Abstract
The first long-acting insulin, protamine insulin, was discovered in the 1930s. This discovery paved the way for the future of basal insulins, including neutral protamine Hagedorn (NPH) and zinc insulin (lente), both introduced in the 1950s. 8 David Owens discusses at length the history of basal insulins and the progress and development leading to the currently used longer-acting insulin analogs. 9
Initiating a patient on insulin requires the provider to take several variables into consideration, including choosing the proper insulin for each patient and weighing the benefits and risk (especially of hypoglycemia) of each of the options. In addition, the clinician must determine the best combination of agents, including oral and injectables, that will allow the patient the best glycemic control without negatively impacting health and compliance. Frank Lavernia highlights the issues with premixed insulin and compares them with the basal/bolus options available when initiating insulin treatment in his article in this supplement: 10 both options can achieve similar glucose control as measured by A1c levels, but with significantly higher insulin dose and an increased weight gain associated with more hypoglycemic events with premixed insulins.
The use of basal insulin analogs varies markedly depending on whether the patient is diagnosed with type 1 or type 2 diabetes mellitus. As Geremia Bolli and co-workers discuss in this supplement, patients with type 1 diabetes are treated with multiple daily injections or continuous subcutaneous insulin infusion. 11 Many studies have compared the two regimens with conflicting results. 12,13 However, meta-analysis does favor insulin pump therapy with a significant reduction in A1c, insulin dose, and hypoglycemia with a possible increased risk of diabetic ketoacidosis. 14 For patients with type 2 diabetes, it is safer to begin initial treatment with once-daily long-acting insulin combined with an oral diabetes medication(s) as opposed to beginning with twice daily premixed insulin and oral diabetes agents. 15 Stephen Davis and colleagues explain the rationale of the use of basal insulins in type 2 diabetes in this supplement. 16
Frequency and risk of hypoglycemia are important factors to consider when comparing basal insulins. However, this comparison is difficult to study consistently, and most clinicians are interested in efficacy of the insulin on A1c. Thus, many studies do not focus on rates of hypoglycemia as a true end point and, instead, look at overall glycemic control. 17 To increase compliance, every attempt must be made to reduce hypoglycemia with addition of any new therapy.
Most patients with type 2 diabetes are initiated with basal insulin and bolus insulin is added with an analog insulin (glulisine, aspart, or lispro) when they are not achieving target glycemic control with basal insulin alone. However, the patients experience increased hypoglycemic episodes and weight gain when switching to two or three premixed insulin injections or adding a prandial insulin to their basal insulin. 10,18 Another approach of transitioning patients into their basal–bolus regimen may be the “basal plus strategy” in an attempt to minimize the negative aspects of adding prandial insulin. “This approach considers the addition of increasing injections of prandial insulin, beginning with the meal that has the major impact on postprandial glucose values.” 19 Javier Ampudia-Blasco and colleagues examine the use of this new strategy in this supplement. 19
It is important to consider the pharmacokinetic and pharmacodynamic properties of each insulin (insulin glargine, detemir, or, later, degludec). In a study conducted in 2000, it was determined that both NPH and ultralente insulins tend to peak, whereas insulin glargine was relatively peakless with a 24-h profile in the majority of the patients. 20 Many studies on basal insulin use in type 2 diabetes have documented a significant reduction of hypoglycemia (overall and/or nocturnal) by as much as 30%. 21 Francesca Porcellati and co-workers 22 and Philip Home and colleagues 17 discuss the data in more detail in this supplement.
