-Insights into the efficacy and safety of the SGLT2 inhibitor dapagliflozin as an adjunct therapy to insulin in type 1 diabetes, presented at the American Diabetes Association’s 78th Scientific Sessions, Orlando, Florida, 22–26 June 2018.
Diabetes is a global and growing clinical and public health challenge. In 2015, 415 million adults were estimated to have diabetes, and this number is predicted to increase to 642 million by 2040.1
HbA1c, also known as glycated haemoglobin, reflects the 3-month average plasma glucose concentration and is used to quantify average hyperglycaemia over time, in contrast with glucose measurements, which only reflect glycaemia at the time of measurement.2 Diabetes is defined as HbA1c equalling or exceeding 6.5% of total haemoglobin.3
Type 1 diabetes (T1D) is due to immune-mediated destruction of the beta cells of the pancreas and constitutes 5–10% of all diabetes cases and 80–90% of diabetes cases in children and adolescents.3,4 American Diabetes Association (ADA) guidelines recommend that most people with T1D should be treated with multiple daily injections of prandial insulin and basal insulin, or continuous subcutaneous insulin infusion. However, insulin therapy alone may not be sufficient to stabilise blood glucose over time.5
Sodium–glucose cotransporter 2 (SGLT2) is a glucose transporter protein whose main function is glucose reabsorption in the kidneys.6 Approximately 180 g of glucose is filtered per day in the glomerulus of the kidneys, and in normoglycaemic adults, 90% of the excreted glucose is reabsorbed by SGLT2.6,7 Glucose reabsorption is increased in people with diabetes, which exacerbates hyperglycaemia.8
SGLT2 inhibitors are small molecule drugs that cause insulin-independent glucose-lowering through inhibition of SGLT2-mediated glucose reabsorption. SGLT2 blockade leads to reduced hyperglycaemia, and modest weight loss and blood pressure reduction. Three SGLT2 inhibitors (canagliflozin, dapagliflozin and empagliflozin) are currently approved for the treatment of type 2 diabetes (T2D).9 Although SGLT2 inhibitors are currently not indicated for the treatment of T1D, they may nevertheless have glycaemic benefits for T1D patients on insulin therapy and are sometimes used off-label to treat T1D.10,11
Importantly, the Food and Drug Administration has recently issued a warning about the risk of diabetic ketoacidosis (DKA) in patients with T1D or T2D treated with SGLT2 inhibitors.12,13 Although potentially life-threatening, DKA is a predictable, detectable and preventable safety concern common to all SGLT2 inhibitors.11
The pathogenesis of DKA is mediated by a shift in cellular energy metabolism from glucose to lipids. Absolute or relative insulin deficiency means that glucose cannot be efficiently delivered to cells and used as an energy source, which leads to enhanced lipolysis and the production of free fatty acids as an alternative energy source. Increased delivery of free fatty acids to the liver and raised glucagon levels promote free fatty acid oxidation, which leads to an increased production of ketone bodies, reduced blood pH and, ultimately, ketoacidosis.11
DKA is normally characterised by hyperglycaemia (blood glucose >250 mg/dl), ketosis and metabolic acidosis (arterial pH <7.3 and serum bicarbonate <18 mEq/L).12,13 Notably, SGLT2-associated DKA may manifest at normal (euglycaemic) glucose levels, as SGLT2 inhibitors stimulate the excretion of excess blood glucose with the urine.11 Symptoms of DKA include abdominal pain, nausea, vomiting, tiredness and trouble breathing. Patients who have symptoms or signs of DKA should stop taking SGLT2 inhibitors and seek immediate medical attention.12-14 In the DEPICT-1 phase 3 clinical trial, the efficacy and safety of the SGLT2 inhibitor dapagliflozin was evaluated as an add-on to adjustable insulin in patients with inadequately controlled T1D. The incidence of DKA in dapagliflozin and placebo-treated patients in DEPICT-1 were similar (placebo: 1.2%; dapagliflozin 5 mg: 1.4%; dapagliflozin 10 mg: 1.7%), and the study investigators concluded that dapagliflozin was a promising adjunct therapy to insulin, capable of improving glycaemic control in patients with inadequately controlled T1D.15
At the ADA’s 78th Scientific Sessions at the Orange County Convention Center, Orlando, Florida, Chantal Mathieu, MD, PhD, professor of medicine at the Catholic University of Leuven, Belgium, presented results from the DEPICT-2 study, a 24-week phase 3 study that evaluated the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled T1D (HbA1c 7.5–10.5%).16
Briefly, study participants (n=813) were randomised to dapagliflozin 5 mg (n=271), dapagliflozin 10 mg (n=270) or placebo (n=272), supplemented with optimally adjusted insulin. Compared with placebo, dapagliflozin 5 mg and 10 mg significantly (p<0.0001) decreased HbA1c (-0.4% for both doses), total daily insulin dose (-10.8% and -11.0%, respectively) and bodyweight (-3.2% and -3.7%, respectively).
