|Year : 2010 | Volume
| Issue : 12 | Page : 556-560
A novel strategy for the treatment of diabetes mellitus - sodium glucose co-transport inhibitors
Asfandyar Khan Niazi, Saad Hameed Niazi
Shifa College of Medicine/Shifa International Hospital, Pitras Bukhari Road, H-8/4, Islamabad, Pakistan
|Date of Web Publication||9-Nov-2011|
Asfandyar Khan Niazi
Shifa College of Medicine/Shifa International Hospital, Pitras Bukhari Road, H-8/4, Islamabad
Source of Support: None, Conflict of Interest: None
Background: Diabetes is one of the most common chronic diseases, affecting almost 3 million in Canada alone and is characterized by increased blood glucose levels. Treatment varies from lifestyle changes to oral anti-diabetics and/or insulin. Sodium glucose co-transport inhibitors may offer promising treatment for patients suffering from diabetes. The inhibitors act by increasing the loss of glucose in urine by decreasing the reabsorption of glucose from the proximal tubules of nephrons. Aims: The aim of this review was to assess the efficacy of sodium glucose co-transport inhibitors in the treatment of diabetes as well as any adverse effects. Materials and Methods : Databases such as MEDLINE, COCHRANE and EMBASE were systematically searched for literature on the efficacy of sodium glucose co-transport inhibitors in improving the glycemic control of patients with diabetes. Results: Research showed that sodium glucose co-transport inhibitors significantly decreased blood glucose levels by increasing glucosuria. Due to the diuretic effects of these inhibitors, diabetic patients who were suffering from hypertension showed a decrease in blood pressure. The caloric loss associated with these inhibitors resulted in weight loss as well. The most common adverse effect seen in patients on these medications was mycotic infection of the urinary or genital tract. Conclusion: Sodium glucose co-transport inhibitors may be an effective line of treatment for diabetes. Although short-term research has shown these drugs to be safe and well-tolerated, studies should be conducted to assess the long-term effects of these drugs.
Keywords: Diabetes mellitus, SGLT-2 inhibitors, glycemic control, glucosuria.
|How to cite this article:|
Niazi AK, Niazi SH. A novel strategy for the treatment of diabetes mellitus - sodium glucose co-transport inhibitors. North Am J Med Sci 2010;2:556-60
|How to cite this URL:|
Niazi AK, Niazi SH. A novel strategy for the treatment of diabetes mellitus - sodium glucose co-transport inhibitors. North Am J Med Sci [serial online] 2010 [cited 2020 Oct 1];2:556-60. Available from: http://www.najms.org/text.asp?2010/2/12/556/86404
| Introduction|| |
Diabetes mellitus is a serious condition that is characterized by fatigue, polyuria, polyphagia, polydipsia, frequent infections, numbness in the hands or feet and weight change. It is the world's fourth leading cause of death and affects an estimated 246 million globally and 3 million in Canada alone  With a further 7 million  developing diabetes each year, this number is expected to hit 438 million worldwide by 2030 [Table 1].
|Table 1: The country and number of people suffering from diabetes mellitus|
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In the developing and the developed world, the population in general lives a sedentary lifestyle, leading to an increased number of those who are overweight or obese. The spread of metabolic syndrome has also exacerbated the number of diabetic patients. Those who are over 40 years of age, are overweight, have high cholesterol or triglyceride levels, have a close relative with diabetes, are smokers, have high blood pressure, have had gestational diabetes or pre-diabetes are at an increased risk of developing diabetes. Diabetes may be any of three types: type 1, type 2 or gestational. Some patients suffer from pre-diabetes, in which the blood glucose level of the patient is raised above normal, but is not sufficient for the blood glucose range for diabetes. Diabetes type 1 involves decreased secretion of insulin by the pancreas, while diabetes type 2 refers to increased resistance of cells to insulin.
