Intensifying Insulin Therapy with Insulin Analog Premixes: Transitioning from Basal Insulin in Type 2 Diabetes

Abstract

Because of the progressive nature of type 2 diabetes, basal insulin alone may not be able to provide sufficient glycemic control over the long term, and thus insulin regimens will typically need to be intensified—especially for controlling postprandial glucose excursions. In patients with type 2 diabetes requiring more intensive intervention, insulin analog premix formulations can offer a simple, effective, and convenient option for tighter management of hyperglycemia in lieu of a traditional basal–bolus regimen.

Introduction

D iabetes is a widely prevalent chronic metabolic disorder characterized by hyperglycemia.¹ In 2007, the Centers for Disease Control and Prevention estimated that 23.6 million Americans (7.8% of the population) had diabetes²; however, a recent report estimates that 26 million Americans (8.3% of the population) have diabetes, and another 79 million may have prediabetes.³ Another projection model suggests that the total prevalence of diabetes in the adult population of the United States, including both diagnosed and undiagnosed cases, will increase to 21% by the year 2050; however, if recent increases in the incidence of diabetes continue and the mortality of diabetes is relatively low, the prevalence could actually increase to 33% by 2050.⁴

A combination of insulin deficiency and insulin resistance with progressive loss of functional pancreatic β-cells characterizes the pathology of type 2 diabetes, which accounts for 90–95% of all diagnosed cases of diabetes in the United States.⁵ Uncontrolled postprandial hyperglycemia has been associated with long-term vascular complications,⁶ increased mortality, and morbidity in patients with type 2 diabetes.^7,8 Effective glycemic control reduces the risk of microvascular complications from type 2 diabetes. Because both fasting plasma glucose (FPG) and postprandial glucose (PPG) contribute to mean daily glucose concentrations (and therefore to glycosylated hemoglobin A1c [A1c]), the American Diabetes Association (ADA), the American Association of Clinical Endocrinologists (AACE), and the American College of Endocrinology have set specific glycemic goals for FPG, PPG, and A1c.^1,9,10

The A1c measurement reflects the cumulative level of glycemic control (or lack thereof) over a period of time, but A1c correlates better with FPG at higher levels of A1c, whereas lower A1c correlates better with PPG.¹¹

Patients with type 2 diabetes frequently require insulin therapy.^9,12 Introduction to insulin often begins with a once-daily injection of a long-acting insulin analog such as insulin glargine or detemir^9,12 because their extended duration of action offers a convenient and effective means of reducing FPG and A1c.^13,14 Patients treated with a basal insulin who still have difficulty attaining glycemic goals will generally require additional treatment to control PPG excursions. The physician may intensify the treatment regimen by means of basal–bolus therapy (BBT) or insulin premixes. Basal–bolus offers more flexibility in dose adjustment than insulin premixes. However, the overall needs of certain patients (i.e., those who are unable or unwilling to inject as frequently) are better met with insulin premixes. The decision should be individualized for each patient. This review describes the rationale, considerations, and evidence that biphasic insulin analogs provide a simple, convenient, and effective solution for providing better glycemic control in patients who need a more intensified regimen than basal insulin alone.

Methods

Several methods were used in order to indentify the most relevant articles to include. A PubMed literature search was conducted to identify peer-reviewed articles published in English between 2000 and 2011. Search terms included “insulin premix,” “insulin analogs,” “rapid-acting insulin,” “biphasic insulin,” “biphasic insulin analog,” “biphasic human insulin,” “biphasic insulin aspart,” “insulin lispro,” “insulin aspart,” “basal insulin,” “insulin glargine,” “insulin detemir,” “regular human insulin,” “neutral protamine Hagedorn,” and “NPH.” Publications that only addressed basal or long-acting insulin types, as well as those that only included oral antidiabetes drugs, were not included, nor were letters, commentaries, or case studies.

Results

Using the search criteria described above, 178 articles were identified. Once the publications that did not meet the preidentified criteria or failed to provide information relevant to this article were excluded, the key results and clinical implications of the remaining 26 articles were included.

Intensifying Insulin Therapy: Insulin Analog Premixes Provide Another Option

While endogenous insulin secretion normally peaks at mealtimes with typically three insulin peaks coinciding with three regular meals per day, endogenous basal insulin is secreted over a 24-h period and is unrelated to food intake.¹⁵ Therefore, to emulate the pattern of endogenous insulin secretion, an individual who has progressed to the stage of absent endogenous insulin will require one injection of a long-acting (i.e., basal insulin) and three injections of rapid-acting insulin at mealtimes to cover basal glucose secretion and PPG excursions, respectively.^16,17 Therefore, as the disease progresses, basal insulin alone will eventually fail to provide optimal glycemic control, and additional insulin, especially to control PPG excursions, will be required.

