Conference Update

SGLT2-inhibitors in type 1 diabetes: DKA risk can be different between agents

Diabetes
8 months ago, OP Editor

Current therapeutic options for treating type 1 diabetes (T1DM) remain very limited, with insulin being the mainstay of therapy. However, the data presented at the European Association for the Study of Diabetes (EASD) 2017 Annual Meeting have revealed that selective sodium-glucose co-transporter 2 (SGLT2) inhibitors in addition to daily insulin may bring additional glycemic control and weight loss, albeit with a varying risk of diabetic ketoacidosis (DKA).1,2

One of the promising approaches being investigated to treat T1DM is to add an adjunct agent on top of insulin therapy, to further control the blood glucose without increasing the risk of hypoglycemia, weight gain, and DKA (which is more common in T1DM).3 Owing to the insulin-independent mechanism of action of SGLT2-inhibitors, several clinical trials have been conducted to examine their adjunct use in treating T1DM patients, two of which (DEPICT-1 and InTandem3) showed that SGLT2-inhibitors are an effective adjunct for inadequately controlled T1DM.4,5

DEPICT-1: Promising outcomes with dapagliflozin in T1DM patients

DEPICT-1 was a phase 3, double-blind, randomized, parallel-controlled, multicenter study that investigated the safety and efficacy of dapagliflozin (5mg or 10mg) plus daily insulin in 833 patients (aged 18-75 years old) with inadequately controlled T1DM (HbA1c between ≥7.7% and ≤11.0%). Patients were randomized at approximately 1:1:1 to three study arms (dapagliflozin 5mg + insulin; dapagliflozin 10mg + insulin; placebo + insulin), with the primary efficacy outcome being the change from baseline in HbA1c at week 24. The results of this unprecedented study were presented by Dr. Paresh Dandona at the EASD 2017 Annual Meeting, and simultaneously published in the Lancet Diabetes and Endocrinology.1,4

At week 24, either dose of dapagliflozin provided clinical benefits as an add-on to adjustable insulin when compared with placebo, including the reduction in HbA1c (5mg: -0.42%; 10mg: -0.45%, p<0.0001 for either dose vs. placebo) and total daily dose of insulin (5mg: -8.80%; 10mg: -13.17%, p<0.0001 for either dose vs. placebo). More patients in the dapagliflozin arms also achieved an HbA1c reduction ≥0.5% without severe hypoglycemia events (Figure 1). Additionally, there was a ≥3% reduction of the adjusted mean change in body weight for both doses of dapagliflozin (p<0.0001).4

OP#6-web_CU#1_fig1

“Our results suggest that dapagliflozin is a promising adjunct treatment to insulin to improve glycemic control in patients with inadequately controlled type 1 diabetes,” mentioned Dr. Dandona. He also emphasized the importance of attaining reduction in body weight with the adjunct SGLT2 inhibitor. “Weight gain and blood-pressure rises are also associated with insulin therapy. As such, there is a need for an adjunct treatment that provides sustained improvement across key parameters including HbA1c, time in glycemic range, body weight, and risk of hypoglycemia.”1

More importantly, the safety analyses identified no new safety signals, as hypoglycemia and adjudicated definite DKA, which are most concerned in T1DM patients, occurred at a similar rate in patients with dapagliflozin or placebo (Table 1). Of note, the total daily insulin dose given to patients during the study was reduced symmetrically in basal and bolus insulin by up to 20% after the first dose of study drug, and was slowly titrated back towards the initial dose.4

“Clearly, no increase in hypoglycemia is seen in this large clinical trial, so we can conclude this drug can be used safely without increase in hypoglycemia,” highlighted Dr. Dandona.1

OP#6-web_CU#1_table1

InTandem3: Benefits and risks of sotagliflozin in T1DM patients

InTandem3 is another phase 3, double-blind trial presented in EASD 2017 Annual Meeting that investigated the efficacy and safety of an investigational SGLT2 inhibitor, sotagliflozin, in patients with inadequately controlled T1DM (HbA1c between ≥7.7% and ≤11.0%). The results were likewise published in the New England Journal of Medicine.2,5

A total of 1,402 patients (aged ≥18 years old) were randomly assigned to receive sotagliflozin 400mg per day + insulin (n=699) or placebo + insulin (n=703) for 24 weeks. The primary endpoint was HbA1c lower than 7.0% at week 24, with no episodes of severe hypoglycemia or DKA after randomization. Secondary endpoints included the change from baseline in HbA1c, body weight, systolic blood pressure, and mean daily bolus dose of insulin.5

