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

The value of self-monitoring of blood glucose (SMBG) levels in patients with non-insulin-treated type 2 diabetes has been debated over the years.

A study was done to compare 3 approaches of SMBG for effects on hemoglobin A1c levels and health-related quality of life (HRQOL) among people with non-insulin-treated type 2 diabetes in primary care practice.

The Monitor Trial study was a pragmatic, open-label randomized trial conducted in 15 primary care practices in central North Carolina. Participants were randomized between January 2014 and July 2015. Eligible patients with type 2 non-insulin-treated diabetes were: older than 30 years, established with a primary care physician at a participating practice, had glycemic control (hemoglobin A1c) levels higher than 6.5% but lower than 9.5% within the 6 months preceding screening, as obtained from the electronic medical record, and willing to comply with the results of random assignment into a study group. Of the 1032 assessed for eligibility, 450 were randomized.

No SMBG, once-daily SMBG, and once-daily SMBG with enhanced patient feedback,  including automatic tailored messages delivered via the meter.

Coprimary outcomes included hemoglobin A1c levels and HRQOL at 52 weeks. A total of 450 patients were randomized and 418 (92.9%) completed the final visit. There were no significant differences in hemoglobin A1c levels across all 3 groups. There were also no significant differences found in HRQOL. There were no notable differences in key adverse events, including hypoglycemia frequency, health care utilization, or insulin initiation.

From the results In patients with non-insulin-treated type 2 diabetes, they observed no clinically or statistically significant differences at 1 year in glycemic control or HRQOL between patients who performed SMBG compared with those who did not perform SMBG. The addition of this type of tailored feedback provided through messaging via a meter did not provide any advantage in glycemic control.

Practice Pearls:

• No intensive education was included in the study.
• Patients with non–insulin treated type 2 diabetes receive no benefit from SMBG.
• The final conclusions are not valid if you do not educate the patients as what to do with the readings.

In another study to review in comparison with Young et al. is a 1-year evaluation of structured self-monitoring of blood glucose. In the Polonsky study, 483 patients with poorly controlled non–insulin-treated type 2 diabetes were randomly assigned to enhanced usual care vs enhanced usual care plus structured SMBG. The structured testing arm participants performed 7-point SMBG profiles on 3 days prior to each scheduled study visit, recording medications, food, and activity in relation to SMBG. More importantly, providers were trained to interpret the structured SMBG profiles and were provided with an algorithm of potential treatment strategies to use depending on the pattern identified. Baseline mean A1c was 8.9%. In the Polonsky study, both treatment arms improved over time, with 12-month A1c results favoring the structured testing group by 0.3% in the intention-to-treat analysis and 0.5% in the per-protocol analysis. Participants in the structured testing group had more medication changes made at their study visits.

Taking into account the balance of the evidence, routine daily SMBG in patients with non–insulin treated, reasonably well-controlled type 2 diabetes is probably a low-value activity on a population level. However, patients with less–well-controlled type 2 diabetes, or those who are using the information in a targeted fashion to gain behavioral insight or to make treatment decisions, probably do derive modest benefit in terms of overall glycemic control, especially when their care providers review and act on the information.

Publisher Comments:  From my experience as a diabetes educator,  I have found that first of all, 90%+ of these patients not on insulin are told to check their blood sugars once daily in the mornings before eating. I never understood why that is the case, so I ask my patients 3 questions, which are:

1.     When does diabetes cause the most damage?  When your blood sugars are high or when they are normal?
2.     When are your blood sugars the highest?  Before you eat or after you eat?
3.     After they answer I add, you just told me that your blood sugars cause the most damage when they are high and they are higher after meals, so why do you only check your blood sugars in the morning when they are usually the lowest prior to eating? Checking your blood sugars 1 1/2 to 2 hours after eating can teach you what different foods can do to your blood sugars. Then you can change your diet to foods that do not raise your blood sugars as much.

This gets patients to check their blood sugars after meals for different foods.  So educating your patients can motivate them to check more often and take action. But, just to have them check their morning blood sugars when most likely no one even checks them may not be the best option.Most of the time their logs are blank or with very few readings.