Transitioning from a basal insulin to a more intensive regimen should be considered in the context of patients' overall A1c levels. When FPG control is adequate and A1c levels are still not at goal, it is appropriate to consider a regimen that can also lower PPG levels more efficiently. Patients with moderate control of diabetes may have relatively higher PPG levels than those with more poorly controlled diabetes, particularly those with A1c >8.4%.¹¹ Thus, the closer one comes to goal, the more important it becomes to reduce PPG.

Several strategies are commonly used to intensify insulin therapy in patients with type 2 diabetes who cannot reach their glycemic goals on basal insulin alone. The first is to add rapid-acting insulin at mealtimes to basal insulin (BBT), which typically requires four or more daily injections. The second option, called a “prandial” insulin regimen, uses rapid-acting insulin analogs without any long-acting insulin component, but an insulin sensitizer such as metformin may be required.^9,18 A third option is to replace the basal insulin injection with biphasic insulin premix, which is commonly injected twice daily but can be used once to three times daily, depending on a patient's needs.¹⁹ Insulin premix formulations may be easier for patients to adopt than conventional BBT, as they can be administered with injections of only a single type of insulin without involving the mixing of different types of insulin and involve fewer injections than BBT.

Three biphasic insulin analog premix formulations and two biphasic human insulin (BHI) formulations are currently available in the United States.^20

–24 The biphasic insulin analogs contain a fixed proportion of a protaminated long-acting form of an otherwise rapid-acting insulin analog to provide basal insulin coverage and the same soluble rapid-acting insulin analog for mealtime coverage, in a ratio of 75:25, 70:30, or 50:50. There is no human isophane insulin suspension or neutral protamine Hagedorn (NPH) insulin in insulin analog premixes. BHI formulations, typically referred to as BHI30, contain NPH as the intermediate-acting component and human insulin as the short-acting component in a 70:30 ratio, respectively.

Differentiating Between Premix Options: Biphasic Analogs Versus BHI

The time–action profiles of insulin analog premixes are more closely matched to endogenous insulin secretion than BHI30. Small modifications in the amino acid sequence of rapid-acting insulin analogs do not favor hexamer formation and account for rapid absorption from subcutaneous tissues after injection.²⁵ A more physiologic and less variable onset of action results.²⁵ Compared with regular human insulin in BHI30, the absorption and clearance characteristics of the rapid-acting component of analog premixes result in distinct, predictable peaks that lend greater flexibility to patients with respect to mealtimes.²⁶ Because of the slow onset of action of regular human insulin, BHI30 must be injected 30–45 min before meals, which can be inconvenient for patients with variable meal schedules or when dining out.²⁶

The pharmacokinetics of the three biphasic analog premixes are similar²⁷ but differ significantly from those of BHI30. For example, a study in 24 healthy subjects showed that biphasic insulin aspart (BIAsp30) was absorbed at a much faster rate than BHI30 and that serum concentrations of BIAsp30 increased more rapidly compared with BHI30.²⁸ The maximum insulin concentration for BIAsp30 was 1.5-fold higher than BHI30, and the median time to maximum insulin concentration of BIAsp30 was approximately half that of BHI30 (60 min vs. 110 min). Other studies have also demonstrated significantly higher maximum insulin concentration values and lower time to maximum insulin concentration values for insulin analog premixes compared with BHI30.^29,30

With regard to the PPG-lowering effectiveness of biphasic insulin analogs versus BHI formulations, several studies have shown that PPG excursions after meals were significantly lower for patients treated with biphasic insulin analogs (either BIAsp30 or lispro mix 75/25) compared with BHI30.^29,31

–34 For example, a three-way crossover trial in patients with type 2 diabetes (n=61) comparing three insulin premix formulations after a single injection before a standard breakfast demonstrated that both BIAsp30 and insulin lispro mix 75/25 were superior to BHI30 in reducing PPG levels and that BIAsp30 was more effective than insulin lispro mix 75/25 (serum glucose excursions 0–5 h postmeal for BIAsp30 were 17% lower than BHI30 [P<0.001] and 10% lower than insulin lispro mix 75/25 [P<0.05]).²⁹

Clinical Experience with Insulin Premix Regimens

Randomized trials comparing regimens with insulin analog premixes to basal insulin

The safety and efficacy of regimens containing twice-daily biphasic insulin analog premixes have been compared against once-daily basal insulin in several randomized trials in patients with type 2 diabetes (Table 1).^35

–41 Reductions in morning and evening PPG were universally higher using a twice-daily insulin premix–containing regimen compared against once-daily basal insulin. Overall glycemic control (A1c) is either as good as or better with insulin analog premixes, whereas the FPG end points achieved are similar. Minor/overall hypoglycemia occurs more frequently with twice-daily insulin premix than with once-daily basal insulin; however, there appear to be no differences in the risk of major (i.e., severe) hypoglycemia. A few representative studies are briefly described in the following sections.