Current treatment for diabetes
Treatment modalities employed for diabetic patients include education, lifestyle modifications regarding physical activity, weight management and diet. Anti-hyperglycemic agents, which include Alpha-glucosidase inhibitors, DPP-4 inhibitors, Sulfonylureas and meglitinides, Thiazolidinediones and biguanides, lower the blood glucose level. Insulin may also be used if the blood glucose level cannot be controlled by oral medications [Table 2].
Oral anti-diabetic drugs act in various ways to lower blood glucose levels. Alpha-glucosidase inhibitors prevent the breakdown of starches, which slow the entry of glucose into the blood stream. The blood glucose level can then be matched with an impaired insulin response or sensitivity. Biguanides reduce the amount of glucose released into the blood stream by the liver and muscles and increase uptake of glucose by them, in effect reducing the blood glucose level. Dipeptidyl peptidase-4 (DPP-4) increases blood concentration of the incretin GLP-1 (glucagon-like-peptide-1), which inhibits glucagon release, the effect of which decreases blood glucose, but, more significantly, increases insulin secretion. Sulfonylureas and meglitinides stimulate the beta cells in the pancreas to increase the endogenous release of insulin; insulin, in turn, decreases the blood glucose level. Thiazolidinediones help to influence insulin-sensitive genes, which enhance the production of messenger RNAs (mRNAs) of insulin-dependent enzymes. Thus, insulin works well in the muscles and also reduces the liver's glucose production.
Adverse effects of oral anti-diabetics
All of the oral anti-hyperglycemic drugs are accompanied by some undesirable side effects. The use of alpha-glucosidase inhibitors may cause diarrhea, bloating or flatulence. Since DPP-4 acts as a suppressor of neoplasms, patients on DPP-4 inhibitors may be at increased risk of developing different types of tumors and cancers. Sulfonylureas and meglitinides produce excessive secretion of insulin and may cause hypoglycemia. Another side effect may be weight gain due to increased insulin secretion, resulting in greater utilization of glucose by the cells. The use of thiazolidinediones may be associated with liver and heart disease. Many patients with biguanide experience dyspepsia and lactic acidosis [Table 3].
SGLT-2 Inhibitor - A Novel Therapeutic Agent
Among the other experimental treatments available, one is the use of sodium glucose co-transporter (SGLT-2) inhibitors. The kidneys play a major role in glucose homeostasis by contributing in two ways. The kidneys can add glucose to the blood stream in periods of fasting by gluconeogenesis or they may remove excess glucose from the blood when present. All of the blood contents, except blood cells and proteins, are filtered into Bowman's capsule of the glomeruli of the kidneys through the process of ultrafiltration. The blood plasma filtered into Bowman's capsule also contains all of the blood's glucose, which is completely reabsorbed into the blood vessels from the proximal convoluted tubules in normal individuals. Approximately 180 g of glucose is filtered daily in the glomeruli of a normal healthy adult. Unless the blood contains an excess of glucose, all of the filtered glucose is reabsorbed with only negligible amounts of glucose being excreted in the urine. The reabsorption of glucose from the proximal tubules of the nephrons to the capillaries surrounding them consists of two steps. First, the glucose must be transported from the tubules into the tubular epithelial cells, and then are transported from the tubular cells to the blood vessels. The transport of glucose from the tubules into the tubular epithelial cells is accomplished by sodium glucose co-transporters (SGLTs). SGLTs encompass a family of membrane proteins that act as carrier proteins for the secondary active co-transport of glucose, amino acids and some other substances across the inner tubular membrane of proximal renal tubules as well as the intestinal epithelium. The kidneys contain two sodium glucose co-transporters, SGLT-2 and SGLT-1, arranged in a series along the length of the proximal tubules. The low-affinity transporter, SGLT-2, is responsible for the reabsorption of most of the glucose in the kidneys.