JAMA Intern Med. 2017 Jun 10. doi: 10.1001/jamainternmed.2017.1233. [Epub ahead of print]

Polonsky WH, Fisher L, Schikman CH, et al. Structured self-monitoring of blood glucose significantly reduces A1C levels in poorly controlled, noninsulin-treated type 2 diabetes: results from the Structured Testing Program study. Diabetes Care. 2011;34(2):262-267. http://care.diabetesjournals.org/content/34/2/262

The Endocrinologic and Metabolic Drugs Advisory Committee also voted 19-0 that the drug’s use in type 2 diabetes patients did not result in excess cardiovascular risk.

An FDA advisory committee voted 17-2 on Tuesday that the diabetes drug liraglutide (Victoza) appeared to reduce cardiovascular risk in patients with type 2 diabetes, but expressed concern about which groups the finding applied to.

Novo Nordisk the maker of Liraglutide is seeking an additional indication for the drug’s use as an adjunct to standard treatment of cardiovascular risk factors to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes and high cardiovascular risk.

The application from Novo Nordisk’s was based entirely on a single trial known as the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial. Although the FDA typically requires at least two trials to support a new efficacy claim, the agency review documents noted that there is precedent to rely on a single trial if it shows strong evidence of a benefit. Its case in point was empagliflozin (Jardiance), which last year became the first diabetes drug to gain a supplemental indication for prevention of cardiovascular death in patients with type 2 diabetes and cardiovascular disease based on the results of the EMPA-REG outcomes trial alone, which showed a 32% reduction of the risk of death from any cause in the empagliflozin group.

The LEADER trial involved 9,340 patients randomized to either liraglutide or placebo; the trial had a minimum duration of 42 months and a targeted minimum number of 611 major adverse cardiovascular events (MACE). Patients who were randomized to liraglutide started with 0.6 mg of the drug and could be escalated weekly to up to 1.8 mg as needed. Inclusion criteria included a hemoglobin A1c of at least 7% and high cardiovascular risk, which was defined in two ways:

• Patients ages 50 to 59 who had one of several risk factors including prior myocardial infarction, more than a 50% stenosis on angiography, chronic kidney disease, or chronic heart failure NYHA class II-III, or
• Patients ages 60 or greater with microalbuminuria or macroalbuminuria, hypertension and left ventricular dysfunction, or ankle/brachial index greater than 0.9.

The trial found that 13% of the patients on liraglutide experienced a MACE, compared with 14.9% of patients on placebo. In addition, 3.9% of patients in the liraglutide group died from cardiovascular disease, compared with 4.9% of the placebo group.

However, when the FDA analysts stratified the results by geographic area, they found that the U.S. patients on liraglutide — who represented 27% of the patients on the drug — actually showed a 3% increase in MACE compared with those from outside the U.S. (HR 1.03, 95% CI 0.84-1.25) while those outside the U.S. had a 19% decrease; similar results were found for cardiovascular deaths in the U.S. liraglutide group (HR 1.04, 95% CI .0.75-1.45), while the non-U.S. group showed a 30% decrease. These findings disturbed many committee members.

Carmen Allegra, MD, chief of hematology and oncology at the University of Florida, added that, “I was very much concerned and swayed by the subgroup analysis who voted “no” on the issue of whether the drug reduced cardiovascular disease risk….I think the U.S. target population is a pretty darn important population to consider. We saw a significant interaction with outcomes versus the region by the FDA’s analysis. It wasn’t a small amount of patients, it was a substantial population given it was a significant percentage of the total.”

In looking at secondary endpoints, the FDA researchers noted a small increase in pancreatic cancer among liraglutide patients, although reviewer Julie Golden, MD, noted that “it is not known if that is attributable to liraglutide, other factors, or chance. The uncertainty decreases our confidence somewhat in the findings.”

The agency also studied incidents of thyroid cancer and found no excess events of overall thyroid neoplasms, C-cell hyperplasia, or medullary thyroid cancer in the liraglutide group compared with placebo, although staff member Shannon Sullivan, MD, PhD, noted that there were “small overall event rates for thyroid neoplasms (0.1%) and a short duration of follow-up (median 3.8 years), which is a relatively short time to observe thyroid events.”

The data from LEADER could potentially impact the current boxed warning for risk of dose-dependent and treatment-duration-dependent thyroid C-cell tumors and precautions about pancreatitis risk on the product label.

