Diabetes is a systemic disease characterized by insulin resistance and relative insulin deficiency due to progressive beta cell dysfunction. Management aims at achieving an HbA1c < 6.5 (AACE), treatment of hypertension and dyslipidemia and risk factor reduction. The presently available anti-hyperglycemic drug therapy is thwarted by the progressive nature of the disease and dose-limiting side effects like hypoglycemia (sulphonylureas and insulin) and weight gain (sulphonylurea, insulin and TZDs). In UKPDS trial, disease progressed despite intensification of therapy1. Similarly, ADOPT showed a worsening of glycemic status over the years after an initial diabetic control with glibenclamide, metformin and rosiglitazone therapy (in decreasing order)2. ACCORD had to be prematurely stopped because of significantly increased incidence of sudden cardiovascular death as a result of possible hypoglycemia in the intensive glycemic control arm. In the Steno diabetes trial only 15% of the aggressively managed diabetics maintained an HbA1c of < 6.5%3. Hence there is a need to understand and focus on newer modalities for maintaining euglycemia. Incretin mimetics and DPP IV inhibitors hold promise but long term data are unavailable and studies are skeptic on effects of non-specific DPP inhibition and risk of pancreatitis.
Kidneys have for long been studied as an organ affected by long term microvascular complication of uncontrolled hyperglycemia. Kidneys play an important role in maintaining normal glucose homeostasis. They contribute for 5-10% of the total glucose output of the body by gluconeogenesis. Blood glucose is freely filtered through the glomerulus and later completely reabsorbed form the proximal convoluted tubules. This reabsorption process is saturated at the tubular maximum (tmax) corresponding to blood glucose levels of approx 180 mg/dl over which glucosuria develops in proportion to blood glucose levels. However tmax for individual nephrons varies ranging from 160-180mg/dl and this phenomenon has been termed as splay.
Glucose reabsorption is mediated through sodium dependent glucose transporters (SGLT1&2) present in the proximal convoluted tubule. SGLT1 is a high affinity low capacity glucose/galactose receptor present in gut, brain, liver, lung and kidney. SGLT1 is responsible for most of the glucose and galactose absorption in the gastrointestinal tract but has low level of expression in S3 segment of PCT. Mutations of SGLT1 cause glucose and galactose reabsorption and mild renal glucosuria. SGLT 2 is a low affinity high capacity transporter expressed exclusively in the S1 and S2 segment of the renal PCT and the main channel responsible for renal glucose reabsorption (90%). Inhibiting the renal reabsorption of glucose through the SGLT 2 receptor blockade is being investigated as a possible therapeutic intervention.
Renal glucosuria has long been known and used as a diagnostic modality in diabetes. High levels of glucosuria has been linked with polyuria and increased thirst due to osmotic fluid loss and loss of high energy fuel. Individuals with blood sugar levels 50% in excess of the renal threshold show a renal glucose excretion of over 144gm/day equivalent to loss of 600 kcal daily. This mode could therefore be paradoxically utilized to maintain euglycemia at blood glucose levels less than the renal threshold esp. in obese type II diabetics and help create a negative energy balance.
Researchers are still skeptic regarding the possible adverse effects of promoting renal glucosuria, but till date there are none has been reported in the studies on SGLT2 inhibitors. Studies conducted on individuals with rare familial renal glucosuria have shown no harmful effects of renal glucosuria in the absence of diabetes. These individuals have mutations of varying portions of the SGLT2 coding gene presenting as varying levels of renal glucosuria4,5, usually diagnosed during either routine medical screening or as contacts of affected individuals. Most of the affected individuals are healthy and reported to have normal lifespan. Salt wasting with natriuresis and activation of rennin angiotensin system has been reported in an isolated case with SGLT2 mutation, with over 60gm/day of glucosuria6. Concern has been raised regarding the possible increased incidence of bacterial or fungal infections of the urogenital tract. However, little evidence exists to suggest correlation of increased bacterial urogenital infections with diabetes. Increased incidence of vaginal candidiasis and balanitis in men has been reported in diabetics but it is not known if it is a result of systemic hyperglycemia or renal glucosuria7.
