The kidneys play an important role in glucose homeostasis by reabsorbing glucose from the glomerular filtrate back into the blood. Under normal conditions, almost all of the filtered glucose is reabsorbed and returned to circulation in the proximal convoluted tubule of the nephron. This glucose reabsorption takes place with the help of sodium-glucose co-transporters (SGLTs) in conjunction with facilitative glucose transporters (GLUTs).

The sodium-glucose co-transporter SGLT2, which is found primarily in the S1 segment of the proximal convoluted tubule, is predominantly responsible for this process, accounting for 90% of glucose reabsorption via the kidneys. This reabsorption of filtered glucose continues despite the presence of hyperglycaemia in Type 2 Diabetes Mellitus.

Selective inhibition of SGLT2 offers a novel approach towards treatment of hyperglycaemia in Type 2 Diabetes.

Dapagliflozin is one such reversible competitive inhibitor of SGLT2 and the only one in this new class of anti-diabetic drugs that is licensed for use in Australia. Another drug in the SGLT2 inhibitor class, canaglifozin, has recently been recommended for approval in the United States of America but is not yet available for use.

Dapagliflozin improves both fasting and postprandial glycaemic control in patients with Type 2 Diabetes Mellitus by reducing renal glucose reabsorption, thereby leading to urinary glucose excretion (glucuresis).

This glucuretic effect is observed following the first dose and continues for the duration of the treatment. Dapagliflozin is 1,000-3,000 times more selective for SGLT2 than for SGLT1, SGLT1 being the major transporter for glucose reabsorption in the gut.

Treatment options for Type 2 Diabetes have thus far focused on the secretion and/or action of insulin. The effect of dapagliflozin is however independent of insulin. It has a low propensity to cause hypoglycaemia in healthy adults as the amount of glucose excreted is dependent on the blood glucose concentration and glomerular filtration rate (GFR). Dapagliflozin also does not impair endogenous glucose production in response to hypoglycaemia.

Glucuresis induced with the use of dapagliflozin is also associated with caloric loss and it therefore offers the additional benefit of causing weight reduction, with the majority of this weight loss being body fat loss including visceral fat rather than lean tissue or fluid loss.

Indications

  • As monotherapy with diet and exercise in patients with Type 2 Diabetes Mellitus for whom metformin is otherwise indicated but not tolerated
  • In addition to diet and exercise as initial combination therapy with metformin to improve glycaemic control in patients with Type 2 Diabetes Mellitus when diet and exercise have failed to provide adequate glycaemic control or there are poor prospects for response to metformin monotherapy
  • In combination with metformin, when metformin alone with diet and exercise does not provide adequate glycaemic control
  • In combination with a sulfonylurea, when a sulfonylurea alone with diet and exercise does not provide adequate glycaemic control, and
  • In combination with insulin (alone or with one or both of metformin or a sulfonylurea) when existing therapy, along with diet and exercise does not provide adequate
    glycaemic control.

Contraindications

In patients with known hypersensitivity to dapagliflozin or any of the tablet ingredients in Forxiga® and in patients with moderate to severe renal failure (CrCl< 60ml/min).

Precautions

Dapagliflozin should not be used in Type 1 Diabetes or for the treatment of diabetic ketoacidosis, in patients with severe hepatic impairment, and in pregnant or breastfeeding women.

Caution must be exercised with use of dapagliflozin in patients with mild renal impairment and it should not be used in patients with moderate to severe renal impairment.

Dapagliflozin is not recommended for use in patients receiving loop diuretics or who are volume depleted.

Dapagliflozin use has been associated with an increased risk of urinary tract infection, therefore temporary interruption of dapagliflozin should be considered while treating pyelonephritis or urosepsis. In cases of recurrent urinary tract infections, discontinuation of dapagliflozin should be considered.

Adverse effects

The most common side effects associated with the use of dapagliflozin are hypoglycaemia (especially when used in combination with add-on sulfonylurea and add-on insulin therapies), urinary tract infections, genital infections (more common in females), back pain, polyuria, dysuria, dyslipidaemia, nausea, headache, dizziness and rash.

Dosage and Administration

Dapagliflozin is available as 10mg tablets under the trade name of Forxiga® (Astra Zeneca and Bristol-Myers Squibb). The recommended dosage is 10mg taken once daily at any time of the day, regardless of meals.

No dosage adjustment is required for patients with mild renal or mild to moderate hepatic impairment. Renal function and the risk of volume depletion should be taken into account when using dapagliflozin in the elderly. Initiation of dapagliflozin in patients over the age of 75 years is generally not recommended.

PBS Information

Bristol-Myers Squibb Australia Pty Ltd made a submission to the Pharmaceutical Benefits Advisory Committee (PBAC) in March 2012 seeking an Authority Required (Streamlined) listing for dapagliflozin for the treatment of patients with Type 2 Diabetes in combination with insulin.

Based on the evidence presented, the PBAC considered there was insufficient evidence to accept the submission’s clinical claim that dapagliflozin (in combination with insulin) is non-inferior in terms of comparative effectiveness and comparative safety to pioglitazone (in combination with insulin).

The PBAC rejected this submission on the basis of an inadequate comparison across appropriate comparators and uncertain comparative clinical effectiveness.

As a result of this decision, dapagliflozin is currently not PBS listed. However, given the amount of interest that the SGLT2 receptor antagonists are generating as a treatment option for Type 2 Diabetes, it would be worthwhile watching this space.

References:

  1. Triplitt C. Understanding the Kidneys’ Role in Blood Glucose Regulation. Am J Manag Care 2012; 18: S11–S16.
  2. Williams R, Stephens J. SGLT2 Inhibitors – A Useful Addition to Therapy? Diabetes Voice 2013; 58 (1): 33–5.
  3. MacEwen A, McKay G, Fisher M. Drugs for Diabetes: Part 8 SGLT2 Inhibitors. Br J Cardiol 2012; 19: 26–9.
  4. Forxiga® (dapagliflozin) Australian Approved Product Information. Mulgrave: Bristol-Myers Squibb Australia Pty Ltd. Approved 22 October 2012, amended
    30 November 2012.
  5. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of Dapagliflozin in patients with Type 2 Diabetes who have inadequate glycaemic control with metformin: A randomised, double-blind, placebo-controlled trial. Lancet 2010; 375: 2223–33.
  6. Pharmaceutical Benefits Advisory Committee. Public Summary Documents – March 2012. Canberra: Australian Government Department of Health and Ageing; 2012.

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