We wanted to understand the effects of once-weekly vs. twice-daily glucagon-like peptide-1 receptor agonism for treatment of patients with type 2 diabetes. The objective of the study was to compare effects of exenatide once weekly (ExQW) and exenatide twice daily (ExBID) on glycemic control, body weight, and safety. This was a 24-wk, randomized, open-label, comparator-controlled study. The study was conducted at 43 sites in the United States. The study population was 252 intent-to-treat patients with type 2 diabetes [baseline (mean ± SD): glycosylated hemoglobin (HbA1c) 8.4 ± 1.2%, fasting plasma glucose 171 ± 47 mg/dl, weight 96 ± 20 kg] that were drug naïve (19%) or previously treated with one (47%) or multiple (35%) oral antidiabetic medications. Interventions included ExQW 2 mg for 24 wk or ExBID 5 μg for 4 wk followed by ExBID 10 μg for 20 wk. The change in HbA1c from baseline to wk 24 was measured. At 24 wk, ExQW produced significantly greater changes from baseline (least squares mean ± SE) vs. ExBID in HbA1c (-1.6 ± 0.1% vs. -0.9 ± 0.1%; P < 0.0001) and fasting plasma glucose (-35 ± 5 mg/dl vs. -12 ± 5 mg/dl; P = 0.0008). Similar reductions in mean body weight from baseline to wk 24 were observed in both groups (-2.3 ± 0.4 kg and -1.4 ± 0.4 kg). Both treatments were generally well tolerated. Transient and predominantly mild to moderate nausea, the most frequent adverse event, was less common with ExQW (14%) than with ExBID (35%). Injection-site reactions were infrequent, but more common with ExQW. No major hypoglycemia occurred. Continuous glucagon-like peptide-1 receptor agonism with ExQW resulted in superior glycemic control, with less nausea, compared with ExBID in patients with type 2 diabetes. Both groups lost weight.

Background: A composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data. Methods: We assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low–glucose and low-glucose hypoglycemia; very high–glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation. Results: The analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals. Conclusion: The GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments.

Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM), lowers blood glucose by inhibiting renal glucose reabsorption and increasing urinary glucose excretion. It has been reported that SGLT2 inhibitors may have potential adverse effects on bone, including increased fracture risk and decreased bone mineral density (BMD). Across clinical studies, canagliflozin was not associated with meaningful changes in serum or urine calcium, vitamin D, or parathyroid hormone. Minimal increases in serum phosphate and magnesium that were within normal limits were seen with canagliflozin versus placebo. Canagliflozin was associated with increases in serum collagen type 1 beta-carboxy telopeptide (beta-CTX), a bone resorption marker, and osteocalcin, a bone formation marker. Decreases in total hip BMD were seen with canagliflozin 100 and 300 mg versus placebo after 2 years (–1.7%, –2.1%, –0.8%; differences of –0.9% and –1.2%), but not at other skeletal sites (normal age-related bone loss, ~0.5-1.0%/year). Changes in beta-CTX and total hip BMD were significantly associated with weight loss, which is known to increase bone resorption markers and decrease BMD. Canagliflozin was associated with a higher fracture incidence in an interim analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) in patients with a history or high risk of cardiovascular disease (incidence per 100 patient-years of 1.6, 1.6, and 1.1 with canagliflozin 100 and 300 mg and placebo), but not in other clinical studies of patients with T2DM. Fractures tended to occur as early as 12 weeks after initiating treatment and were primarily located in the distal parts of the upper and lower extremities. The reason for increased fracture risk with canagliflozin treatment is unknown, but is likely not related to a direct effect of canagliflozin on bone-related biomarkers. Data from ongoing canagliflozin studies, including CANVAS, will provide additional information on fracture risk in patients with T2DM.

Rapid‐acting insulins (RAIs) have been instrumental in the management of diabetes because of their improved postprandial glucose (PPG) control compared with regular human insulin. However, their absorption rate and time action following subcutaneous administration still falls short of the normal physiological response to meal consumption, increasing the risk of early postmeal hyperglycaemia and late postmeal hypoglycaemia. Increased demand for faster acting insulins, which can quickly control PPG excursions without increasing the risk of late hypoglycaemia, led to the development of ultra‐rapid–acting insulins, including ultra‐rapid lispro (URLi). URLi is a novel formulation of insulin lispro with accelerated absorption driven by two excipients: treprostinil, which increases local vasodilation, and citrate, which increases local vascular permeability. Clinical pharmacology studies consistently showed an earlier onset and shorter duration of action with URLi compared with Lispro. In a head‐to‐head study with Faster aspart, Aspart and Lispro, URLi was absorbed faster, provided earlier insulin action, and more closely matched physiological glucose response than the other insulins tested. URLi's unique pharmacokinetic properties increase its potential for improved PPG control beyond that achieved with RAIs. Indeed, in pivotal phase 3 trials, URLi was superior to Lispro for PPG control both at 1 and 2 hours after a meal in type 1 and type 2 diabetes with multiple daily injections, and in type 1 diabetes with continuous subcutaneous insulin infusion. This was achieved without increasing the risk of hypoglycaemia. In this review, we focus on the clinical and pharmacological evidence for URLi in the treatment of diabetes and discuss the potential benefits and considerations with URLi compared with RAIs.

Aims MYL‐1501D, recently approved by the European Medicines Agency, is being developed as a biosimilar (European Union) or a follow‐on biologic (United States) to insulin glargine. This study assessed efficacy, insulin dose, safety, and immunogenicity when patients with type 1 diabetes mellitus switched between MYL‐1501D and reference insulin glargine (Lantus®; Sanofi‐Aventis US LLC, Bridgewater, NJ). Materials and methods Eligible patients from INSTRIDE 1 who completed 52 weeks of reference insulin glargine treatment were randomized 1:1 to the reference sequence (n = 63; reference insulin glargine for 36 weeks) or to the treatment‐switching sequence (n = 64; MYL‐1501D [weeks 0–12], reference insulin glargine [weeks 12–24], MYL‐1501D [weeks 24–36]). Change in glycated hemoglobin (HbA_1c) from baseline to week 36 was the primary efficacy endpoint used to demonstrate equivalence between the 2 treatment sequences. Secondary endpoints included change in fasting plasma glucose (FPG), self‐monitored blood glucose (SMBG), and insulin dose; immunogenicity; and adverse events, including hypoglycemia. Results Mean changes in HbA_1c (least squares [LS] mean [standard error]) from baseline to week 36 were − 0.05 (0.032) and − 0.06 (0.034) for the treatment‐switching and reference sequences, respectively (LS mean difference [95% CI], 0.01 [−0.085, 0.101]). Treatment sequences were comparable in terms of secondary endpoints, including FPG, SMBG, and insulin dose, and the safety and immunogenicity profiles of the 2 sequences were similar. Conclusions Switching patients between MYL‐1501D and reference insulin glargine demonstrated equivalent efficacy and similar safety and immunogenicity, demonstrating that patients taking reference insulin glargine can safely switch to MYL‐1501D.