Targeting the Kidney in Type 2 Diabetes: Rationale for Novel Treatment Approaches

Course Director

Vivian Fonseca, MD

Vivian Fonseca, MD
Tulane University Health Sciences Center
New Orleans, Louisiana


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Part 1 of a 2-part series

Dr. Fonseca provides expert feedback to the questions submitted by your peers during a recent survey on this topic.

Overview

The kidney plays an important role in the maintenance of glucose homeostasis, filtering up to almost 200 g/d of glucose. This mechanism is regulated by sodium glucose transporters in the proximal tubule. In patients with type 2 diabetes, this reabsorption process increases, putting more glucose into the bloodstream and thereby contributing to chronic hyperglycemia. The SGLT system can now be targeted through the use of SGLT2 inhibitors, which induce glucosuria, in turn reducing HbA1c. In this activity, Dr. Vivian Fonseca discusses the role of these new treatments, which may provide clinicians with oral agents that effectively lower glucose with an insulin-independent mechanism, with the added benefit of some weight loss, and without the risk of hypoglycemia.


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What is the role of sodium-glucose cotransporters (SGLTs) in maintaining glucose homeostasis?

Dr. Fonseca: What is the role of sodium glucose cotransporters, or SGLTs, in maintaining glucose homeostasis? And how does this role differ in patients with type 2 diabetes?

SGLTs are important in maintaining the balance of glucose. They are responsible for carrying glucose in the gut from the lumen of the gut into the cells and then into the blood. Very little glucose is excreted, because in the [proximal renal] tubule all this glucose is reabsorbed through transporters. This is a two-step process: The SGLTs absorb the glucose from the urine into the tubular cells, and then another transporter transports it into the blood.1-4

There are two important SGLTs in the kidney. One is the SGLT1, and the SGLT2 is probably more important [in the kidney], and is responsible for reabsorption of approximately 90% of the filtered glucose in the urine that reaches the proximal tubule.3-5 If these transporters are not functioning well, then glucose will be excreted in the urine.6 This is seen in patients with renal glycosuria, where other homeostatic mechanisms maintain a normal blood glucose.

There is a threshold above which these transporters are saturated and you reach a maximum reabsorptive capacity. This is usually considered to be around 180 mg/dL of blood glucose—and above that level, the renal threshold, it is no longer possible to reabsorb the large amount of glucose in the urine, and therefore you get glycosuria, and this occurs in diabetes.6,7

Since the transporter SGLT2 has such a major role in reabsorbing glucose in the renal tubule, inhibiting its action would lead to a lack of reabsorption, and therefore increase the glucose excretion in the urine. That can be exploited by using drugs that can block SGLT2 and increase glucosuria.

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Is increasing glucose secretion by the kidney really a good idea? Increased excretion of glucose has historically been a marker of poorer control/prognosis.

Dr. Fonseca: So is increasing glucose excretion by the kidney really a good idea? And what do we know about the potential long-term effects of glycosuria on renal function?

Well, we have historically used urine glucose excretion as a marker of poor glucose control, because you got glycosuria whenever you exceed the renal threshold of 180 [mg/dL] or so. However, that type of testing was abandoned when it became much easier and reliable to measure blood glucose using capillary blood.

Now, in terms of whether it's a good idea to increase glucose excretion, it all depends on what happens in overall glucose homeostasis. If you lose glucose in the urine, there is less reabsorption [and a net loss of calories from the body], and therefore whatever contribution that reabsorption is making towards maintaining blood glucose at a particular level is taken away. So even if it is 20 mg/dL to 40 mg/dL, which would be the level of lowering of blood glucose.

Over and above that, there is another advantage: calorie loss in the urine, which may contribute to overall energy homeostasis, and if you lose sufficient amounts, you will have weight loss.5

Narrator: Regarding the possibility of volume depletion with SGLT2 inhibitors, clinical trials for canagliflozin and dapagliflozin have shown that osmotic-related events, such as pollakiuria and polyuria, are slightly increased, and usually occur within the first few months of treatment only. These studies do not show a large increase in postural-related events or orthostatic hypotension, however.8,9

