medwireNews Hot Topic Reviews provide up-to-date overviews of fast-moving areas of research in order to help healthcare providers keep abreast of the latest developments that may influence patient care.
Glycemic control is a long-standing problem for patients with type 1 diabetes, with the proportion achieving glycated hemoglobin (HbA1c) levels of 7.5% (58 mmol/mol) or below persistently hovering at around 30% [1, 2]. The promising results of the DEPICT 1 and inTandem3 trials [3, 4], reported at the 2017 EASD congress, are the latest in a series of sustained efforts to find a medication that can complement insulin and bring down patients’ HbA1c levels.
Medicine Matters editorial board member John Wilding argues that it is too soon to assume that sodium-glucose cotransporter (SGLT)2 inhibition represents this particular holy grail, but what else has so far been tried?
In this Hot Topic Review, we outline which medications have been tested to date and summarize the key trials showing their efficacy or otherwise.
Which non-insulin medications have been tested in patients with type 1 diabetes?
Besides SGLT2 inhibitors, the largest research focus to date has been on glucagon-like peptide (GLP)-1 receptor agonists, with some studies also looking at dipeptidyl peptidase (DPP)-4 inhibitors and metformin.
What is the basis for believing they might help?
Of the approaches so far tested, SGLT2 inhibition has perhaps the most obvious biologic basis; it helps to control blood glucose levels by reducing the reabsorption of glucose by the kidneys – organs that are not directly compromised by the destruction of beta cells in type 1 diabetes. Incretin-based medications, on the other hand, enhance the release of insulin from beta cells, which is pertinent only in type 2 diabetes. However, the key incretin GLP-1 also suppresses glucagon and reduces gastric motility, so medications that activate its receptor (GLP-1 receptor agonists) or slow its breakdown (DPP-4 inhibitors) can potentially help to control blood glucose via these alternative means. Metformin also acts independently of insulin production, reducing the production of glucose by the liver and increasing the sensitivity of peripheral tissues to insulin.
Have any non-insulin medications so far been approved for type 1 diabetes?
It depends on where you live. Pramlintide, an injectable amylin analog that is taken at mealtimes to suppress post-prandial glucagon secretion and slow gastric emptying, was approved by the FDA in the USA in 2005 as an adjunct treatment for insulin-dependent patients with type 1 or type 2 diabetes [5].
Pramlintide’s FDA approval was based on two 52-week phase III trials. The most recent of these showed an HbA1c reduction of 0.29% to 0.34%, depending on the pramlintide dose, at 52 weeks, compared with a 0.04% reduction in the placebo group [6]. Insulin needs were not reduced, but patients taking pramlintide lost an average of 0.4 kg bodyweight, compared with an average 0.8 kg increase among those taking placebo.
But pramlintide has not been tested or submitted for approval in Europe.
How have other medications performed in clinical trials?
Metformin
Despite it being continuously available in the UK since its approval for type 2 diabetes in 1958, metformin has only recently been seriously investigated as an adjunct medication in type 1 diabetes patients. The early small trials produced inconsistent evidence, and the two large recent trials showed only a slight and transient effect of metformin on glycemic control.
In a trial based on the T1D Exchange Clinic Network and conducted specifically in overweight or obese adolescents, HbA1c was an average of 0.3% lower in the metformin than placebo groups after 13 weeks, but this difference did not persist at week 26 [7]. The more recent REMOVAL trial was designed to assess the cardiovascular effects of metformin, but among its secondary endpoint results was a 0.24% HbA1c improvement with metformin at 3 months that did not persist [8]. The chief investigator of REMOVAL, John Petrie (University of Glasgow, UK), has suggested that this apparent loss of efficacy could be due to patients reducing their insulin dose to regain “their comfort zone with respect to fear of hypoglycaemia” [9].
However, both trials found that taking metformin slightly reduced patients’ insulin needs, by an average of 0.1 U/kg per day at 6 months in the T1D Exchange Clinic Network and by just 0.023 U/kg per day after 6 months in REMOVAL.
These recent findings are broadly consistent with a meta-analysis that pooled the results of earlier, smaller studies and reported a reduction in insulin needs (by 5.7–10.1 U/day) among metformin users in most studies but inconsistent findings with respect to HbA1c levels [10].
Incretin-based medications
A fairly large number of studies have explored the effects of GLP-1 receptor agonists and DPP-4 inhibitors in type 1 diabetes patients, but these have, for the most part, been small.
The only large placebo-controlled trials to publish so far have involved liraglutide: the ADJUNCT ONE and TWO trials, and the Lira-1 trial. Although broadly successful, these trials did not demonstrate a sufficiently positive risk–benefit balance for liraglutide’s manufacturer to pursue an expansion of the licensing indication [11].