Table 1.

Randomized Clinical Trials Comparing Twice-Daily Biphasic Insulin Premix Formulations with Basal Insulin in Patients with Type 2 Diabetes

		A1c (Δ baseline) (%)		FPG (Δ baseline) (mmol/L)
Treatment groups, premix BID vs. comparator	Design (n)	Premix	Basal	Premix	Basal	PPG (parameters as specified), premix vs. basal	Hypoglycemia (% of patients), premix vs. basal
Lispro mix 75/25 + Met vs. glargine OD + Met³⁵	32-week crossover (105)	−1.3	−0.9	−0.74	−1.6	% achieving target <10 mmol/L: 72–80% vs. 43–63%^a	Nocturnal hypoglycemia ND: 54% vs. 38%
Lispro mix 75/25 + Met vs. Glargine OD + Met³⁶	32-week crossover (97)	−1.0	−0.4	−0.42	−1.0	% achieving target <10 mmol/L: 64–66% vs. 40–42%^a	Overall ND, nocturnal hypoglycemia: premix<basal
Lispro mix 75/25 + OAD vs. glargine OD + OAD³⁷	24-week crossover with test meal (20)	−1.5	−1.1	NR/ND	NR/ND	Mean combined meal: 0.9 mmol/L premix < basal Combined meal AUC_PPG: 12.6 mmol/L·h premix<basal	No severe in either group: 40% vs. 15%
BIAsp30 vs. NPH BID^38b	16-week parallel DB (403)	−0.7	−0.6	−1.5	−1.4	Mean PPG: 0.69 mmol/L premix<basal	<2% severe in either group, 38% vs. 34% minor
BIAsp30 + Met vs. glargine OD + Met⁴¹	28-week parallel open TTT (233)	−2.8	−2.4	−6.9	−7.0	Overall PPG: 25% premix<basal	One major episode in basal group, 43% vs. 16% minor
BIAsp30 + Met vs. glargine OD + Glim³⁹	28-week parallel open (255)	−1.6	−1.1	−2.6	−2.2	Mean PPG: 0.8 mmol/L premix<basal	ND in major, 20% vs. 9% minor
BIAsp30 vs. detemir OD or BID⁴⁰	52-week open (708)	−1.3	−0.8	NR/ND	NR/ND	NR/ND	Hypoglycemic events/patient-year: 5.7 vs. 2.3

AM and PM values; lunchtime values were comparable.

Oral antidiabetes drugs (OADs) discontinued before treatment in both groups.

AUC, area under the plasma glucose concentration curve; BIAsp30, biphasic insulin aspart; BID, twice daily; DB, double-blind; FPG, fasting plasma glucose; Glim, glimepiride; Met, metformin; ND, no difference between groups; NPH, neutral protamine Hagedorn; NR/ND, not reported/not determined; OD, once daily; PPG, postprandial glucose; TTT, treat to target.

Malone et al.^35,36 conducted two randomized crossover studies, each with two 16-week periods, comparing twice-daily insulin lispro mix 75/25 with once-daily insulin glargine, both in addition to metformin (n=202). Results from these two studies indicate that end-point A1c levels were significantly lower (by 0.4–0.6%) after insulin lispro mix 75/25 treatment than after insulin glargine treatment (P≤0.002). In the insulin lispro mix group, 64–80% achieved target post-breakfast and post-dinner PPG levels (<10 mmol/L) compared with 40–63% in the insulin glargine groups (P=0.036 to <0.001). However, fasting blood glucose reached lower values in the insulin glargine groups in both studies (6.8–7.4 mmol/L vs. 7.7–7.8 mmol/L; P=0.007). Overall hypoglycemia occurred more frequently in one of the studies with insulin lispro mix 75/25 than with insulin glargine (0.39±1.24 vs. 0.68±1.38 episodes/patient per 30 days, P=0.041),³⁵ but the incidence was not different in the other (0.61±1.41 vs. 0.44±1.07 episodes/patient/30 days, P=0.477).³⁶