Note:  In the Empaglifozin trial they found a relative reduction of 32% in the risk of death from any cause in the empagliflozin group.

Practice Pearls:

• The trial found that 13% of the patients on liraglutide experienced a MACE, compared with 14.9% of patients on placebo.
• 3.9% of patients in the liraglutide group died from cardiovascular disease, compared with 4.9% of the placebo group.
• U.S. patients on liraglutide — who represented 27% of the patients on the drug — actually showed a 3% increase in MACE compared with those from outside the U.S.

FDA Briefing June 20, 2017

However, in 2016, Novo Nordisk halted the development of their basal oral insulin tablet.

An oral insulin formulation has been a desirable product among patients and healthcare providers because the ease of administration would increase medication compliance. It would also allow patients with type 2 diabetes to initiate insulin earlier in their disease to gain quicker glycemic control. However, low bioavailability of insulin in an oral formulation has made it difficult to produce adequate plasma concentrations. One drug company, Novo Nordisk, has been developing an oral insulin formulation, OI338GT, in GIPET I tablet technology. The GIPET technology uses absorption enhancers to increase the plasma concentrations of insulin.

Researchers of Novo Nordisk presented their research at the ADA 77th Scientific Session on the safety and efficacy of OI338GT compared to injectable insulin glargine. Participants with type 2 diabetes who were included in the study were insulin naïve and uncontrolled on metformin alone or in combination with other oral antidiabetic medications. 50 participants were enrolled in the phase 2a double-blind, double dummy study for 8 weeks. They were randomized in a 1:1 ratio. 25 participants received once-daily oral OI338GT and a placebo injection while the remaining 25 participants received insulin glargine U100 and a placebo oral tablet. The study groups were titrated up to achieve target fasting blood glucose levels between 80 and 126 mg/dL. Baseline characteristics between the two study groups were similar and the primary outcome, improvement of glycemic control, was measured by a change in fasting blood glucose levels from baseline to week 8. Other outcomes of interest included HbA1c, fructosamine, c-peptide and rate of adverse effects.

Using a linear mixed model for repeated measurements, the results indicated oral insulin was as efficacious as insulin glargine in lowering fasting blood glucose levels [Treatment Difference = 5.2 mg/dL (95%CI: -8.8 to 19.1) p = 0.4567]. Participants treated with oral insulin had similar decrease in average HbA1c from baseline (8.1% vs. 8.2%) to week 8 (7.3% vs. 7.1%) compared to placebo [Treatment Difference = 0.30% (95% CI: -0.33 to 0.63) p = 0.0774]. Fructosamine (p = 0.3700) and fasting c-peptide (p = 0.6799) were also reduced similarly between the two groups. There was no difference in the number of treatment emergent hypoglycemia between the two study groups and no events of severe hypoglycemia were reported.

This study proves it is feasible to formulate an oral insulin tablet with comparable efficacy to injectable insulin. Novo Nordisk has unfortunately stopped further development and research of OI338GT until technological advances can make this product commercially viable in large scale manufacturing. The biggest issue is the low bioavailability, which requires large amounts of the medication to produce adequate plasma concentration levels. However, other companies, such as Oramed Pharmaceutical, are also researching and developing their own oral insulin formulation (ORMD-0801). Therefore, it is still possible to see an oral formulation come into the market in a few years.

Practice Pearls:

• OG338GT, an oral insulin tablet, is just as efficacious in lowering fasting blood glucose and HbA1c levels as insulin glargine injections.
• Novo Nordisk, manufacturer of OG338GT, has stopped further development and research because a large scale manufacturing of their product would not be commercially viable.
• Oral insulin formulations may still be available in the upcoming years due to continued research and development from various pharmaceutical companies.

References:

American Diabetes Association. Daily, Long-Acting Oral Insulin Tablet Provides Comparable Glycemic Control to Insulin Glargine Injection in Patients with Type 2 Diabetes. Press Release. Available at: http://www.diabetes.org/newsroom/press-releases/2017/wassermann-scientific-sessions-2017.html. Accessed June 21, 2017.