Significantly more patients met the primary endpoint with sotagliflozin, showing a 13.4% difference when compared with placebo (28.6% vs. 15.2%, p<0.001) (Figure 2). Moreover, sotagliflozin demonstrated better outcome than placebo in other efficacy endpoints, including mean change from baseline for HbA1c (-0.46%), body weight (-2.98%), systolic blood pressure (-3.5mmHg among those with baseline ≥130mmHg) (p≤0.002 for all comparisons with placebo).5

OP#6-web_CU#1_fig2

However, the increased risk of DKA with sotagliflozin may discourage its use in T1DM patients. As summarized in Table 2, the acidosis-related adverse events at week 24 occurred 6.2% more in patients with sotagliflozin.5 Dr. John B. Buse, the study commentator, pinpointed that “those rates were 4.4% vs. 0.7% among insulin-pump users and 2.1% vs. 0.5% in those using injections, suggesting that at least some of the DKA cases related to device failure rather than the drug.”2

The observation is surprising as some had theorized that sotagliflozin’s combination of SGLT1 and SGLT2 inhibition might lead to lower DKA rates than SGLT2 inhibition alone, owing to the less carbohydrate delivery to the circulation and lower urinary glucose excretion by SGLT1 inhibition.2

OP#6-web_CU#1_table2

Expert commentary on the use of SGLT2 inhibitors in T1DM

Several physicians have expressed their opinions regarding the breakthrough findings, generally recognizing the efficacy of adjunct SGLT2 inhibition in T1DM. Dr. John Petrie from the University of Glasgow, Scotland, believed that “DEPICT-1 provided encouraging short-term data for the efficacy of adjunct SGLT2 inhibition in type 1 diabetes but might also provide insights into how the risk of ketoacidosis can be minimized.”6

Nevertheless, some physicians are more conservative due to the potential increment in the DKA risk. Dr. David M Nathan, chief of the Diabetes Center at Massachusetts General Hospital, Boston, suggested that the side-effect profile of sotagliflozin could outweigh the potential benefit without risk minimization measures. “Unfortunately, the results of this trial suggested that the increased risk of ketoacidosis counterbalances the increased likelihood of achieving a glycated hemoglobin level of less than 7%”. He also added the risk and benefits can hardly be judged based on the information from such short-term studies.7

In particular, the risk of DKA, which was the culprit that deterred the initial enthusiasm for off-label use of SGLT2 inhibitors in T1DM, was not increased with the use of dapagliflozin. Comparing both DEPICT-1 and InTandem3, Dr. Petrie believed that “the ketoacidosis rates [in DEPICT-1] are reassuring, but we have to remember that this [DEPICT-1] was a phase 3 trial in which participants were closely supervised. The sotagliflozin data from InTandem3 derived from a more pragmatic design. But in my view, this does not account for higher rates of ketoacidosis in that study on active medication, as rates were lower on placebo — and ketoacidosis was classified in an almost identical manner.”1

SGLT2 inhibition provides meaningful benefits, but did pose some risks to patients with T1DM. Dr. Petrie believed that DEPICT-1 “provided a very simple rule that insulin doses should be reduced by no more than 20% when study medication was started and that they should subsequently be titrated back toward the initial dose.”1

Despite the fact that cardiovascular outcome data and further clinical studies are currently lacking, Dr. Petrie concluded that “SGLT2 inhibitors are back on the road towards approval for an indication in type 1 diabetes.”1

 

  1. DEPICT-1: Dapagliflozin Works in T1D With Little Ketoacidosis. Medscape. (Accessed October 6, 2017, at http://www.medscape.com/viewarticle/885671#vp_1)
  2. InTandem3: Sotagliflozin Has Benefits and Risks in Type 1 Diabetes. Medscape. (Accessed October 6, 2017, at http://www.medscape.com/viewarticle/885615)
  3. American Diabetes Association. Standards of Medical Care in Diabetes – 2017. Diabetes Care. 2017;40(Suppl. 1):1-142.
  4. Dandona P, Methieu C, Phillip M, 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 [Epub ahead of print].
  5. Garg SK, Henry RR, Banks P, et al. Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. N Engl J Med. 2017. [Epub ahead of print]
  6. Petrie JR. SGLT2 inhibitors in type 1 diabetes: knocked down, but up again? Lancet Diabetes Endocrinol. 2017. [Epub ahead of print]
  7. Nathan DM. Adjunctive Treatments for Type 1 Diabetes. N Engl J Med. 2017. [Epub ahead of print]

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