Mechanism of Action of SGLT-2 Inhibitors
SGLT2 inhibitors block the reabsorption of filtered glucose, leading to the excretion of glucose in urine, bringing the blood glucose levels back to normal. The mechanism is as follows: as the blood plasma is filtered into Bowman's capsule, all the glucose in the blood is also filtered into Bowman's capsule. The glucose passes along to the proximal tubule, as the SGLT-2 inhibitors have blocked the reabsorption of glucose into the blood. Most of the glucose that is filtered into Bowman's capsule is excreted in the urine, thus lowering the blood glucose level of the patient. This action holds potential promise for patients suffering from diabetes mellitus in terms of improvements in glycemic control. In addition, the loss of glucose in the urine, which is associated with SGLT-2 inhibition, provides an additional benefit of weight loss and the diuretic properties of SGLT-2 inhibition may help counter hypertension in diabetics. Although the action of these inhibitors would suggest that they may be effective for both type 1 and type 2 diabetes, research to date has focused exclusively on type 2 diabetes.
| Methods|| |
A systematic search was performed for clinical trials and pre-clinical information using the MEDLINE, COCHRANE and EMBASE literature databases. In addition to original studies, systematic reviews were also identified and their references examined for other studies. The search was limited human researches, which were published during or after 2005 and included searches for sodium glucose co-transport inhibitor, SGLT inhibitor, SGLT-2 inhibitor diabetes, renal transporter inhibitor diabetes and sodium glucose co-transporter diabetes. The studies which had an unreliable study design,, were limited to a specific ethnic group or reported incomplete results were excluded from this review. The literature was also assessed for quality of methods independently by the two authors and the results were compared.
Fifty-eight original studies and reviews were selected with seven additional studies identified through other sources. Of the total 65 articles, 38 were focused on rats and therefore were excluded. The remaining 27 articles were assessed for quality, relevance to this review, clarity and completeness of reported results and study methods. After a detailed analysis, six studies were identified for inclusion in this review [Figure 1].
| Results|| |
Most of the trials had been performed with dapagliflozin, which is a SGLT-2 inhibitor. All of the research reported that the SGLT-2 inhibitors were significantly effective in decreasing blood glucose levels and in weight reduction. However, urinary and genital tract infections were found to be a side effect in patients taking these medications. In three randomized controlled trials with SGLT-2 inhibitors ,, , significant improvement in glycemic control was reported. Similar results were reported in another randomized controlled trial  . This trial compared the efficacy of different doses of dapagliflozin with insulin. Patients were divided into three groups randomly; the first group was given insulin, the second group 10 mg dapagliflozin and the third group 20 mg dapagliflozin. Although the patients receiving 20 mg dapagliflozin showed the most decrease in blood glucose levels, this group also showed more genital infections than the other groups. A randomized controlled trial  carried out in type 2 diabetic patients showed significant glucosuria and thus reduction in blood glucose levels. The patients also demonstrated decrease in serum uric acid and increase in serum magnesium, serum phosphate, hematocrit and urine volume, although these changes were small.
Sergliflozin etabonate, another SGLT-2 inhibitor, has also been shown to decrease blood glucose levels. In a clinical trial  , healthy and type 2 diabetic patients were given sergliflozin etabonate. The patients showed decreased blood glucose levels, although the effect was not very significant. There are few clinical trials performed in humans, however, there have been a significant number of trials carried out in rats. The trials  conducted in rats showed improved glycemic control. The same effects were also seen in mice and dogs, as demonstrated in many trials , . Sergliflozin etabonate has been shown to increase glucosuria and decrease blood glucose levels in rats  . Remogliflozin etabonate, another SGLT-2 inhibitor, has been documented as a potential anti-hyperglycemic drug in rodent models by improving hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and insulin resistance  .
Adverse Effects of SGLT-2 Inhibitors
The adverse effects of SGLT-2 inhibitors may include fatigue, hypoglycemia, increased urine output, increased hematocrit and mycotic genital or urinary tract infections. Constipation, diarrhea and nausea are other possible side effects. Small changes in serum uric acid, magnesium and phosphate may also occur.
