A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers

Diabetes Care 2009 original article

Randomised double blinded placebo controlled trial

Conducted across US and Canada in 26 centres simultaneously

OBJECTIVE To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs).

Background Treatment of hyperglycemia as insulin requirement increases is still a challenge Newer drugs over a period of time has become ineffective weight gain increasing insulin resistance progressive failure in insulin secretion hypoglycemic episodes Need for newer oral drugs does persist

Dapagliflozin SGLT 2 blocker Selective blocker of Sodium glucose cotransporter 2(SGLT 2)

SGLT 2 is located in the proximal tubule of nephron where 90% of glucose is reabsorbed.
when this cotransporter is selectively blocked the glucose is excreted in the urine - resulting in renal glucosuria therby reducing the blood sugar

Till recently, it was believed that the liver was solely responsible for gluconeogenesis under normal physiological conditions Renal synthesis of glucose became significant only during prolonged fasting or acidosis. It is now recognized that the kidney has a significant role in glucose homeostasis under both physiological and pathological conditions.

Study design All patients provided written informed consent. The trial consisted of a 10- to 21-day qualification period, 12-week treatment phase, and 4-week follow-up phase

The patients were assigned into three groups First entering into placebo group Second with 10 mg dapaglifozin Third group with 20 mg dapaglifozin

The insulin dosage was 50 % of their initial requirement and similar method for metformin.

Inclusion criteria
1.Men and women with type 2 diabetes, 2.aged 1875 years 3. BMI < 45 kg/m2 4. A1C 7.510%, 5.Patients were receiving stable-dose insulin sensitizer therapy (metformin >1,000 mg and/or pioglitazone >30 mg or rosiglitazone 4 mg) for >6 weeks 6.insulin therapy for >12 weeks before enrollment (insulin dose must have been >50 units of U100 daily and stable for >6 weeks). 7.Laboratory criteria included serum creatinine < 1.5 mg/dL

Exclusion criteria
1.History of type 1 diabetes, 2. SGOT, SGPT > 3 times normal 3.Creatine kinase 3 times the upper limits of normal, 4.Symptoms of severely uncontrolled diabetes, 5. A history of severe hypoglycemia, and 6.Unstable condition / serious cardiovascular, renal, or Hepatic disease.

Patients performed self-monitoring of blood glucose five times daily during the 35 days before clinic visits at weeks 1, 2, 4, 6, 8, 10, and 12.

No dose modifications of blinded study medication or OAD(s) were allowed during the treatment phase.

For any fasting plasma glucose (FPG) level > 240 mg/dl at weeks 4 and 6, > 220 mg/dl at week 8, or >200 mg/dl at week 10, the insulin dose could be increased after a retest. Patients lacking glycemic control despite up-titration or whose modified insulin dose exceeded baseline were discontinued from the study.

Study outcome The primary outcome measure was change from baseline in A1C at week 12
Secondary outcome Baseline in FPG and total daily dose of insulin (TDDI), the proportion of patients achieving a decrease in A1C 0.5% from baseline, Proportion of patients achieving A1C 7%.

Tertiary end points Changes in - baseline in total body weight - in postprandial glucose (PPG) measured by an oral glucose tolerance test. - Safety outcomes were assessed by treatmentemergent adverse events, - vital signs, - laboratory measurements, including 24-h urine collections for volume and electrolytes.

Results

1. Group 2 and 3 showed statistically significant reduction in HbA1C 2. At week 12, 66 % of dapaglifozine showed > 0.5% reduction in HbA1C when compared to 13 % of placebo group 3. Weight change 1.9Kg in placebo 4.5 4.9 Kg dapaglifozine 4.Reduction in blood pressure observed in dapaglifozin

Adverse effects Nausea Vomiting Giddiness, postural fall of BP Vulvovaginal infection Anxiety Back pain
Hypoglycemia

Drawbacks 1.Small size 2.Shorter duration of study

In phase III trials

KIDNEY AS THE NEXT TARGET IN TREATMENT OF DIABETES IN EMPHASISED BY THE STUDY

SIMILAR ARTICLES
1. Sodium-Glucose Cotransport Inhibition With Dapagliflozin in Type 2 Diabetes Diabetes care 2009

Dapagliflozin improved hyperglycemia and facilitates weight loss intype 2 diabetic patients by inducing controlled glucosuria with urinary loss of 200300kcal/day. Dapagliflozin treatment demonstrated no persistent, clinically significant osmolarity,volume, or renal status changes.

SIMILAR ARTICLES
2.Sodium Glucose Cotransporter 2 Inhibitors as a New Treatment for Diabetes Mellitus

SGLT2 inhibitors are showing promise as a useful addition to the current therapeutic options in type 2 diabetes mellitus. Journal of Clinical endocrinology