Appropriate Use of Insulin Analogs in an Increasingly Complex Type 2 Diabetes Mellitus (T2DM) Therapeutic Landscape

Director, Georgia Center for Diabetes, Atlanta, Ga

Because diabetes mellitus is a progressive disease, treatment should advance with the evolving needs of the patient. Within the last decade, newer insulin analogs have become available to replace standard insulin formulations and novel agents and delivery devices have been developed. Within this complex landscape of treatment options, physicians must develop treatment strategies that will enable patients to achieve glycemic goals.

The American Diabetes Association (ADA) recommends the following goals: glycosylated hemoglobin A1C (A1C) <7.0%; fasting plasma glucose (FPG) between 90 and 130 mg/dL; and peak postprandial glucose (PPG) <180 mg/dL.¹ Basing their recommendations on data from the United Kingdom Prospective Diabetes Study, which demonstrated that the risk for macrovascular and microvascular complications begins to increase at A1C >6.5%, the American Association of Clinical Endocrinologists (AACE) recommends even stricter targets: A1C <6.5%; FPG <110 mg/dL; and PPG <140 mg/dL. Thus, although differing somewhat on the exact treatment goals, both the ADA and AACE affirm the importance of glycemic control.² This article will provide an overview of insulin analogs and newer antidiabetes agents and evaluate their utility in the treatment of type 2 diabetes mellitus (T2DM).

 

Progression of Therapy in T2DM

Lifestyle modifications

A healthy diet and exercise plan constitute the foundation of T2DM treatment. Patients with mild to moderate disease may initially utilize diet and exercise alone to restore effective glycemic control. As diabetes progresses, however, most patients will require pharmacologic intervention. A proactive, target-oriented approach to reaching glycemic goals is essential if patients are to avoid the comorbidities associated with prolonged hyperglycemia.³

Oral antidiabetes drug therapy

Pharmacologic therapy for T2DM is typically initiated with an oral antidiabetic drug (OAD). Various types of OADs with differing mechanisms of action are available, and their efficacy is well documented (TABLE 1).⁴ As these agents typically lower A1C levels by 0.5% to 1.5%, they are most appropriate for patients with a baseline A1C ≤9.0%.⁵ Importantly, patients with severe hyperglycemia at initial diagnosis should be treated initially with insulin; upon resolution of the hyperglycemia, OAD therapy may be initiated.

As T2DM progresses, the majority of patients will require more than one agent to control hyperglycemia (FIGURE 1). In some instances, the use of a second OAD can restore glycemic control. However, OADs cannot compensate for the decline in pancreatic β-cell function observed in T2DM, and thus most patients will eventually require the addition of exogenous insulin, which is the only therapeutic agent to address the dual defects of diabetes (insulin resistance and insulin deficiency).⁴

OADs used in the treatment of T2DM⁴

Insulin therapy

Insulin is acknowledged as a highly effective antidiabetes medication for lowering hyperglycemia.⁶ Although investigators initially speculated that hyperinsulinemia contributed to atherogenesis and the development of cardiovascular disease (CVD) or other symptoms of metabolic syndrome, more recent evidence suggests that the insulin-resistant state, not insulin itself, contributes to CVD.^7-10 Specifically, the anti-inflammatory effects of insulin may help control glycemia, dyslipidemia, and epigenetic cellular phenomena and thereby counteract CVD progression.^9,11-13

Basal insulin therapy

Early addition of insulin to oral therapy, easily initiated with a simple basal insulin regimen providing 24-hour control of FPG, has been shown to improve A1C levels significantly in patients with T2DM (FIGURE 2).^3,14 As formulations of insulin vary in timing of onset and duration of action, the dose and number of injections required depend on the formulation used and the level of glycemic control needed.^15-17 The ideal basal insulin replacement should approximate physiologic insulin secretion as closely as possible and have a duration of action lasting 24 hours, without any periods of pronounced peak activity.

Time profiles of available insulin formulations15-17

Neutral protamine Hagedorn insulin

Neutral protamine Hagedorn (NPH) insulin is an intermediate-acting insulin with a duration of action of approximately 13 hours (TABLE 2).¹⁵ NPH insulin is dosed twice daily, which may impact convenience and increase the risk for nocturnal or morning hyperglycemia, thereby potentially decreasing compliance. Additionally, NPH insulin is associated with intersubject pharmacodynamic variability.¹⁵ Newer basal insulin analogs, which require fewer daily doses and are associated with a lower risk of hypoglycemia, are a convenient and effective alternative to NPH insulin. Two insulin analogs are currently available, insulin glargine and insulin detemir.

