News from ADA 2018

Real-World Study of More than 700,000 People with Type 2 Diabetes (T2D) Shows No Increased Risk of Below-Knee Lower Extremity Amputations with Canagliflozin Compared to Other Diabetes Medications

A new real-world analysis of more than 700,000 U.S. T2D patients found no increased risk of below-knee lower extremity (BKLE) amputation with canagliflozin compared to other sodium glucose cotransporter 2 inhibitors (SGLT2i) or non-SGLT2i anti-hyperglycemic medicines. In addition to the general T2D population, similar results were also seen in a sub-set of patients with T2D and established cardiovascular disease. The Janssen Pharmaceutical Companies of Johnson & Johnson market canagliflozin as INVOKANA^®.

OBSERVE-4D is the largest, most comprehensive real-world observational study to evaluate the risk of BKLE amputation and hospitalization for heart failure (HHF) across anti-hyperglycemic therapies. Full findings from the late-breaking presentation were highlighted in the American Diabetes Association’s (ADA) 78^th Official Press Program in Orlando, Florida and simultaneously published in Diabetes, Obesity and Metabolism.

“We initiated OBSERVE-4D to better characterize the real-world use of INVOKANA and the SGLT2i class, so physicians and their patients could make better informed treatment decisions,” says Paul Burton, MD, PhD, FACC, vice president, Medical Affairs, Janssen Scientific Affairs, LLC. “Prior to this analysis, no real-world study had evaluated head-to-head comparative evidence on amputation and hospitalization for heart failure across individual SGLT2i medicines.”

Researchers observed no increased risks across the therapy comparisons for BKLE amputations in the general T2D population:

• INVOKANA all non-SGLT2i medicines: HR (95% CI): 0.75 (0.40, 1.41), p=0.30.
• INVOKANA other SGLT2i medicines: HR (95% CI): 1.14 (0.67, 1.93), p=0.53.
• Other SGLT2i medicines vs. all non-SGLT2i medicines: HR (95% CI): 0.84 (0.27, 2.55), p=0.68.

These amputation rates were also consistent in a sub-population with established cardiovascular disease:

• INVOKANA all non-SGLT2i medicines: HR (95% CI): 0.72 (0.34-1.51), p=0.29.
• INVOKANA other SGLT2i medicines: HR (95% CI): 1.08 (0.63-1.82), p=0.85.

“OBSERVE-4D depicts how INVOKANA and other SGLT2is are being used by people with type 2 diabetes, including in those with established CV disease, in the real world,” says John Buse, MD, PhD, chief of the Division of Endocrinology and Director of the Diabetes Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. “The overall benefit-risk profile of SGLT2is is positive, and physicians should feel comfortable and confident in prescribing the class to their appropriate patients.”

In addition to showing no significant imbalance of BKLE amputation, the study also identified a HHF reduction in the general T2D population that was consistent with rates seen in randomized clinical trials and other real-world evidence studies including the SGLT2i class. The HHF result is a positive confirmatory finding and supports the internal validity of the study results:

• INVOKANA was associated with a 61 percent reduction in the risk of HHF compared to non-SGLT2i medicines: HR=0.39 (95% CI): 0.26, 0.60, p=0.01.
• Similar risk reductions were seen with INVOKANA other SGLT2i medicines: HR (CI) 0.90: 0.71, 1.13, p=0.28.

“The OBSERVE-4D findings are welcome news for patients and the physicians who treat them,” says Ralph DeFronzo, MD, professor of medicine and chief of the Division of Diabetes at UT Health. “These data reaffirm the confidence we’ve always had in the SGLT2i class.”

SGLT2is, including INVOKANA, are anti-hyperglycemic therapies prescribed for the treatment of T2D. Evidence was published last year from the CANVAS (CANagliflozin cardioVascular Assessment Study) Program, which was the first program to assess the efficacy, safety, and durability of INVOKANA in more than 10,000 patients with T2D who had either a prior history of CV disease or at least two CV risk factors.

However, an increased risk of BKLE amputation was seen with INVOKANA in the CANVAS Program and is reflected in its U.S. prescribing information. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657.^, INVOKANA (canagliflozin) U.S. Prescribing Information. Available at http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/INVOKANA-pi.pdf.

Oral Semaglutide Demonstrated Significant Reduction in Blood Sugar vs Placebo in PIONEER 1 Trial

Oral semaglutide, an investigational GLP-1 receptor agonist taken as a once-daily tablet, achieved significant reductions in blood sugar versus placebo in adults with type 2 diabetes, according to findings from the PIONEER 1 phase 3a trial. The trial evaluated the efficacy and safety of 3, 7 and 14 mg oral semaglutide compared with placebo as monotherapy over 26 weeks in adults with type 2 diabetes. The new data were presented at the American Diabetes Association’s 78^th Scientific Sessions (ADA) in Orlando, Fla.

