Apart from Sotagliflozin’s use in the treatment of  people with type 2, SGLT-1 and SGLT-2 inhibitors effects on type 1 currently being explored.

For many years, SGLT-1 and SGLT-2 inhibitors have been widely used among people with type 2 diabetes. Both inhibitors work on the sodium-glucose cotransporter where SGLT-1 inhibitors primarily transport glucose and galactose in the gastrointestinal tract, and SGLT-2 inhibitors aide with renal glucose reabsorption. SGLT-1 inhibitors furthermore help improve postprandial glucose levels, as well as, release GI peptides like GLP-1 to aide with appetite suppression. SGLT-2 inhibitors help reduce hemoglobin A1c levels, lower body weight and blood pressure. Moreover, little hypoglycemic effects are seen with SGLT-2 inhibitors. The use of these inhibitors in people with type 2 diabetes helps maintain glycemic control while preventing weight gain and now studies using SGLT inhibitors in the treatment of people with type 1 diabetes, in conjunction to insulin therapy, shows some promising results in glycemic control.

In a recent study, titled Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes, researchers hypothesized that given the history of SGLT inhibitors on people with type 2, administering these inhibitors to type 1 patients will help to improve glycemic control, as well as facilitate the use of insulin without weight gain. They predicted that the use of SGLT inhibitors, especially SGLT-1 inhibitors will lower postprandial glucose levels in addition to reducing insulin bolus dose thus decreasing risks of hypoglycemia.

The randomized, multicenter, placebo-controlled, double-blind study focused on testing the effects of sotagliflozin in adult patients with type 1. The study included 36 patients where 3 patients were placed in the open-label pioneer group and the remaining 33 patients were placed in the randomized, placebo-controlled, double-blind group. The participants were required to remain on insulin therapy via multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII) via pumps. Patients using either MDI or CSII were then enrolled in the placebo-controlled group. The individuals were randomly placed in a 1:1 double-blind fashion where one group received a daily dose of 400mg sotagliflozin and the other a placebo. Both study drugs were taken 15 minutes prior to having breakfast. Baseline insulin levels were recorded during the initial 7 days, in an inpatient setting. On the first day of the study, one treatment dose was given prior to a mixed-meal tolerance test (MMTT) and before breakfast; no bolus insulin was given. Short-acting insulin dosage was adjusted at each meal.

On the second day of the study, the patients were discharged and instructed to resume their regular daily routines. An Enlite subcutaneous glucose sensor was used to obtain a blinded continuous glucose monitoring (CGM) data on each patient throughout the study.

The primary outcome of the study included treatment effect of total daily bolus insulin from baseline throughout the outpatient setting. One of the secondary outcomes included changes in insulin regimen including daily bolus insulin given with each meal and total daily basal insulin.

Another secondary outcome involved glycemic control when assessing the effects of sotagliflozin treatment during fasting state and after MMTT was administered. Effects of sotagliflozin treatment included treatment on hemoglobin A1c and changes in GLP-1. The intent to treat group included all randomized patients in the placebo-control group.

Results indicated that changes from baseline in total daily insulin use was -32% in the sotagliflozin treatment group and -6.4% for the placebo group. Reductions in bolus insulin from baseline were recorded at different times of the day for both study groups. At breakfast, results among the sotafliglozin treatment group and placebo group were -28.4% vs, 13.6% (P=0.046), respectively. At lunch, results were -25.9% for the treatment group and 7.1% for the placebo group (P=0.08). Finally, results at dinner showed -23.8% for the treatment group and 39.3% for the placebo (P=0.052). Among patients using MDI or CSII, the effects of sotagliflozin on bolus insulin regimens were similar. Furthermore, the use of basal insulin between both groups was similar with a minor decrease from baseline of 2.4% for the sotagliflozin group and 0.2% in the placebo group (P=0.53). In addition, the use of sotagliflozin lowered the mean daily glucose in the outpatient setting; 148.8mg/dL in the treatment group and 170.3 mg/dLfor the placebo group (P=0.010). Sotagliflozin treatment also produced promising results on glycemic control pos-prandially: -16.7mg/dL vs. -4.2mg/dL, at breakfast for the treatment and placebo group, respectively (P=0.034). Hemoglobin A1c also decreased significantly by 0.55% after 29 days of treatment.

There were some adverse events reported in the study, however, none significant enough to discontinue the study. In addition, two cases of diabetic ketoacidosis were reported in patients using the insulin pump, treated with sotagliflozin. According to researchers, the two cases of diabetic ketoacidosis were primarily related to the use of the insulin pump and not to the sotagliflozin.