The open-label, 28-week, treat-to-target INITIATE (INITiation of Insulin to reach A1c TargEt) study compared twice-daily BIAsp30 with once-daily insulin glargine in 233 patients with type 2 diabetes concomitantly treated with metformin.⁴¹ BIAsp30 was associated with a 25% reduction in PPG glucose exposure as well as with larger reductions in A1c than insulin glargine (2.8% vs. 2.4%, P<0.01), although changes in FPG were −125 mg/dL for both groups. The incidence of minor hypoglycemia was higher in the group receiving BIAsp30 compared with insulin glargine (3.4 and 0.7 episodes/patient-year, respectively; P<0.05); serious hypoglycemia was limited to one report in the insulin glargine group.⁴¹

In a 24-week study, patients previously on insulin glargine therapy were assigned to receive either three times daily insulin lispro mix 50/50 or a basal–bolus insulin regimen with once-daily insulin glargine at bedtime and three times daily injections of insulin lispro at mealtimes.⁴² Both therapies significantly improved glycemic control compared with baseline within 6 weeks. A1c levels in patients receiving the insulin lispro mix 50/50 regimen were reduced by 1.87% to 6.95% and by 2.09% to 6.78% in patients receiving BBT (P=0.021 for comparison of end-point A1c levels). No significant difference occurred in the incidence of either severe hypoglycemia or overall hypoglycemia (mean rate of overall hypoglycemia for prandial insulin lispro mix 50/50 and BBT, 51.20 and 48.70 episodes/patient/year, respectively; P=0.619).⁴²

In a substudy of the DURABLE (Assessing Durability of Basal Versus Lispro Mix 75/25 Insulin Efficacy) trial,⁴³ patients who were inadequately controlled (A1c >7%) with basal insulin glargine were switched to twice-daily injections of insulin lispro mix 75/25 (n=200) or to a basal–bolus regimen containing once-daily injection of insulin glargine plus three times daily insulin lispro at mealtimes (basal–bolus) (n=199). Patients who had initiated insulin therapy with twice-daily injections of insulin lispro mix 75/25 were switched to three times daily dosing of insulin lispro mix 50/50 (n=174) or the basal–bolus regimen (n=171). Intensifications with insulin premixes were found to be non-inferior to BBT. Rate of hypoglycemia incidence (overall, nocturnal, or severe) was similar across the three treatment arms (mean hypoglycemia rate, 10.1 vs. 11.2 episodes/patient/year for insulin lispro mix 75/25 and basal–bolus, respectively [P=0.730] and 11.1 vs. 12.1 episodes/patient/year for insulin lispro mix 50/50 and basal–bolus, respectively [P=0.623]).⁴³

One-year interim results from the open-label, multicenter 4-T (Treating to Target in Type 2 Diabetes) trial showed superiority of an insulin premix regimen over a basal insulin regimen in patients inadequately controlled with maximum tolerable doses of metformin and sulfonylureas (n=708).⁴⁰ Although switching to any one of the three insulin regimens—BIAsp30 twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (or twice daily if needed)—reduced A1c levels significantly (P<0.001), the biphasic aspart and the prandial aspart regimens reduced A1c levels significantly more than basal insulin alone (1.3% in the BIAsp30 group and 1.4% in the prandial aspart group compared with 0.8% in the insulin detemir group [P<0.001 for both comparisons with the basal group]). More patients treated with both BIAsp30 and prandial aspart (17.0% and 23.9%, respectively) compared with 8.1% treated with insulin detemir reached the A1c target of ≤6.5% after 1 year of treatment (P=0.001 for the comparison with the BIAsp30 group and P<0.001 for comparison with the prandial aspart group). Hypoglycemia was highest in the prandial insulin group, followed by the biphasic insulin group, and lowest in the basal insulin group (12.0, 5.7, and 2.3 mean number of hypoglycemic events [uncategorized] per patient-year, respectively).⁴⁰

Switching to insulin premixes when basal insulin isn't enough: observational trials in real-world practice

Several prospective observational studies conducted outside of randomized clinical trials reflect real-world practice settings and reinforce that intensification of treatment by switching from a basal insulin regimen to one that contains insulin premixes improves glycemic control.