Non-specific inhibition of renal and intestinal glucose transport by phlorizin has been well known to improve glucose control in animal studies but is unsuitable for clinical use. Being non-selective it causes intestinal malabsorption of glucose and galactose and also has an active metabolite that inhibits facilitative glucose transporter GLUT-1, which interferes with glucose uptake in a variety of tissues. T1095 a (non-specific SGLT inhibitor) and Serglilfozin (7 imes more selective for SGLT2) have shown increase in glucosuria, modest weight loss and no hypoglycemia in animal models8-10. These initial positive results form the proof of principle for discovering more selective SGLT2 inhibitors. Recent development of selective SGLT2 inhibitors of renal glucose reabsorption like Dapagliflozin, remogliflozin, ISIS 388626 has shown promise and are in various phase of trials.
Dapagliflozin is a selective SGLT2 inhibitor 1000 times selective over SGLT1. When administered in doses ranging from 5-100 mg daily it has shown to increase glucose excretion to 45gm/day in healthy volunteers and 80gm/day in diabetics and 2 week administration improved glucose tolerance11. In a 12 week study comparison of Dapagliflozin (2.5-50mg OD) with placebo and metformin (1.5 gm/day in XR formulation) in treatment naïve newly diagnosed type II diabetics, a dose dependent reduction in fasting glucose, glucose area under the curve and HbA1c was reported for all dose ranges above 2.5 mg/day11,12. A significant increase in glucosuria (51.8 to 85gm/day) and urine volume (107 to 470ml/day) was reported in comparison to placebo and metformin therapy. Only few patients (1.4%) reported polyuria while none reported nocturia. A weight loss of 2.5-3.4 kg was reported in the Dapaglifozin arm in comparison to 1.2 and 1.7kg in the placebo and metformin arm. Incidence of bacterial genitourinary infection was similar in active treatment and placebo group, however a few cases of fungal genitourinay infections were reported with high dose of therapy. Increased sodium excretion without a drop in serum sodium levels was observed consistent with the mode of action, possible accounting for the drop in systolic blood pressure observed with the active treatment group. Results of ongoing phase 3 studies are still are awaited.
Remogliflozin is a novel SGLT2 inhibitor, which has been shown to be effective in Zucker diabetic fatty (ZDF) rat models13. Similarly ISIS 388626, a RNAase H chimeric antisense oligonucleotide through a in vivo gene therapy approach in rodents and dogs has shown promise by knocking out the expression of SGLT2 gene. It is so designed to selectively target the renal PCT and produces 80% SGLT2 gene expression by once weekly expression producing increase in glucosuria, improvement in blood glucose control and lowering of HbA1c in animal models14.
Practical advantages of SGLT2 inhibition
In type II diabetes primary aim of therapy is control of hyperglycemia, firstly bacause it is the means of monitoring glucose homeostasis, hyperglycemia is linked with microvascular complications and to a lesser extent with macrovascular complications and thirdly because it is in itself a self-perpetuating cause of diabetes (glucotoxicity). SGLT2 inhibition addresses these therapeutic goals, by promoting renal glucose loss and control of plasma glucose levels with reversal of glucotoxicity with reduction of hepatic glucose output15. SGLT2 inhibition produces an energy loss of 100-300kcal/day equivalent to intestinal lipase inhibitor orlistat16 and hence carries a potential for weight reduction in addition to glucose control. SGLT2 inhibitors do not stimulate insulin secretion and therefore monotherapy does not carry risk of hypoglycemia. Inhibition of sodium absorption in the PCT mediated by SGLT2 inhibition and concomitant fall in systolic blood pressure analogous to thiazide type diuretics may translate into a useful adjunct of therapy. A recently published study reported that SGLT2 expression was upregulated in spontaneously hypertensive rats and suggested that sodium reabsorption mediated by SGLT2 transporters may be responsible for persistence of hypertension17.
Although results of phase 3 trials with SGLT2 inhibitors are awaited, these group of drugs hold promise as antihyperglycemic drugs with a novel mode of action, which promote reversal of glucotoxicity, weight loss, carry no reported risk of hypoglycemia or oedema and have mild antihypertensive effects.
REFERENCES

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