The authors conclude that the use of 400mg sotagliflozin reduced bolus insulin dose while improving glycemic control among type 1 patients. In addition, sotagliflozin produced a significant decrease in post-prandial glucose levels during the 3-h plasma glucose. Moreover, patients treated with the study drug showed weight loss and decreased systolic blood pressure. These results suggest that the use of sotagliflozin in reducing bolus insulin use can help lower the risk for postprandial hypoglycemia. By using SGLT inhibitors in people with type 1 diabetes, the challenge of using insulin therapy alone for management becomes decreased.

Practice Pearls:

• SGLT inhibitors are currently being used off-label for the treatment of people who have type 1 diabetes.
• SGLT-1 inhibitors work by inhibiting that transport of glucose and galactose in the GI tract whereas SGLT-2 inhibitors inhibit glucose reabsorption in the kidneys.
• SGLT inhibitors reduce post-prandial hypoglycemia, reduce the for bolus insulin dose, and reduce weight gain in people with type 1 diabetes.

References:

Sands, Arthur T., Brian P. Zambrowicz, Julio Rosenstock, Pablo Lapuerta, Bruce W. Bode, Satish K. Garg, John B. Buse, Phillip Banks, Rubina Heptulla, Marc Rendell, William T. Cefalu, and Paul Strumph. “Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes.” Diabetes Care 38.7 (2015): 1181-188. Web. 5 July 2017.

Nuha Awad, Doctor of Pharmacy Candidate: Class of 2018; ACCP FSHP

People with type 1 diabetes receiving once-daily injection of glucagon-blocking drug, REMD-477 can reduce their insulin use considerably and improve blood glucose levels without altering hypoglycemia.

It has been widely studied that glucagon has opposing actions to insulin by raising blood glucose levels through gluconeogenesis and glucose efflux from the liver. When present simultaneously in the healthy pancreatic islet, insulin serves to prevent glucagon secretion and allow for lipid and carbohydrate storage. The presence of insulin in islets of Langerhans allows a-cells to receive high concentration levels of insulin. However, because the range of paracrine levels reaching a-cells is high (2000-4000 UL/mL), it becomes difficult to achieve via the administration of insulin alone. In instances where insulin is deficient, an imbalance between the insulin-glucagon ratio arises. As such, glucagon begins to overproduce glucose and as a result leads to hyperglycemia in diabetics. Therefore, rather than administering monotherapy insulin to treat hyperglycemic episodes and improve clinical outcomes of people with type 1, the more ideal treatment method is to minimize the actions of glucagon.

Many studies have been formulated to minimize the actions of glucagon as an alternative to administering higher doses of insulin, in treating hyperglycemia. A study conducted on the first orally available glucagon antagonist BAY 27-9955 was tested on healthy men but was later discontinued. Several other attempts to block glucagon’s actions were made, including Merck’s MK-0893, which helped reduce fasting, and post-prandial plasma glucose levels in people with type 2 diabetes.  Moreover, in an issue of Diabetes Care, Christof Kazda et al review outcomes of phase 2a and 2bc clinical trials of the glucagon receptor antagonist (GRA) LY2409021. It was discovered that this GRA lowered blood glucose levels without increasing LDL levels. Administration of LY2409021 also reduced HbA1c levels by >2% thus placing emphasis on the fact that GRAs improve glycemic control without altering hypoglycemia better than providing insulin treatment alone. This discovery opened opportunities to explore GRAs actions in treating type 1 patients.

In more recent studies, the GRAs effects have been observed in people with type 1. In an article titled Glucagon-Blocking Drug Reduces Need for Insulin and Improves Blood Glucose Levels for Patients with Type 1 Diabetes, researchers observed the effects of a single dose of a glucagon-blocking drug REMD-477 in controlling blood glucose, without affecting hypoglycemia levels, in people with type 1 diabetes. A double-blind, randomized, placebo-controlled study was conducted with 21 adults; 8 of which were men and 13 were women. Prior to the study, individuals’ blood glucose levels were monitored via Continuous Glucose Monitoring (CGM). The patients were also given the same meals and IV insulin infusions. Of the patients, 10 received a single 70 mg injection of REMD-477 while the remaining 11 received a placebo injection. Patients receiving REMD-477 and the placebo injection were observed on the first day of the study and again on the fourth day.

With daily insulin use and continuous blood glucose monitoring, results indicated that individuals receiving REMD-477 were able to reduce their insulin use by 12 units versus those receiving the placebo (p=0.02). Blood glucose levels assessed for 8 weeks were 20-31 mg/dL lower in patients receiving REMD-477 compared to those receiving the placebo (p<0.05). Because the effects of REMD-477 are long acting, this poses a possibility for the drug to be administered once weekly versus every day.