Dr. Fonseca: In terms of what the long-term effects of glycosuria on renal function are, this will need to be studied in long-term outcome studies. Animal data does not indicate any impact on renal function, and theoretically, that urine flows very quickly down into the bladder and is excreted. Therefore, it should have no real effect on renal function.10 There is a possibility that glucose in large amounts in the urine and in the bladder may make an individual more susceptible to [lower] urinary [tract] infections [or infections of the genitalia], and that has been documented in clinical trials. Fortunately, these are lower urinary infections, and not pyelonephritis, which is much more severe and serious. The consequences seen in clinical trials have not been [serious nor] detrimental [in the long term].3,4,8

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Do SGLT2s have a role in the management of this patient: a 65-year-old obese woman, on metformin, exenatide, and insulin glargine, with an HbA1c of 7.5%. She has mild renal impairment, with an eGFR of 55, as well as hypertension.

Dr. Fonseca: Do SGLT2 inhibitors have a role in the management of patients with renal impairment? For example, a 65-year-old obese woman on metformin, exenatide, and insulin glargine, with an A1c of 7.5%, who has mild renal impairment, with an eGFR of 55, as well as hypertension.

This is a common scenario in clinical practice. Metformin is contraindicated in patients with moderate and severe chronic renal insufficiency, and so is exenatide, but for different reasons.11,12 It is fairly safe to use metformin and exenatide in patients who have an eGFR of 55, although these patients need to be monitored. Once the eGFR falls below 45 or 40, metformin should be discontinued—and if at some point, maybe less than 30, exenatide should be discontinued.

The studies that have been done so far indicate no safety concern with using SGLT2 inhibitors in patients with renal impairment.13 However, once the eGFR falls below 40 or 45, they don't work very efficiently on lowering glucose, and there's a good explanation for that. This class of drugs relies on filtered glucose and blocks its reabsorption in the tubule, and thereby causes glycosuria, as we discussed earlier. In patients with renal impairment, filtration is inefficient, and so glucose is not very well filtered, and that effect on reabsorption in the tubule is irrelevant.  

Narrator: Canagliflozin, currently the only SGLT2 inhibitor approved by the FDA, is contraindicated in patients with an eGFR of <45;14 dapagliflozin is not recommended in patients with an eGFR of <60.15

Dr. Fonseca: So the issue is not so much a contraindication in patients with renal impairment for safety reasons, but just the lack of efficacy by the very mechanism of action. In terms of the patient we discussed, who has an eGFR of 55, it would be quite appropriate to use an SGLT2 inhibitor, just as it is still appropriate to use metformin and exenatide.

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References

  1. Wright EM et al. J Intern Med. 2007;261:32-43.
  2. Marsenic O. Am J Kidney Dis. 2009;53:875-883.
  3. Cefalu WT et al. 72nd Annual Meeting of the American Diabetes Association (ADA 2012). Poster 38-LB.
  4. Musso G et al. Ann Med. 2012;44:375-393.
  5. Neumiller JJ et al. Drugs. 2010;70:377-378.
  6. Bakris GL et al. Kidney Int. 2009;75:1272-1277.
  7. Nair S, Wilding JP. J Clin Endocrinol Metab. 2010;95:34-42.
  8. Ferrannini E et al. Diabetes Care. 2010;33:2217-2224.
  9. Stenlöf K et al. 48th Annual Meeting of the European Association for Diabetes (EASD 2012). Poster 058.
  10. Kim Y, Babu AR. Diabetes Metabol Syndr Obes. 2012:5:313-327.
  11. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. http://www.kidney.org/professionals/KDOQI/guideline_diabetes/guide2.htm. Accessed April 9, 2013.
  12. National Institute for Health and Clinical Excellence (NICE). The management of type 2 diabetes. http://www.nice.org.uk/nicemedia/live/12165/44320/44320.pdf. Accessed April 9, 2013.
  13. Yale JF et al. ADA 2012. Poster 41‐LB.
  14. Invokana (canagliflozin) Prescribing Information. http://www.janssenmd.com/pdf/invokana/PI-INVOKANA.pdf. Accessed May 7, 2013.
  15. European Medicines Agency. Summary of Product Charactertistics: Forxiga (dapagliflozin). http://ec.europa.eu/health/documents/community-register/2012/20121112124487/ anx_124487_en.pdf. Accessed May 7, 2013.

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The Role of SGLT2 Inhibition in Type 2 Diabetes

  1. Weighing the Evidence: SGLT2 Inhibition in Type 2 Diabetes