains to be seen how precisely these drugs will alter the Na dynamics and if these alterations will have significant effects on physiology or disease modulation. But here is an excerpt from Chao et al regarding the long term safety of these drugs, hope it helps:
“Perhaps the most compelling evidence for the long‐term safety of this class of agents that affect glucose reabsorption is found from studying individuals with familial renal glycosuria — an autosomal genetic disorder resulting from mutations in the gene encoding SGLT2; its mode of transmission is thought to be co‐dominant with incomplete penetrance. Familial renal glycosuria is characterized by persistent isolated glycosuria of approximately 10–120 g per day, in the face of normal fasting serum glucose, normal glucose tolerance tests, the absence of any signs of general renal tubular dysfunction or other pathological changes, and normal life expectancies. Individuals with familial renal glycosuria usually report no complaints, and only rarely have hypoglycae‐
mia or hypovolaemia.”