This study supports the assumption that blocking glucagon levels can greatly impact the treatment of people with type 1 diabetes. However as with all small molecule antagonists, there has been some elevation in plasma liver enzymes but no elevation in bilirubin levels or indication of liver damage. The elevation in liver enzymes is associated with the pharmacology of glucagon, therefore posing no drug-drug interaction when combining GRAs with other anti-diabetic agents. Since the study focused on a single dose of REMD-477, researchers are inclined to perform alternate studies using more patients and observing the effects of weekly injections of two different strengths of said drug over a longer time period.

Practice Pearls:

• Past studies have been conducted to observe the effects of glucagon receptor antagonists in the treatment of diabetes.
• The glucagon-blocking drug, REMD-477 has shown promising results in the treatment of people with type 1 diabetes without altering hypoglycemia.
• More studies showing the effects of REMD-477 and other glucagon receptor antagonists on a wider population and over a longer time period are under way.

References:

“Glucagon-Blocking Drug Reduces Need for Insulin and Improves Blood Glucose Levels for Patients with Type 1 Diabetes.” American Diabetes Association. N.p., n.d. Web. 28 June 2017.

McCormack, James. “Glucagon antagonism.” Management – Diapedia, The Living Textbook of Diabetes. N.p., n.d. Web. 28 June 2017.

Pearson, Mackenzie J., Roger H. Unger, and William L. Holland. “Clinical Trials,     Triumphs, and Tribulations of Glucagon Receptor Antagonists.” Diabetes Care. American Diabetes Association, 01 July 2016. Web. 28 June 2017.

Nuha Awad, Doctor of Pharmacy Candidate: Class of 2018; ACCP|FSHP

In adults with two or more antibodies predicting the development of type 1 diabetes, treatment with daily oral insulin therapy did not prevent development of the disease, but a small subset experienced a 31-month delay in clinical diabetes development.

Close relatives of people with type 1 diabetes who had certain autoantibodies that put them at high risk of progression to clinical type 1 diabetes did not benefit from taking oral insulin vs placebo, according to a new trial. The participants were mostly children and adolescents, with a median age of 8. However, “surprisingly,” among a small subset of participants with the same autoantibodies against islet cells but with low  insulin secretion, those who received insulin tablets were diagnosed with type 1 diabetes 2.5 years later than those who got placebo.

This was the largest trial ever performed using oral insulin and even though the results were not a homerun, a pre-specified secondary hypothesis was met and there were no significant adverse events. The results showed an incremental advance as it was able to delay type 1 diabetes for 2.5 years in a subset.

Dr. Carla J. Greenbaum, who presented the results, stated that people with close relatives with type 1 diabetes have a 15-fold increased risk of developing the disease themselves.

An earlier study had suggested that if such individuals also had high levels of micro insulin autoantibodies (mIAA), taking oral insulin might buy time until they were diagnosed with the same disease. Thus, the researchers aimed to determine if insulin tablets might delay or prevent type 1 diabetes in high-risk individuals with high levels of mIAA plus certain other islet autoantibodies (the primary outcome). They also aimed to gather information from individuals with different profiles of islet autoantibodies (secondary outcomes).

From 2007 to 2015, the researchers screened almost 140,000 individuals who had a close relative with type 1 diabetes at 87 sites in eight countries, and they enrolled 560 individuals. Participants were either 3 to 45 years old with a first-degree relative (child, parent, or sibling) with type 1 diabetes or 3 to 20 years old with a second-degree relative (uncle, aunt, niece, nephew, cousin, or grandparent) with type 1 diabetes. The enrolled subjects had a median age of 8.25. They were in phase 1 of the continuum of type 1 diabetes disease progression. That is, they had normal blood glucose and two or more islet autoantibodies, including mIAA, islet-cell antibodies (ICA), glutamic acid decarboxylase (GAD) antibodies, or islet antigen-2 (IA-2) antibodies. The study subjects were then divided into four groups:

• Primary stratum: 389 participants with mIAA and ICA or GAD plus IA-2 and high insulin secretion (above threshold).
• Secondary stratum 1: 55 patients with mIAA and ICA or GAD plus IA-2 and low insulin secretion.
• Secondary stratum 2: 114 patients with mIAA and GAD or IA-2 and high insulin secretion.
• Secondary stratum 3: Two patients with mIAA and GAD or IA-2, and low insulin secretion.

