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Oxidative stress, through the production of reactive oxygen species (ROS), has been proposed as the root cause underlying the development of insulin resistance, b-cell dysfunction, impaired glucose tolerance and type 2 diabetes mellitus (T2DM). It has also been implicated in the progression of long-term diabetes complications, including microvascular and macrovascular dysfunction. Excess nourishment and a sedentary lifestyle leads to glucose and fatty acid overload, resulting in production of ROS. Additionally, reaction of glucose with plasma proteins forms advanced glycation end products, triggering production of ROS. These ROS initiate a chain reaction leading to reduced nitric oxide availability, increased markers of inflammation and chemical modification of lipoproteins, all of which may increase the risk of atherogenesis. With the postulation that hyperglycaemia and fluctuations in blood glucose lead to generation of ROS, it follows that aggressive treatment of fasting and postprandial hyperglycaemia is important for prevention of micro and macrovascular complications in T2DM.

Insulin has been available for the treatment of diabetes for almost a century, and the variety of insulin choices today represents many years of discovery and innovation. Insulin has gone from poorly defined extracts of animal pancreata to pure and precisely controlled formulations that can be prescribed and administered with high accuracy and predictability of action. Modifications of the insulin formulation and of the insulin molecule itself have made it possible to approximate the natural endogenous insulin response. Insulin and insulin formulations had to be designed to produce either a constant low basal level of insulin or the spikes of insulin released in response to meals. We discuss how the biochemical properties of endogenous insulin were exploited to either shorten or extend the time-action profiles of injectable insulins by varying the pharmacokinetics (time for appearance of insulin in the blood after injection) and pharmacodynamics (time-dependent changes in blood sugar after injection). This has resulted in rapid-acting, short-acting, intermediate-acting, and long-acting insulins, as well as mixtures and concentrated formulations. An understanding of how various insulins and formulations were designed to solve the challenges of insulin replacement will assist clinicians in meeting the needs of their individual patients.

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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.

AimsSince 2005, several glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) have been approved to treat people with type 2 diabetes. These agents are considered for use at the same point in the treatment paradigm as basal insulins. A comprehensive comparison of these drug classes, therefore, can help inform treatment decisions. This systematic review and meta‐analysis assessed the clinical efficacy and safety of GLP‐1 RAs compared with basal insulins.Materials and methods MEDLINE, EMBASE, CENTRAL and PubMed databases were searched. Randomized clinical trials (RCTs) of ≥16 weeks’ duration comparing GLP‐1 RAs vs basal insulins in adults with type 2 diabetes inadequately controlled with oral antihyperglycemic drugs were included. Data on the change from baseline to 26 weeks (±10 weeks) of treatment in hemoglobin A1c (HbA1c) and weight, as well as the proportion of patients experiencing hypoglycaemia, were extracted. Fixed‐effect pairwise meta‐analyses were conducted where data were available from ≥2 studies.ResultsFifteen RCTs were identified and 11 were meta‐analysed. The once‐weekly GLP‐1 RAs, exenatide long acting release (LAR) and dulaglutide, led to greater, statistically significant mean HbA1c reductions vs basal insulins (exenatide: −0.31% [95% confidence interval −0.42, −0.19], dulaglutide: −0.39% [−0.49, −0.29]) whilst once‐daily liraglutide and twice‐daily exenatide did not (liraglutide: 0.06% [−0.06, 0.18], exenatide: 0.01% [−0.11, 0.13]). Mean weight reduction was seen with all GLP‐1 RAs while mean weight gain was seen with basal insulins. Interpretation of the analysis of hypoglycaemia was limited by inconsistent definitions and reporting. Because of the limited number of available studies sensitivity analyses to explore heterogeneity could not be conducted.ConclusionsAlthough weight reduction is seen with all GLP‐1 RA’s, only the once‐weekly agents, exenatide LAR and dulaglutide, demonstrate significant HbA1c reductions when compared to basal insulins.

Here we review the capabilities and benefits of CGM, including cost-effectiveness data, and discuss the potential limitations of this glucosemonitoring strategy for the management of patients with diabetes. Funding: Sanofi US, Inc.

BACKGROUND | Glycemic control is suboptimal in many individuals with type 2 diabetes. Although use of flash continuous glucose monitoring (CGM) has demonstrated A1C reductions in patients with type 2 diabetes treated with a multiple daily injection or insulin pump therapy regimen, the glycemic benefit of this technology in patients with type 2 diabetes using nonintensive treatment regimens has not been well studied.METHODS | This retrospective, observational study used the IBM Explorys database to assess changes in A1C after flash CGM prescription in a large population with suboptimally controlled type 2 diabetes treated with nonintensive therapy. Inclusion criteria were diagnosis of type 2 diabetes, age ,65 years, treatment with basal insulin or noninsulin therapy, naive to any CGM, baseline A1C $8%, and a prescription for the FreeStyle Libre flash CGM system during the period between October 2017 and February 2020. Patients served as their own control subject.RESULTS | A total of 1,034 adults with type 2 diabetes (mean age 51.6 6 9.2 years, 50.9% male, baseline A1C 10.1 6 1.7%) were assessed. More patients received noninsulin treatments (n 5 728) than basal insulin therapy (n 5 306). We observed a significant reduction in A1C within the full cohort: from 10.1 6 1.7 to 8.6 6 1.8%; D 21.5 6 2.2% (P ,0.001). The largest reductions were seen in patients with a baseline A1C $12.0% (n 5 181, A1C reduction 23.7%, P ,0.001). Significant reductions were seen in both treatment groups (basal insulin 21.1%, noninsulin 21.6%, both P ,0.001).CONCLUSION | Prescription of the flash CGM system was associated with significant reductions in A1C in patients with type 2 diabetes treated with basal insulin or noninsulin therapy. These findings provide evidence for expanding access to flash CGM within the broader population of people with type 2 diabetes.