Basal and prandial insulin formulations used in the treatment of T2DM

Insulin glargine

Insulin glargine, which can be titrated using a simple algorithm and administered with simple once-daily dosing (TABLE 3), has an activity profile similar to physiologic insulin secretion.¹⁸ It has no pronounced peak, a 24-hour duration of action, and less intersubject variability than NPH insulin (TABLE 2).^15,18 Several trials evaluated insulin glargine versus NPH insulin added to existing OAD therapy. Results found that treatment with either agent resulted in similar improvements in glycemic control, with the majority of patients in both the insulin glargine and NPH insulin groups achieving A1C goals.^18-20

Insulin glargine is associated with less nocturnal hypoglycemia compared with NPH insulin, likely due to its 24-hour pharmacokinetic profile.^18-20 Furthermore, a meta-regression analysis revealed that at equivalent rates of hypoglycemia, insulin glargine is associated with significantly lower A1C levels compared with NPH insulin.²¹ Consequently, the insulin glargine dose can be increased as needed to achieve target A1C goals with reduced hypoglycemic risk.

A simple algorithm for the titration of insulin glargine

Insulin detemir

Insulin detemir activity peaks at approximately 8 hours, has a mean residence time of approximately 14 hours in adults, and exhibits less pharmacokinetic variability compared with NPH insulin (TABLE 2).²² Addition of NPH insulin or insulin detemir twice daily to existing OAD treatment in patients with T2DM resulted in similar improvements in A1C levels. Furthermore, insulin detemir was associated with less nocturnal hypoglycemia and less weight gain compared with NPH insulin.²³ Data comparing the pharmacokinetics and efficacy of insulin glargine and insulin detemir are conflicting.^24-27 Jungmann recently demonstrated that patients receiving once-daily insulin glargine achieved lower levels of blood glucose compared with patients receiving once- or twice-daily insulin detemir.²⁶ In contrast, Rosenstock et al observed that treatment with either insulin glargine or insulin detemir resulted in similar decreases in A1C levels, a similar proportion of patients achieving goal (A1C <7.0%), and comparable relative risk of overall and nocturnal hypoglycemia.²⁷

When choosing a basal insulin, dosing is one important factor to consider; once-daily dosing may aid in compliance, especially in insulin-naive patients with T2DM. Patients taking NPH insulin or insulin detemir may require 2 injections, typically before breakfast and in the evening within 1 hour before dinner, to achieve clinical efficacy.^23,28

Prandial insulin therapy

If overall glycemic control or if PPG target levels are not achieved with basal insulin therapy, therapy with a rapid-acting insulin can be added. Prandial insulin is typically initiated with 1 injection at the largest meal of the day; if necessary, additional injections can be added at other mealtimes to obtain glycemic control. The ideal profile for prandial insulin replacement would blend a rapid onset with a short duration of action, similar to physiologic insulin secretion at mealtimes. Regular human insulin (RHI) has a relatively long onset and must be injected 30 minutes prior to a meal.²⁹ As a result, patients are at increased risk for hypoglycemia if they deviate from their scheduled mealtimes.

Newer rapid-acting insulin analogs, such as insulin glulisine, insulin lispro, and insulin aspart, provide greater dosing flexibility, with an onset of action of approximately 15 minutes, a peak near 60 minutes postdose, and a duration of action of 3 to 4 hours (TABLE 2).^29,30 Insulin glulisine and insulin lispro are both approved for premeal or postmeal administration.²⁹ Additionally, insulin glulisine can be titrated using a simple dosing algorithm: patients receive a fixed dose of mealtime glulisine that is adjusted weekly by 1, 2, or 3 units, depending upon premeal glucose patterns. Patients using this algorithm achieved similar glycemic control with less symptomatic hypoglycemia compared with patients using the gold standard, carbohydrate counting, which many patients find complex.³¹

Premixed insulin formulations

Premixed insulin or insulin analog formulations combine an intermediate- or long-acting insulin with a short-acting insulin in a fixed-dose regimen and can provide convenience with regard to the number of injections needed for basal-prandial coverage. However, the requirement for strict adherence to mealtimes and exercise schedules and the increased risk of hypoglycemia are important considerations when evaluating their clinical utility.³²

 

