Christopher Sorli

Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial

BACKGROUND Despite a broad range of pharmacological options for the treatment of type 2 diabetes, optimum glycaemic control remains challenging for many patients and new therapies are necessary. Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue in phase 3 development for type 2 diabetes. We assessed the efficacy, safety, and tolerability of semaglutide monotherapy, compared with placebo, in treatment-naive patients with type 2 diabetes who had insufficient glycaemic control with diet and exercise alone. METHODS We did a double-blind, randomised, parallel-group, international, placebo-controlled phase 3a trial (SUSTAIN 1) at 72 sites in Canada, Italy, Japan, Mexico, Russia, South Africa, UK, and USA (including hospitals, clinical research units, and private offices). Eligible participants were treatment-naive individuals aged 18 years or older with type 2 diabetes treated with only diet and exercise alone for at least 30 days before screening, with a baseline HbA1c of 7·0%-10·0% (53-86 mmol/mol). We randomly assigned participants (2:2:1:1) to either once-weekly subcutaneously injected semaglutide (0·5 mg or 1·0 mg), or volume-matched placebo (0·5 mg or 1·0 mg), for 30 weeks via prefilled PDS290 pen-injectors. Participants did their own injections and were encouraged to administer them on the same day of each week in the same area of their body; the time of day and proximity of meal times was not specified. We did the randomisation with an interactive voice or web response system. Investigators, participants, and the funder of the study remained masked throughout the trial. The primary endpoint was the change in mean HbA1c from baseline to week 30, and the confirmatory secondary endpoint was the change in mean bodyweight from baseline to week 30. We assessed efficacy and safety in the modified intention-to-treat population (ie, all participants who were exposed to at least one dose of study drug); both placebo groups were pooled for assessment. This trial was registered with ClinicalTrials.gov, number NCT02054897. FINDINGS Between February 3, 2014, and August 21, 2014, we randomly assigned 388 participants to treatment; 387 received at least one dose of study medication (128 0·5 mg semaglutide, 130 1·0 mg semaglutide, 129 placebo). 17 (13%) of those assigned to 0·5 mg semaglutide, 16 (12%) assigned to 1·0 mg semaglutide, and 14 (11%) assigned to placebo discontinued treatment; the main reason for discontinuation was gastrointestinal adverse events such as nausea. Mean baseline HbA1c was 8·05% (SD 0·85); at week 30, HbA1c significantly decreased by 1·45% (95% CI -1·65 to -1·26) with 0·5 mg semaglutide (estimated treatment difference vs placebo -1·43%, 95% CI -1·71 to -1·15; p<0·0001), significantly decreased by 1·55% (-1·74 to -1·36) with 1·0 mg semaglutide (estimated treatment difference vs placebo -1·53%, -1·81 to -1·25; p<0·0001), and non-significantly decreased by 0·02% (-0·23 to 0·18) with placebo. Mean baseline bodyweight was 91·93 kg (SD 23·83); at week 30, bodyweight significantly decreased by 3·73 kg (95% CI -4·54 to -2·91) with 0·5 mg semaglutide (estimated treatment difference vs placebo -2·75 kg, 95% CI -3·92 to -1·58; p<0·0001), significantly decreased by 4·53 kg (-5·34 to -3·72) with 1·0 mg semaglutide (estimated treatment difference vs placebo -3·56 kg, -4·74 to -2·38; p<0·0001), and non-significantly decreased by 0·98 kg (-1·82 to -0·13) with placebo. No deaths were reported in any of the study groups and most reported adverse events were of mild or moderate severity. The most frequently reported adverse events in both semaglutide groups were gastrointestinal in nature: nausea was reported in 26 (20%) who received 0·5 mg semaglutide, 31 (24%) who received 1·0 mg semaglutide, and 10 (8%) who received placebo, and diarrhoea was reported in 16 (13%) who received 0·5 mg semaglutide, 14 (11%) who received 1·0 mg semaglutide, and three (2%) who received placebo. INTERPRETATION Semaglutide significantly improved HbA1c and bodyweight in patients with type 2 diabetes compared with placebo, and showed a similar safety profile to currently available GLP-1 receptor agonists, representing a potential treatment option for such patients. FUNDING Novo Nordisk A/S, Denmark.

An Analysis of Data Management Tools for Diabetes Self-Management: Can Smart Phone Technology Keep Up?

In this issue of Journal of Diabetes Science and Technology, Rao and colleagues present a comparison of three iPhone diabetes data management applications: the Diamedic Diabetes Logbook, Blood Sugar Diabetes Control, and WaveSense Diabetes Manager. These applications provide patients the ability to enter blood glucose readings manually, view graphs and simple statistics, and email data to health care providers. While these applications show promise, they are limited in their current forms. All require manual data entry and none convert insulin-to-carbohydrate ratios to insulin dose. Future development of these types of technology should consider integration with blood glucose meters and expanded calculation capabilities, as well as monitoring of other risk factors, e.g., blood pressure and lipids, and tracking of preventive examinations, e.g., eye, foot, and renal.