In each group, subjects were randomized to receive 7.5 mg/day of oral insulin or placebo. They had oral glucose-tolerance tests every 6 months to assess if they had developed type 1 diabetes. In the primary-stratum group, 8.8% of subjects treated with oral insulin vs 10.2% of subjects who received placebo developed diabetes each year, during an 8-year follow-up, which was not a significant difference (HR, 0.87; P = .42). Similarly, oral insulin did not have a significant effect on the development of type 1 diabetes in the combined secondary-strata 2 and 3 groups or in the overall study sample. However, in the secondary-stratum 1 group, 18.1% of those treated with oral insulin vs 34.1% of subjects who received placebo developed diabetes each year during follow-up, which was a significant 55% reduction (HR 0.45; 95% CI, 0.22–0.91; P = .01). This translated into a 2.5-year delay in the median time to type 1 diabetes with oral insulin in this subgroup.

It was emphasized that the results further support the understanding that not everyone develops type 1 diabetes in the same way and is an early step toward developing specific targeted therapies. Plus it clearly shows that more research is needed to explore why certain people may respond to oral insulin and others don’t.

Although the trial was the largest study ever done with oral insulin and the results were negative in the “main stratum” of studied patients, nonetheless this dramatic result in this subset of patients” is definitely something to follow up with in future research.

Practice Pearls:

• Over 8 years, over 140,000 individuals with a first- or second-degree relative with type 1 diabetes were screened and 560 were enrolled into the study. Subjects were randomized to 7.5mg or oral insulin or placebo.
• Oral insulin did not have a significant effect on the development of type 1 diabetes in the combined secondary-strata 2 and 3 groups or in the overall study sample.
• In the secondary-stratum 1 group, 18.1% of those treated with oral insulin vs 34.1% of subjects who received placebo developed diabetes each year during follow-up, which was a significant 55% reduction (HR 0.45; 95% CI, 0.22–0.91; P = .01), which translated into a 2.5-year delay in the median time to type 1 diabetes with oral insulin in this subgroup.

American Diabetes Association 2017 Scientific Sessions; June 12, 2016; San Diego, California. Type 1 Diabetes Immune Intervention Trials. Session 5-IT-SY07  TrialNet Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus

Nuha Awad, Doctor of Pharmacy Candidate: Class of 2018; ACCP|FSHP

Research will still continue due to its safety.

Current treatments used in managing type 1 diabetes, such as insulin and pramlintide, do not cure or prevent the disease. However, clinical research is still actively searching for possible cures and prevention. Recently, a pilot study was conducted in order to evaluate the efficacy of Alum-GAD (Diamyd) as a potential vaccine for preventing type 1 diabetes. In this autoimmune disease, the immune system forms autoantibodies in response to certain autoantigens. Having autoantibodies, particularly to Glutamic acid decarboxylase (GAD), can increase a patient’s risk of developing type 1 diabetes.

The use of Alum-GAD in previous studies have suggested it may preserve beta cell function. Thus, investigators theorized immune tolerance to Alum-GAD vaccine injections would prevent or even delay the progression of type 1 diabetes.

DIAPREV-IT, a double-blind, investigator initiated study, enrolled 50 children between the ages of 4 and 18 (median age = 5.2 years old) who were at high risk of developing type 1 diabetes. High risk was defined as participants with positive GAD antibodies and at least one additional type 1 diabetes associated autoantibody (IA, 2Ab, ZnT8R/W/QAb or IAA). At randomization, 25 participants received 20 micrograms of Alum-GAD on days 1 and 30. The remaining 25 participants received a placebo injection on days 1 and 30. Intravenous and oral glucose tolerance tests were conducted together at baseline and alternated every six months for the 5-year followup period. Assessment of the safety of Alum-GAD was performed by physical examinations and documentation of adverse events.

The results, presented at the ADA 77th Scientific Sessions, indicated Alum-GAD was safe to use in children at high risk of developing type 1 diabetes. Researchers did not report any serious adverse events, nor did they observe an increase in the progression to type 1 diabetes. However, the study did not prevent or delay type 1 diabetes in these children (p = 0.573). In fact, 18 out of the 50 participants, or 36%, developed type 1 diabetes during the 5-year trial period. The authors also indicated that subgroup analysis could not be performed because 26 participants had impaired glucose tolerance at baseline while 24 participants did not.

Although the results of the study determined the Alum-GAD vaccine did not prevent or delay the progression of type 1 diabetes in high-risk children, investigators have not discontinued research. They believe Alum-GAD may still be a possible prevention when tested in various doses or in combination with other agents. Currently, there are four ongoing clinical trials exploring the use of Alum-GAD with a larger number of participants and an extended trial period; DIAGNODE-1, DiAPREV-IT 2, EDCR IIa and GABA/DIAMYD.