Newer therapeutic options

Inhaled human insulin

Human insulin inhalation powder was approved in 2006 for prandial coverage in adults with T1DM or T2DM (TABLE 4). Inhaled insulin can be used in combination with oral agents or basal insulin.³³ Similar to rapid-acting insulin analogs, inhaled insulin has a rapid onset of action and a duration of action comparable to subcutaneously administered RHI and thus may be most appropriate for control of prandial glucose excursions.³³ In a 24-week randomized trial evaluating the safety and efficacy of adding inhaled human insulin or metformin to existing sulfonylurea therapy in patients with T2DM, inhaled insulin treatment resulted in a mean reduction in A1C of –2.17% from baseline in patients with baseline A1C >9.5% and –1.94% in patients with baseline A1C ≤9.5%.³⁴ Hypoglycemia and increased cough were more common in the inhaled-insulin group, while other adverse events and changes in pulmonary function parameters were similar between groups.³⁴ No data are available comparing the efficacy of inhaled insulin with rapid-acting insulin analogs.

Important considerations when using inhaled insulin include dosing, convenience, and patient satisfaction. Inhaled insulin, available as a 1-mg (equivalent to ~3 IU subcutaneous RHI) or 3-mg (equivalent to ~8 IU subcutaneous RHI) dose, should be titrated based on patient blood glucose monitoring results.³³ Inhaled insulin is contraindicated in patients who smoke, who discontinued smoking within 6 months of initiating therapy, or who have underlying lung disease. In addition, the forced expiratory volume (FEV) should be assessed in all patients prior to initiating therapy. Inhaled insulin is not recommended in patients with a baseline FEV <70% of predicted value.³³ Some patients may find the inhalation device preferable to injection; however, active patients or those who travel extensively may find it cumbersome and difficult to transport discreetly owing to its large size relative to insulin pen devices.

Newer therapeutic options for the treatment of T2DM

Incretin mimetics and dipeptidyl-peptidase IV inhibitors

Incretin mimetics and dipeptidyl-peptidase IV (DPP-IV) inhibitors are 2 new classes of antidiabetes agents. Incretin mimetics promote insulin secretion, decrease glucagon secretion, delay gastric emptying and promote satiety.³⁵ Glucagon-like peptide-1 (GLP-1) is an incretin with a relatively short half-life and is rapidly degraded in the body. One strategy being used to exploit the incretin effect in diabetes treatment is the development of a GLP-1 analog that is resistant to enzyme degradation. A second strategy is to inhibit DPP-IV, the peptidase responsible for GLP-1 degradation. Clinical studies have shown that patients with T2DM have reduced concentrations of active GLP-1, and preliminary study results suggest that both classes of agents may improve β-cell function.³⁶

Exenatide

The GLP-1 analog exenatide has a prolonged duration of action compared with endogenous GLP-1 (TABLE 4).^37,38 Exenatide is indicated for adjunctive therapy in patients with T2DM inadequately controlled with metformin and/or a sulfonylurea and is administered through subcutaneous injection 60 minutes prior to breakfast and dinner.³⁸

In clinical trials, treatment with exenatide 5 μg or 10 μg twice daily reduced A1C from baseline in patients treated with sulfonylurea (–0.46% and –0.86% for the 5 μg and 10 μg doses, respectively), metformin (–0.40% and –0.78%, respectively), or both (–0.6% and –0.8%, respectively).³⁷ Exenatide 10 μg twice daily compared with insulin glargine once daily resulted in similar reductions in A1C (1.1%), similar percentages of patients achieving A1C ≤7.0% (46%-48%), and a similar incidence of hypoglycemia in patients with T2DM who were inadequately controlled with metformin and a sulfonylurea (FIGURE 3).³⁹ In evaluating glucose levels, patients receiving insulin glargine achieved lower FPG values, while patients receiving exenatide achieved lower PPG values; thus exenatide may be best utilized for prandial control.³⁹

Exenatide should be initiated at 5 μg twice daily and can be increased to 10 μg twice daily.³⁸ Positive aspects of exenatide treatment include weight loss and the availability of a fixed dose.^37-39 Potential limiting factors include cost, the need for twice-daily dosing, gastrointestinal side effects, the increased risk of hypoglycemia, particularly when used in conjunction with a sulfonylurea, and the potential for interactions with oral contraceptives and oral antibiotics.^37-39 It is unknown whether exenatide will be effective in patients with advanced disease because residual insulin secretion is necessary for exenatide to exert its effects. Exenatide is not a substitute for insulin in insulin-requiring patients, and preliminary data suggest that substitution of basal insulin with exenatide may result in deterioration of glycemic control.^38,40 Additionally, exenatide is not approved for use in conjunction with insulin, but studies addressing the safety and efficacy of combination therapy are under way and suggest that exenatide may allow for a reduction in the insulin dose in some patients.^40,41