Both fasting hyperglycemia and postprandial hyperglycemia contribute to the rise in A1c values in patients with type 1 or 2 diabetes. There has been a debate as to the main contributor to overall hyperglycemia. It has been proposed that it is postprandial hyperglycemia in relatively well-controlled patients and fasting plasma glucose in the uncontrolled patients with type 2 diabetes. 23 Louis Monnier and colleagues discuss these factors in this supplement at greater length. 24 In addition, recent data presented by Riddle et al. 25 at the American Diabetes Association and European Association for the Study of Diabetes meetings in 2010 showed similar but larger contributions (70–80%) by elevated fasting plasma glucose to the rise in A1c levels across all levels of glucose control (A1c from 8% to >10%) in patients with type 2 diabetes without initiating basal insulin therapy, thus challenging Monnier's concept. Consideration of these parameters is important in determining the ideal therapeutic approach to improving glucose control in patients by individualizing therapy.
Many patients will eventually need additional agents in order to maintain their desired glycemic control. These agents (DPP-IV inhibitor and GLP analogs) allow for the targeted reduction of postprandial glucose without an increased risk for hypoglycemia. 26 A recent investigator–initiated pilot study using DPP-IV inhibitor, sitagliptin, in patients with type I diabetes reported improved A1c values and better glucose variability indices as documented by continuous glucose monitoring data. 27 “GLP-1 mimetics target postprandial glucose and should complement the activity of basal insulins; they are also associated with a relatively low risk of associated hypoglycemia and moderate, but significant, weight loss.” 28 Many other studies have previously shown improvements in glycemic control, weight loss and/or reduced weight gain, and lower hypoglycemic events when GLP-1 analogs were compared with premixed insulin or insulin glargine with or without oral hypoglycemic agents and/or metformin. 28 –31 Buse et al. 32 recently reported improved glucose control with less weight gain from the first randomized trial combining insulin glargine and exenatide (off-label). Generally, patients with type 2 diabetes have an increased mortality due to cardiovascular disease and cancer, decreasing their life expectancy. “Current recommendations for a healthy lifestyle based on good diet, physical exercise, and weight management in order to control diabetes-related complications are likely to apply in reducing the risk of many forms of cancer and should be advocated for all patients.” 33 George Dailey analyzes the current impact of diabetes on mortality and the methods to help improve mortality in patients with diabetes in this supplement. 33
The use of devices to monitor glucose and/or deliver insulin (pens and pumps) has significantly impacted diabetes care for insulin-requiring patients with diabetes. With the development of continuous glucose monitoring, more patients requiring insulin treatment are obtaining better glycemic control with more time spent in the euglycemic range with fewer hypoglycemic events. 34 –36 Many companies are currently working on a closed-loop system that will link continuous glucose monitoring with insulin pumps creating an artificial pancreas. 37 Alfred Penfornis and colleagues explain the evolution of devices in diabetes management in more depth in this supplement. 38
Since the use basal insulin alone or in combination with oral agents has become the cornerstone of diabetes management, 39 many pharmaceutical companies have been working to develop even better basal insulins. The basal insulins that are currently in development have the potential to have an even greater impact on the treatment of diabetes. Novo Nordisk and Eli Lilly have new basal insulins that look to transform the field and may improve glycemic control with reduced hypoglycemic episodes and glucose variability. 40 CeQur is taking a different approach by using a patch pump to deliver insulin continuously. Similarly, V-GO (Valeritas) recently got Food and Drug Administration clearance 41 for another patch pump that can continuously deliver a rapid-acting-insulin analog (aspart) as a basal insulin. Additionally, smartly engineered insulins are currently in preclinical testing that have a built-in sensor to release the required amount of insulin. 42 The future of diabetes management is discussed further by Airin Simon and Hans DeVries. 43
We would like to thank all of the authors who contributed to this supplement for their hard work. This supplement would not have been possible without their time and dedication.
Footnotes
Author Disclosure Statement
S.K.G. has received grants for clinical research from and is on Advisory Boards for Novo Nordisk, Eli Lilly and Company, Merck, Mannkind, Biodel, Halozyme, DexCom Inc., and Sanofi-Aventis. He discloses that he does not have any stocks for any pharmaceutical or device companies. E.G.M. reports no conflicts of interest.