Two distinct approaches to evaluating the effects of oral semaglutide were applied in the PIONEER 1 trial; a primary approach utilizing an intention-to-treat principle required by recent regulatory guidance, evaluating the treatment effect including the effect of any rescue medication and regardless of premature trial product discontinuation; a secondary approach utilizing an on-treatment principle evaluated the treatment effect while on trial product and without use of rescue medication.

Applying the intention-to-treat principle, the trial achieved its primary objective by demonstrating that people treated with any of the three doses of oral semaglutide achieved significant A1C reductions compared to placebo (p<0.001 for all estimated treatment differences [ETD] in A1C for oral semaglutide vs placebo). Furthermore, people treated with 14 mg oral semaglutide achieved significant reductions (p<0.001) in weight vs placebo while weight reductions with 7 mg and 3 mg doses did not reach statistical significance.

When applying the on-treatment principle, from a mean baseline A1C of 8.0%, people treated with 3, 7 and 14 mg oral semaglutide achieved A1C reductions of 0.8%, 1.3% and 1.5%, respectively, compared to 0.1% with placebo (p<0.001 vs placebo for ETD of oral semaglutide vs placebo).¹ In addition, 59%, 72% and 80% of people respectively treated with oral semaglutide achieved the ADA treatment target of A1C below 7%, compared to 34% treated with placebo (p<0.001 for odds for achieving the target).

Furthermore, when applying the on-treatment principle, people treated with 3, 7 and 14 mg oral semaglutide experienced a weight loss of 1.7 kg (3.7 lb), 2.5 kg (5.5 lb) and 4.1 kg (9.0 lb), respectively, compared to 1.5 kg (3.3 lb) with placebo (p<0.001 for ETD of oral semaglutide 14 mg vs placebo, p<0.05 for oral semaglutide 7 mg vs placebo, oral semaglutide 3 mg vs placebo was not statistically significant). Moreover, 21%, 29% and 44% of people treated with oral semaglutide achieved a weight reduction of 5% or more compared to 16% with placebo.

The most common adverse events (>5%) were mild or moderate nausea, which occurred in 5–16% of people treated with oral semaglutide and diminished over time, compared with 6% in those treated with placebo. Overall, adverse events were reported by 58%, 53% and 57% of people treated with 3, 7 and 14 mg oral semaglutide, respectively, and in 56% of people treated with placebo. Treatment discontinuation due to adverse events ranged from 2% to 7% for people treated with oral semaglutide, compared to 2% for people treated with placebo.

Semaglutide Provided Greater Weight Reductions for Adults with a Baseline BMI ≥25kg/m² than Those with Lower Baseline BMI <25kg/m², in a SUSTAIN 7 Post-Hoc Analysis

Semaglutide injection 0.5 mg or 1 mg provided greater weight reductions vs dulaglutide 0.75 mg or 1.5 mg, respectively, in adults with type 2 diabetes, regardless of baseline body mass index (BMI), with the greatest reductions occurring in adults with a baseline BMI ≥25 kg/m². While the primary endpoint of SUSTAIN 7 was change in A1C, this post-hoc exploratory analysis examined the secondary endpoint of change in body weight by baseline BMI. The results were presented at the American Diabetes Association’s 78^th Scientific Sessions (ADA) in Orlando, Fla. Novo Nordisk markets semaglutide as Ozempic^® 

Greater weight reductions were demonstrated across all BMI subgroups (<25, 25–<30, 30–<35, ≥35 kg/m²) with Ozempic 0.5 mg vs dulaglutide 0.75 mg (range of weight reduction across all subgroups: 3.6–5.5 kg vs 0.9–3.4 kg) and with Ozempic 1 mg vs dulaglutide 1.5 mg (range of weight reduction across all subgroups: 5.2–7.6 kg vs 2.0–3.8 kg), from a mean baseline of 95.2 kg.¹ Adults with a higher baseline BMI (≥25 kg/m²) taking Ozempic generally achieved greater weight reductions than those with lower baseline BMI (<25 kg/m²).

In addition, more people achieved weight reduction of ≥5% and ≥10% with Ozempic vs dulaglutide in all BMI subgroups.

“Globally, up to ninety percent of people with type 2 diabetes are overweight or have obesity.² Therefore, it is important to consider how to manage weight in this population,”  says Adie Viljoen, SUSTAIN 7 chief investigator and consultant chemical pathologist, East and North Hertfordshire NHS Trust, UK. “Based on the SUSTAIN clinical trial program, Ozempic can help people living with type 2 diabetes manage their A1C and has the potential to help them lose some weight.”