Liraglutide

Phase 3 trials began in February 2006 for liraglutide, a long-acting GLP-1 analog that has a longer pharmacokinetic half-life relative to exenatide (14 hours vs 2.4 hours, respectively), and its effects on blood glucose are sustained for 24 hours, suggesting that once-daily dosing may be possible.^35,42 Initial data indicate that treatment with liraglutide results in improved glycemic control and modest weight loss.⁴²

Sitagliptin and Vildagliptin

The oral DPP-IV inhibitor, sitagliptin, was approved in October 2006 and is indicated for use as monotherapy or in combination with metformin or a thiazolidinedione in patients with T2DM. In clinical trials, sitagliptin 100 mg once daily provided significant improvements in A1C, FPG, and PPG levels (P<0.001 vs placebo). Additionally, combination therapy with sitagliptin±metformin or sitagliptin±pioglitazone was superior to monotherapy with either metformin or pioglitazone. The overall incidence of adverse events was similar between the sitagliptin and placebo groups.^36,43

Vildagliptin, also an oral DPP-IV inhibitor, is in late-stage clinical development and has been shown to improve insulin secretion and sensitivity and glycemic control in patients with diabetes (TABLE 4).⁴⁴ Added to existing metformin treatment in patients with T2DM, vildagliptin 50 mg once daily reduced A1C 0.5% to 0.6% from baseline after 12 weeks, with improvement maintained to week 52.^44,45 Moderate hypoglycemia occurred in 4 of 56 vildagliptin-treated patients, and body weight did not significantly change in the vildagliptin group during the 12-week trial.⁴⁵

GLP-1 analogs and DPP-IV inhibitors may be dependent on residual insulin secretion to exert their physiologic effects and thus may not be appropriate for patients with advanced disease. Additionally, DPP-IV has physiologic activities beyond that of metabolic control. Early studies have implicated DPP-IV in the normal development and function of the immune system, and in vitro studies with DPP-IV inhibitors have shown inhibition of T-cell activity. Furthermore, DPP-IV acts on a number of substrates in vivo, including hormones, neuropeptides, and chemokines.³⁶ Additional studies are necessary to adequately evaluate the impact of DPP-IV inhibitors on physiologic pathways other than glucose control.

 

Pramlintide

Pramlintide is a synthetic analog of amylin (TABLE 4), a naturally occurring hormone secreted by pancreatic β-cells in response to food intake.^46,47 Pramlintide complements the effects of insulin by suppressing postprandial glucagon secretion and regulating the rate of gastric emptying.⁴⁷ Administered through subcutaneous injection at mealtimes immediately prior to major meals, pramlintide is indicated for adjunctive therapy in patients with T1DM or T2DM inadequately controlled on prandial insulin with or without concurrent sulfonylurea and/or metformin therapy.⁴⁶

The addition of pramlintide to insulin therapy results in modest reductions in A1C levels: pramlintide 120 μg twice daily or 75 to 150 μg 3 times daily reduced A1C levels by 0.6% after 1 year of treatment in patients with T2DM treated with insulin.^48,49 Pramlintide was also associated with weight loss and no overall increase in the rate of severe hypoglycemic events.^48-50

In patients with T2DM, pramlintide should be initiated at a dose of 60 μg and titrated to a maintenance dose of 120 μg.⁴⁶ Patients should be monitored frequently, and dose reductions in concomitant short-acting or fixed-mix insulin formulations should be made to minimize the risk of hypoglycemia.⁴⁶ Pramlintide may be most appropriate in obese patients who are insulin-deficient, although more data are needed.

 

Summary

Effective glycemic control can substantially reduce the micro- and macrovascular complications associated with diabetes. As evidenced by the recent consensus statement and treatment algorithm jointly issued by the ADA and the European Association for the Study of Diabetes, substantive evidence-based research supports the use of OAD regimens and insulin analogs for fasting and postprandial control of glucose. Furthermore, numerous studies have revealed the benefits of early, intensive treatment of hyperglycemia with insulin. Unlike incretin mimetics or DPP-IV inhibitors, treatment with insulin can address the dual physiologic defects of diabetes: insulin resistance and insulin deficiency.

Notwithstanding the promise that newer and emerging agents hold providing effective glycemic control, studies evaluating their long-term efficacy and safety (as monotherapy and in combination therapy), as well as head-to-head comparisons with existing treatments, are necessary to determine the role of these agents in the diabetes treatment algorithm.

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