The 1-2-3 Study evaluated the effects of BIAsp30, self-titrated over 48 weeks, in patients with type 2 diabetes who were poorly controlled on various oral antidiabetes (OAD) drugs or at least one OAD drug plus a daily injection of basal insulin.¹⁹ Prior basal insulin was discontinued, and patients began therapy with a single injection of BIAsp30 before dinner. After 16 weeks, once-daily injection of BIAsp30 before dinner along with their OAD drug regimen enabled 21% of patients to achieve the AACE goal of A1c ≤6.5% and 41% to achieve the ADA A1c target of <7%. Those who did not achieve the AACE goal by week 15 added a pre-breakfast injection of BIAsp30. After addition of a second injection, 52% and 70% achieved the AACE and ADA goals by 32 weeks, respectively. The remaining patients added a third injection before lunch, resulting in 60% and 77% of patients achieving targeted goals, respectively. The rate of minor hypoglycemic events was 15.4, 22.4, and 12.0 events per patient-year for once-daily, twice-daily, and three times daily injections of BIAsp30. Major hypoglycemic events were reported by seven patients with no withdrawals attributed to hypoglycemia.¹⁹

The multinational PRESENT (Physicians' Routine Evaluation of Safety & Efficacy of NovoMix^® 30 Therapy) study⁴⁴ observed a subset of 3,800 patients with type 2 diabetes previously treated with either a human basal insulin (including both intermediate and long-acting human insulin) (n=3,414) or analog basal insulin (n=348), who were switched to BIAsp30 once, twice, or three times daily as required.⁴⁵ The majority of patients were switched to a twice-daily regimen of BIAsp30. After 6 months, patients experienced reductions from baseline in A1c levels of 1.42% and 1.6% for patients who had received human basal and analog basal insulin, respectively (P<0.0001). Patients also experienced significant reductions in FPG by 2.8–3.7 mmol/L and in PPG levels by 5.1–5.9 mmol/L after switching (P<0.0001). Overall rates of hypoglycemia were similar when patients were switched from a long-acting insulin analog to twice-daily BIAsp30 (P=0.84), although the rate of major hypoglycemia was significantly lower after switching (P=0.035). Patients switching from human insulin also experienced a significantly lower incidence of overall hypoglycemia as well as lower rates for both major and minor episodes of hypoglycemia (P<0.001).

Another multinational observational 26-week study, IMPROVE (Impact of Managed Pharmaceutical Care on Resource Utilization and Outcomes in Veterans Affairs Medical Centers), evaluated the effects of switching from basal insulin therapy to BIAsp30 in a subset of patients with type 2 diabetes (n=748) who were poorly controlled on either NPH insulin (n=497) or a basal insulin analog (n=245).⁴⁶ Patients were switched to BIAsp30 once, twice, or three times daily, depending on their previous basal regimen. At the end of the study, 75.8%, 6.3%, and 17.8% were using BIAsp30 twice, once, and three times daily, respectively. Significant improvements in all glycemic parameters (P<0.001) were observed over the 26-week study period, including mean reductions in A1c and fasting blood glucose of 1.7% and 2.35 mmol/L, respectively. Reductions in PPG after breakfast, lunch, and dinner were 4.36, 3.59, and 3.44 mmol/L, respectively. Of the analyzed patients, 39% reached the A1c <7% target level recommended by the ADA, and 33.8% did so without hypoglycemia. Moreover, the percentage of patients reporting major and minor hypoglycemic events decreased from 2.4% to 0.3% and from 27% to 17%, respectively, after the 26-week study period.

Conclusions

Because of the progressive nature of type 2 diabetes as well as the contribution of PPG to overall A1c, a single injection of basal insulin may eventually cease to provide adequate glycemic control. Clinical trials, both randomized and observational, have demonstrated that insulin analog premixes provide more effective control over basal insulin in terms of PPG excursions and, in most cases, over A1c with comparable effects on FPG. The option of using an insulin premix formulation is especially suitable for patients who are unwilling or unable to perform multiple injections or mixing of different types of insulin. Biphasic analog premix formulations mimic endogenous insulin more closely than biphasic human insulin and have more physiological and predictable time–action profiles that can enhance the mealtime flexibility of the insulin-containing regimen. Thus, insulin analog premixes offer patients a simple and effective solution for intensifying therapy and achieving glycemic targets.

Footnotes

Acknowledgments

The author would like to thank Devi Mukherjee, Ph.D. and Aric Fader, Ph.D. of MedVal Scientific Information Services, LLC for providing medical writing and editorial assistance. This manuscript was prepared according to the International Society for Medical Publication Professionals' Good Publication Practice for Communicating Company-Sponsored Medical Research: The GPP2 Guidelines. Funding to support the preparation of this manuscript was provided by Novo Nordisk Inc.

Author Disclosure Statement

Dr. Shanik has received payment from Novo Nordisk Inc. for lectures including service on speakers bureaus.

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