Compared with placebo, dapagliflozin-treated patients also demonstrated improved, stable glycaemic values, with an increase in time-in-range over 24 hours of 2h 10min in the 5 mg group and of 2h 30min in the 10 mg group. Treatment with dapagliflozin also improved mean interstitial glucose, mean amplitude of glucose excursion and mean percent of readings within the target glycaemic range (>70–≤180 mg/dL) at week 24.
Compared with placebo, there was also an increase in patients treated with dapagliflozin who reduced their HbA1c by ≥0.5% without severe hypoglycaemia (odds ratios [95% CI]: 2.71 [1.81, 4.06] and 3.07 [2.05, 4.60] for dapagliflozin 5 and 10 mg respectively).
The rates of severe hypoglycaemia were balanced in the three treatment groups (placebo: 7.7%; dapagliflozin 5 mg: 6.3%; dapagliflozin 10 mg: 8.5%), but DKA was more frequently reported in the dapagliflozin treatment groups compared with placebo (placebo: 0%; dapagliflozin 5 mg: 2.6%; dapagliflozin 10 mg: 2.2%).
Dr Mathieu explained that the results of DEPICT-2 add to a growing body of evidence demonstrating that SGLT2 inhibitors have potential as promising adjunct therapies in people with T1D who are not consistently in their target blood glucose range. ‘Results of the DEPICT-2 study were consistent with those of its twin study, DEPICT-1, which followed mostly European and American patients with T1D,’ Dr Mathieu said. ‘This new study had a greater global reach, with about a quarter of patients being from Asia. The benefits seen in both studies are important to people with T1D. Introduction of dapagliflozin as an adjunct therapy could be an interesting and exciting new treatment for T1D, almost 100 years after the discovery of life-saving insulin.’
However, Dr Mathieu cautions that adding dapagliflozin to an insulin regimen needs to be balanced against the increased risk of DKA and emphasised that dapagliflozin therapy should be complemented with intensive educational measures to cope with the small, but real risks posed by DKA.
The twin DEPICT-1 and DEPICT-2 phase 3 trials evaluated the efficacy and safety of dapagliflozin as an adjunct to insulin therapy in more than 1,600 patients with inadequately controlled T1D. Both trials consistently demonstrated improved glycaemic control, and no consistent dose-dependent effects on hypoglycaemia or severe hypoglycaemia were observed. However, DKA was reported more frequently in study participants treated with dapagliflozin compared with placebo-treated study participants. The increase in DKA incidence was small, but still warrants caution.
Although DKA is a potentially life-threatening safety concern common to all SGLT2 inhibitors, it is also predictable, detectable and preventable if coupled with rigorous patient and healthcare professional educational programmes focused on preventive measures, rapid diagnosis and early interventions aimed at restoring fluid and glucose homeostasis.9,11
In summary, DEPICT-1 and DEPICT-2 have demonstrated consistent clinical benefits of dapagliflozin for patients with T1D, and the small but real increased risk of DKA can be mitigated through intensive educational programmes aimed at both patients and healthcare providers. Dapagliflozin constitutes a promising insulin-independent means of stabilising glucose levels in patients with inadequately controlled T1D and is likely to improve the lives of T1D patients currently struggling to control hyperglycaemia with insulin alone.
1.Ogurtsova K, et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017;128:40–50.
2.Florkowski C. HbA1c as a diagnostic test for diabetes mellitus – reviewing the evidence. Clin Biochem Rev. 2013;34:75–83.
3.Daneman D. Type 1 diabetes. Lancet. 2006;367:847–58.
4.Dabelea D, et al. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA. 2014;311:1778–86.
5.Chamberlain JJ, et al. Cardiovascular disease and risk management: review of the American Diabetes Association Standards of Medical Care in Diabetes 2018. Ann Intern Med. 2018 ;168(9):640–50.
6.Wright EM, et al. Biology of human sodium glucose transporters. Physiol Rev. 2011;91:733–94.
7.Liu JJ, et al. Why do SGLT2 inhibitors inhibit only 30–50% of renal glucose reabsorption in humans? Diabetes. 2012;61:2199–204.
8.Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27:136–42.
9.Zurek AM, et al. A review of the efficacy and safety of sodium–glucose cotransporter 2 inhibitors: a focus on diabetic ketoacidosis. Diabetes Spectr. 2017;30:137–42.
10.Yang Y, et al. Safety and efficiency of SGLT2 inhibitor combining with insulin in subjects with diabetes: systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 2017;96:e6944.
11.Rosenstock J, et al. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38:1638–42.
12.FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. https://www.fda.gov/Drugs/DrugSafety/ucm475463.htm (accessed 12 Aug 2018).
13.Modi A, et al. Euglycemic diabetic ketoacidosis: a review. Curr Diabetes Rev. 2017;13:315–21.
14.Peters AL, et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium–glucose cotransporter 2 inhibition. Diabetes Care. 2015;38:1687–93.
15.Dandona P, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24-week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5:864–76.
16.Mathieu C, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes – DEPICT-2 study. Diabetes. 2018;67(Suppl1) [ePub ahead of print].