Concerns related to SGLT-2 inhibition include glucose elevation in the urine that can theoretically lead to urinary tract and genital infections, electrolyte imbalances and increased urinary frequency. Although short-term studies have shown the safety and efficacy of SGLT-2 inhibitors, long-term studies are lacking. The observation that individuals with familial renal glycosuria, in which there is a mutation in the genes encoding for SGLT-2 proteins, maintain normal long-term kidney function provides some reassurance that this mode of action will not adversely affect renal function. Similarly, comparisons between SGLT-2 inhibitors and other treatment options for diabetes type 2 have also not yet been conducted.
| Conclusion|| |
There are two means of glucose transport, facilitative and secondary active transport, each of which involves different classes of transporters. Facilitative transport, which is driven by the concentration gradient across cellular membranes, occurs in essentially all cell types and is controlled by the GLUT transporter family. Secondary active transport is the first step in transcellular glucose transport in the intestine and kidney and is mediated by the SGLT transporter family. SGLT-2 is a high-capacity, low-affinity transporter expressed chiefly in the kidney and accounts for approximately 90% of glucose reabsorption. SGLT-2 inhibitors block the reabsorption of filtered glucose, leading to glucosuria. In addition, the glucosuria seen with SGLT2 inhibition is associated with caloric loss, thus providing a potential benefit of weight loss. The diuretic effect observed with SGLT-2 inhibitors may also help to control hypertension. Although long-term safety data are lacking, studies to date have generally found SGLT-2 inhibitors to be safe and well-tolerated.
| Further research|| |
SGLT-2 inhibitors are a promising treatment for patients with diabetes type 1 and type 2. Although the current research has mainly focused on its efficacy in improving the glycemic control in patients with diabetes type 2, theoretically it may also benefit patients with diabetes type 1. The efficacy of SGLT-2 inhibitors has been tested in rats, mice and dogs through many trials, although trials in humans are severely lacking. Trials assessing the long-term usefulness of these drugs in diabetic patients have not been conducted as yet. The research on SGLT-2 inhibitors has mainly focused on Dapagliflozin; other SGLT-2 inhibitors should also be assessed in humans. SGLT-2 inhibitors may also benefit patients suffering from renal glucosuria due to diabetes mellitus as well as other causes (e.g. familial renal glycosuria and obesity, etc.). All of the effects of SGLT-2 inhibitors on these diseases should be investigated.
| References|| |
|1.||Danièle P, Sara M. Bariatric surgery for the management of type 2 diabetes: Where does it belong. Can J Diabetes 2010;23(3):1-13. |
|2.||Trial watch: SGLT-2 inhibitor shows promise in type 2 diabetes, 2010. (Accessed November 5, 2010, at http://www.nature.com/nrd/journal/v9/n3/full/nrd3127.html). |
|3.||Komoroski B, Vachharajani N, Feng Y. Dapagliflozin, a novel selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin Pharmacol Ther 2009; 85(5):513-519. |
|4.||Miriam E. Dapagliflozin lowers glucose by raising glycosuria. Clin Endocrinol News 2008; 3(7):15. |
|5.||Wilding JP, Norwood P. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care 2009;32(9):1656-1662. |
|6.||James F, Vincent W, Enrique M. Sodium glucose co-transport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009;32(4):650-657. |
|7.||Hussey EK, Clark RV, Amin DM. Single-dose pharmacokinetics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy volunteers and patients with type 2 diabetes mellitus. J Clin Pharmacol 2010; 50(6):623-635. |
|8.||Katsuno K, Fujimori Y, Takemura Y. Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level. J Pharmacol Exp Ther 2007; 320(1):323-330. |
|9.||Han S, Hagan DL, Taylor JR. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 2008; 57(6):1723-1729. |
|10.||Meng W, Ellsworth BA, Nirschl AA: Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem 2008; 51(5):1145-1149. |
|11.||Fujimori Y, Katsuno K, Nakashima I. Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose co-transporter (SGLT2) inhibitors, exhibits anti-diabetic efficacy in rodent models. J Pharmacol Exp Ther 2008; 327(1): 268-276. |
[Table 1], [Table 2], [Table 3]