Across BMI subgroups, fewer people reported gastrointestinal (GI) adverse events with the low dulaglutide dose (0.75 mg) compared with the other three treatment groups (Ozempic 0.5 and 1 mg, and dulaglutide 1.5 mg). The most common adverse events (≥5%) for both Ozempic dosages were GI adverse events.

Insulin Degludec Injection Demonstrated Significantly Lower A1C and Rates of Hypoglycaemia vs Insulin Glargine U-300 in Real-World Evidence Study

Findings from CONFIRM – a large, retrospective real-world evidence (RWE) study comparing the effectiveness of insulin degludec injection 100 U/mL, 200 U/mL versus insulin glargine U-300 in more than 4,000 adults with type 2 diabetes who were starting basal insulin for the first time showed that after six months those treated with Tresiba^® had significantly lower A1C compared to those treated with insulin glargine U-300 (-1.5% vs -1.2% respectively; p=0.029). The full results were presented at the American Diabetes Association’s 78^th Scientific Sessions (ADA) in Orlando, Fla. Novo Nordisk markets insulin degludec injection as Tresiba^®

As a secondary endpoint, there was a 30% lower rate of hypoglycaemic episodes with Tresiba compared to insulin glargine U-300 (p=0.045). In this study, hypoglycaemic events were registered using the International Classification of Diseases (ICD) codes 9/10 following diagnosis from a health care provider.

This real-world study also showed in another secondary endpoint that people treated with Tresiba were more likely to stay on their treatment. Those treated with insulin glargine U-300 had a 37% higher rate of discontinuing treatment after two years (p<0.001).

“Real-world studies, such as CONFIRM, are important to understand how clinical trials may translate to patients in everyday clinical practice,” says Todd Hobbs, vice president and US chief medical officer of Novo Nordisk. “One of the most feared complications for people living with diabetes is hypoglycaemia, and the CONFIRM results add to the body of evidence on Tresiba for adults with type 2 diabetes.”

Study Show Patients Using CONTOUR^®NEXT ONE Smart Meter and App Reported Better Understanding and Engagement in Diabetes Management

This week at the American Diabetes Association 78^th Scientific Sessions, data were presented from a study sponsored by Ascensia Diabetes Care that assessed user experience for the CONTOUR^®NEXT ONE smart meter and app system. The results of this study are featured in three poster presentations that showed that the majority of subjects in the trial responded that the system would provide them with a better understanding of their diabetes and  helped them feel more engaged with their diabetes self-management.

The results were obtained in a 6-week study of 46 insulin-using individuals with diabetes who were using the CONTOUR^®NEXT ONE smart meter and a prototype version of the CONTOUR^®DIABETES app (Release 2). The latest version of the app, which was released in the United States in May 2018, includes the new My Patterns feature, which uses innovative algorithms to more intelligently analyze blood glucose results received from the meter, and delivers personalized meaningful feedback to patients. It is based on the Information, Motivation and Behavioral Skills (IMB) model of health behavior change, that has been applied to diabetes self-management. The IMB model emphasizes the need for actionable information, motivation to act, and behavioral skills for acting effectively, to strengthen self-management of diabetes.

Data presented in the first poster showed that almost all subjects strongly agreed/agreed that using the meter and app system provided them with a better understanding of their disease (98%) and helped them feel more engaged with their diabetes management program (91%). More than three out of four subjects (76%) strongly agreed/agreed that they felt more motivated to adhere to their health care provider’s therapy and testing recommendations. In addition, subjects strongly agreed/agreed that the “My Patterns” pattern recognition feature was helpful in managing their diabetes (73%).

Fructosamine levels and HbA1c  were also measured during the study. The predetermined analysis presented in the second poster that was part of the study protocol showed that mean fructosamine levels, which correlate to blood glucose levels over the prior 2-3 weeks, decreased significantly from the beginning to the end of the study (P = 0.0076). The average change in HbA1c for subjects was not significant between their two study visits.

Additional post hoc analyses in the third poster revealed  a significant decrease in the number of above-target (“high”) blood glucose measurements at the end of the study compared to the beginning (P <0.0003). The average number of blood glucose tests performed per week increased significantly over the course of the study (P <0.0001), indicating the potential effects of using the system on encouraging patient adherence to treatment and better control of blood glucose levels. A consistent decrease in the average blood glucose values for fasting, before meal, and after meal was also observed, but this was not statistically significant.