New Developments in Insulin Therapy for Type 2 Diabetes

Insulin has classically been considered a treatment of last resort for individuals with type 2 diabetes, delayed until all other efforts by the patient and healthcare provider have failed. Recent treatment guidelines recommend the use of insulin, in particular basal insulin, as part of a treatment regimen earlier in the disease process. Many patients are reticent about initiating insulin, so therapies that allow insulin treatment to be more tailored to individual needs are likely to result in greater acceptance and patient adherence with therapy. To meet this need, a range of insulin products are in development that aim to increase absorption rate or prolong the duration of action, reduce peak variability and weight gain associated with insulin treatment, and offer alternative delivery methods. This review describes insulin products in clinical development, new combination therapies, and new devices for insulin delivery.

The dynamic relationship between current and previous severe hypoglycemic events: a lagged dependent variable analysis among patients with type 2 diabetes who have initiated basal insulin

Abstract Background and objective: Past studies have found episodes of severe hypoglycemia (SH) to be serially dependent. Those studies, however, only considered the impact of a single (index) event on future risk; few have analyzed SH risk as it evolves over time in the presence (or absence) of continuing events. The objective of this study was to determine the dynamic risks of SH events conditional on preceding SH events among patients with type 2 diabetes (T2D) who have initiated basal insulin. Methods: We used an electronic health records database from the United States that included encounter and laboratory data and clinical notes on T2D patients who initiated basal insulin therapy between 2008 and 2011 and to identify SH events. We used a repeated-measures lagged dependent variable logistic regression model to estimate the impact of SH in one quarter on the risk of SH in the next quarter. Results: We identified 7235 patients with T2D who initiated basal insulin. Patients who experienced ≥1 SH event during any quarter were more likely to have ≥1 SH event during the subsequent quarter than those who did not (predicted probabilities of 7.4% and 1.0%, respectively; p < 0.01). This effect was stronger than the impact of history of SH before starting basal insulin (predicted probabilities of 1.0% and 3.2%, respectively; p < 0.01) or of a history of SH during the titration period (predicted probabilities of 1.1% and 2.8%, respectively; p < 0.01). Conclusions: The risk of experiencing a SH event is highly dependent on a patient’s immediate history of SH events and therefore the value of preventing one SH event may be substantial. These results can inform patient care by providing clinicians with dynamic data on a patient’s risk of SH, which in turn can facilitate appropriate adjustment of the risk–benefit ratio for individualized patient care. These results should, however, be interpreted in light of the key limitations of our study: not all SH events may have been captured or coded in the database, data on filled prescriptions were not available, we were unable to adjust for basal insulin dose, and the post-titration follow-up period could have divided into time units other than quarters (3 month blocks) resulting in potentially different conclusions. Further real-world studies on how to best to identify patients at risk for SH events based on the presence of recent SH events, rather than on more distant ‘prior’ events, can help healthcare providers to better manage patients starting basal insulin.

Insulin Therapy in Type 2 Diabetes: A Reflection on the State of the Art Today, and the Potential Journeys Yet to Come

It will not be long before we are celebrating the centenary of the clinical use of insulin. Indeed, it is already more than 100 years since Sir Edward Albert Sharpey-Schafer (in 1910) coined the term “insulin” (meaning “island”) for a putative hormone that was then believed to be a product of the islets of Langerhans, and the absence of which was considered to be the cause of diabetes. The outlook for people diagnosed with diabetes at that time, however, was still bleak. Most recognized cases of diabetes were of what we would now term “type 1 diabetes,” and although a low carbohydrate diet could extend life expectancy by months, at best, a diagnosis of diabetes usually was regarded as a death sentence. But things were about to change. In little more than a decade, Banting, Best, Collip, and Macleod had succeeded in isolating insulin, and in 1922 it was used clinically for the first time, famously saving the life of a 14-year-old patient, Leonard Thompson, who survived for a further 13 years courtesy of his insulin injections. Since that time, the refinement of insulin therapy has been an ongoing process, gathering pace in the last 2 decades with the arrival of insulin analogs, new delivery technologies, and a plethora of clinical studies informing us about the optimal use of insulin and the clinical impact of targets for glycemic control. Progress in insulin therapy has been accompanied by a progressive improvement in the prognosis of people with type 1 diabetes, and some recent studies suggest that the gap in life expectancy between those with type 1 diabetes and those without diabetes is narrowing quickly, although the quality of life of patients with type 1 diabetes might be reduced by diabetic complications. Alongside this predominantly positive story, another less palatable one has been unfolding in the guise of the growing pandemic of obesity and type 2 diabetes. It is difficult to make accurate assertions about the prevalence of these

Elderly Patients Experience a Lower Rate of Nocturnal Hypoglycemia with Insulin Degludec Than with Insulin Glargine: A Meta-Analysis of Phase 3a Trials

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