McConaghie, Andrew. Pharmphorum. Oral insulin could still be a reality, says Novo Nordisk. News. Available at: https://pharmaphorum.com/news/oral-insulin-still-reality-says-novo-nordisk/. Accessed June 21, 2017.

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

The DEVOTE trial compared cardiovascular safety in two basal insulins; insulin degludec was found to have additional benefits.

Insulin therapy, although effective in lowering blood glucose levels in patients with type 2 diabetes (T2DM), is typically reserved for those who have failed combination oral antidiabetic therapies. This is due to the extensive classes of oral antidiabetic agents available and the risk of hypoglycemia associated with insulin therapy. If untreated, severe hypoglycemia can lead to coma, seizures and death. Basal insulin therapies, compared to bolus insulin therapies, lowers the risk of hypoglycemia, particularly nocturnal hypoglycemia. In 2015, the FDA approved insulin degludec, an ultra-long acting insulin with approximately 42 hours of effect and low intra-patient variability. The DEVOTE trial, recently published in June 2017, investigated the cardiovascular safety of insulin degludec in patients with type 2 diabetes and high risk for cardiovascular events. Researchers compared degludec to glargine, because cardiovascular safety of glargine has already been established in the ORIGIN trial.

The DEVOTE trial randomized 7,637 participants in a 1:1 ratio and followed participants for approximately 2 years. Participants received glargine or degludec once daily in addition to standard of care. Majority of the participants (85.2%) had a history of cardiovascular disease and/or moderate chronic kidney disease; the remainder of the participants had high risk for developing cardiovascular complications. The two study groups had similar baseline characteristics; the mean age was 65 years old and the mean duration of diabetes was 16.4 years. The primary outcome was a composite of first occurrence of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke. The data was analyzed using a cox proportional-hazard regression model to test for non-inferiority. The secondary outcomes, including severe hypoglycemia and nocturnal severe hypoglycemia were analyzed using a negative binomial-regression model and a logistic-regression model.

Results of the DEVOTE trial indicated that degludec was not inferior to glargine in the primary outcome (8.5 vs 9.3%; HR: 0.91; 95% CI 0.78 to 1.06; one-sided p < 0.001). Individual components (first occurrence of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke) was not considered statistically different between the two study groups. Participants in the degludec study group had a lower incidence of severe hypoglycemia compared to the participants in the glargine study group (3.70 vs 6.25 events per 100 patient years; Ratio Rate: 0.60; 95% CI 0.48 to 0.76; one-sided p < 0.001). This corresponds to a 40% overall reduction in the total episodes of hypoglycemia in this study. Researchers consider degludec superior to glargine in reducing the risk of nocturnal severe hypoglycemia by 53% (0.65 vs 1.40 events per 100 patient years; Ratio Rate: 0.47; 95% CI 0.31 to 0.73; p < 0.001). Lastly, the authors observed a decreased rate in adverse effects in the degludec study group compared to the glargine study group.

The trial assures healthcare providers that insulin degludec is comparable to glargine in cardiovascular safety for adult patients with type 2 diabetes. Degludec also has the added benefit of reducing the risk of severe hypoglycemia and nocturnal hypoglycemia, two major concerns of insulin therapy. This is potentially explained by degludec’s ultra-long duration of effect and lower intra-patient variability.

Practice Pearls:

•        The use of basal insulin therapy can increase glycemic control and decrease the risk of hypoglycemia for patients who fail first line oral antidiabetic combination therapies.
•        Insulin degludec can be regarded as a safe option in patients with type 2 diabetes and high risk of cardiovascular complications.
•        Insulin degludec demonstrated decreased risk of severe hypoglycemia and nocturnal hypoglycemia compared to insulin glargine.

References:

Marso S, McGuire D, Zinman B, et al. Efficacy and Safety of Degludec vs Glargine in Type 2 Diabetes. The New England Journal of Medicine. 2017. Epub 2017/06. doi: 10.1056/NEJMoa1615692

American Diabetes Association. New, Long-Acting Insulin Therapy Demonstrates Cardiovascular Safety and Reduces the Risk of Severe Hypoglycemia. Press Release. Available at: http://www.diabetes.org/newsroom/press-releases/2017/buse-and-marso-scientific-session-2017.html. Accessed June 15, 2017.

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