ADJUNCT ONE involved 1393 patients treated for 52 weeks, by which point HbA1c levels in those receiving the highest liraglutide dose of 1.8 mg were 0.2% lower than in those taking placebo. Bodyweight and total insulin dose fell significantly in patients taking liraglutide versus placebo, but the rate of symptomatic hypoglycemia and hyperglycemia with ketosis increased [12].
In ADJUNCT TWO, 832 patients were treated for 26 weeks and the findings were much the same, despite insulin doses being capped to ensure improved glycemic control could not be thwarted by patients’ reluctance to intensify treatment [13]. Lira-1 was a smaller study, conducted in 100 overweight type 1 diabetes patients, and showed a similar, albeit nonsignificant, difference in HbA1c levels over 24 weeks of treatment, along with reduced insulin needs and a reduction in bodyweight [14].
A recent systematic review and meta-analysis of seven GLP-1 receptor agonist studies found that treatment produced an average 0.2% improvement in HbA1c levels versus placebo, in addition to about a 3.5 kg weight reduction and a reduction in insulin needs, specifically bolus insulin [15].
However, the mode of action of incretin-based medications does suggest one specific use: as an adjunct in patients using a closed-loop insulin delivery system (artificial pancreas) to help to control postprandial glucose increases, which the insulin delivery algorithms do not yet adequately control. A small trial using sitagliptin demonstrated this possibility, with patients having significantly lower mealtime glucose concentrations if they took the DPP-4 inhibitor [16].
DPP-4 inhibitors in general have been much less studied in type 1 diabetes, and usually for very specific indications. One study looked at the effect of sitagliptin on postprandial glucagon and other parameters including HbA1c in 141 type 1 diabetes patients over 20 weeks and found no changes [17]. Another, which was a post-hoc analysis of five pooled phase III studies, showed that saxagliptin effectively lowered HbA1c in type 2 diabetes patients with glutamic acid decarboxylase antibodies (ie, those with latent autoimmune diabetes in adults) [18]. A third study investigated whether the combination of sitagliptin and lansoprazole could preserve beta cell function in newly diagnosed type 1 diabetes patients, but reported disappointing negative results [19].
SGLT2 inhibitors
SGLT2 inhibition for type 1 diabetes has been under the spotlight recently thanks to the publication of the two aforementioned large randomized trials: inTandem3 and DEPICT-1. Both trials reported a reduction in HbA1c levels and insulin dose without additional hypoglycemia, but there were signs of an increased risk for diabetic ketoacidosis, previously reported in case studies of off-label SGLT2 inhibitor use.
Watch Parth Narendran discussing the findings of DEPICT-1 and inTandem3.
The inTandem3 trial investigated sotagliflozin, which inhibits both SGLT1 and 2, versus placebo in 1402 patients with type 1 diabetes, and found it reduced HbA1c levels by an average 0.46% over 24 weeks of use. In all, 28.6% versus 15.2% of patients in the respective treatment groups attained the primary endpoint of HbA1c below 7.0% without severe hypoglycemia or diabetic ketoacidosis [4]. And in DEPICT-1, which involved 834 patients, HbA1c improved by 0.42% and 0.45% in those taking dapagliflozin 5 mg and 10 mg, respectively, versus placebo for 24 weeks [3].
The inTandem3 findings showed an increased risk for ketoacidosis, with rates of 3.0% with sotagliflozin versus 0.6% in the placebo group, whereas in DEPICT-1, 1–2% of patients in the dapagliflozin groups and 1% of those in the placebo group developed diabetic ketoacidosis.
However, the two trials differed in their approach to preventing ketoacidosis. All participants of inTandem3 received information about the detection of ketosis with urinary strips and of its treatment, but DEPICT-1 went further, issuing patients with blood ketone monitors and requiring them to test for ketones every time they had any symptom suggestive of ketosis. Patients were also asked to contact their site investigators if their blood ketone reading was 0.6 mmol/L or more, irrespective of their glucose levels.
Although this implies that the risk for ketoacidosis can be mitigated, this low risk was achieved in a clinical trial setting, and real-world data will be needed to accurately assess the risk–benefit balance of SGLT2 inhibition. In addition, only longer studies will ascertain whether the HbA1c reductions are sustained, or whether they are lost over the longer term as seen with metformin treatment.
In the meantime, a 28-week extension phase of DEPICT-1 is ongoing, and results for empagliflozin in the EASE-2 and EASE-3 trials are expected soon.
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