Practice Pearls:

• At this time, type 1 diabetes can only be managed by insulin. There is no known prevention or cure yet.
• In this study, the use of the Alum-GAD vaccine (Diamyd) did not prevent or delay the progression of type 1 diabetes in high risk children.
• Research on Alum-GAD will still continue despite the disappointing results.

References:

American Diabetes Association. Autoantigen GAD-Vaccine is Safe for Children at High Risk for Developing Type 1 Diabetes. Press Release. Available at: http://www.diabetes.org/newsroom/press-releases/2017/larsson-scientific-sessions-2017.html. Accessed June 21, 2017.

Joanna Martinez-Mendez, PharmD Candidate 2018, Lake Erie College of Osteopathic Medicine School of Pharmacy: FL Campus

Results presented in the ADA 77th Scientific Sessions suggest the use of an investigational glucagon-blocking agent can improve glycemic levels and reduce insulin requirements.

A balance of insulin and glucagon are necessary for optimal blood glucose levels. However, patients with diabetes not only have a decrease in insulin, but an increase in glucagon levels as well. Glucagon will then stimulate gluconeogenesis and the breakdown of glycogen and fats to contribute to hyperglycemia. In theory, using a glucagon-blocking agent in patients with type 1 diabetes should reduce blood glucose levels and lower the insulin dose required to maintain target blood glucose concentrations. REMD-477, an investigational glucagon-blocking drug, is a monoclonal antibody that has been shown to normalize blood glucose levels in rodent studies without the need for exogenous insulin.

A phase 1 study was recently conducted to evaluate the effects of REMD-477 in patients with type 1 diabetes. The randomized, double-blind, placebo-controlled trial admitted a total of 21 patients for observation in an inpatient setting for a period of 5 days. Continuous glucose monitoring (CGM) data was gathered for approximately two weeks prior to the start of the study and the investigators maintained participant’s glucose levels by providing identical meals and continuous insulin infusions. On day 2, ten participants received a 70 mg subcutaneous REMD-477 injection while eleven participants received placebo injections. The study gathered data on the daily insulin use and glucose levels on days 3 and 4 as well as CGM data for approximately 8 weeks after administration of the study dose.

Results of the study indicated that on day 4, participants treated with REMD-477 reduced the amount of daily insulin use by 26% or 12 units compared to placebo (-14 vs 12; p = 0.02). The average daily blood glucose concentration was 20-31mg/dL lower in the REMD-477 treatment group compared to placebo (p < 0.05) in the first three weeks after the study dose. This can be contributed to the long half-life of the investigational drug (7-10 days). During the first week after the conclusion of the study, participants in the REMD-477 study group experienced more time in target glycemic range (71 vs 56; p = 0.001), less time in hyperglycemia (23 vs. 39; p = 0.001) and similar time in hypoglycemia (6 vs 5) compared to those in the placebo study group.

The results of this study show a single dose of REMD-477 can significantly reduce the daily insulin dose requirement, reduce time spent in hyperglycemia and increase the total time spent in target range without an increased risk of hypoglycemia in patients with type 1 diabetes. These qualities can help patients gain better control and management of their disease. These promising results of the phase 1 trial have launched a follow-up phase 2 trial to compare two different dose strengths of REMD-477 for an even longer trial period in an outpatient setting.

Practice Pearls:

• Hyperglycemia in patients with type 1 diabetes is caused by an imbalance of insulin and glucagon.
• In this phase 1 study, a single dose of REMD-477 reduced the daily insulin dose requirement by 12 units on day 4 and increase time spent in target glucose concentration in patients with type 1 diabetes.
• REMD-477 will begin a phase 2 trial to gain better understanding on the effects of this investigational drug is multiple doses.

References:

American Diabetes Association. Glucagon-Blocking Drug Reduces Need for Insulin and Improves Blood Glucose Levels for Patients with Type 1 Diabetes. Press Release. Available at: http://www.diabetes.org/newsroom/press-releases/2017/pettus-scientific-sessions-2017.html. Accessed June 21, 2017.

REMD Biotherapeutics. Results of Phase 1 Study presented in President’s Oral Session Presentation at the American Diabetes Association 77th Scientific Sessions. News. Available at: http://www.remdbio.com/new-media. Accessed June 21, 2017.

Joanna Martinez-Mendez, PharmD Candidate 2018, Lake Erie College of Osteopathic Medicine School of Pharmacy: FL Campus