Reconsidering Strategies for Insulin Intensification

Basal, prandial, NPH, ultra-long, inhaled, 70/30, 75/25, 50/50, U-100, U-200, U-300, and U-500 insulin … the list of options for patients with diabetes requiring insulin continues to expand. Current guidelines for glycemic management of patients with type 2 diabetes provide specific recommendations for the initiation of insulin therapy, but not insulin intensification. This is due to a lack of clinical trials comparing treatment strategies. Recent studies, however, provide a foundation for making evidence-based clinical decisions.

For patients with type 2 diabetes who require insulin, the 2016 American Diabetes Association (ADA) guidelines recommend that therapy begin with a single daily dose of basal insulin.¹ For patients who require additional glucose control after titrating the basal insulin dose, the ADA suggests one of three options: add a single bolus dose of short-acting insulin with the largest meal (hereafter referred to as “basal-plus”), switch to twice daily premixed insulin (“biphasic”), or add a GLP1 receptor agonist. To achieve post-prandial glycemic goals after optimizing basal insulin, the 2016 American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) guidelines recommend basal-plus therapy, or the addition of a GLP-1 receptor agonist, SGLT-2 inhibitor, or DPP4 inhibitor.² Alternative insulin products such as biphasic, NPH, or regular insulin are categorized by AACE/ACE as “less desirable” options. To date, there has been insufficient evidence to favor one treatment over another.

The LanScape trial, published in 2015, directly compared two different insulin intensification strategies — basal-plus vs. biphasic insulin — in patients with type 2 diabetes.³ This study examined not only glycemic outcomes but also adverse events and patient satisfaction. The study was a 24-week multi-center trial conducted in Australia and the United Kingdom. (See Table 1)

Table 1. Study Designs & Baseline Characteristics of Participants

A similar trial, the 4-T trial, was initially reported in 2007 and with a 3-year follow-up study published in 2009.^4,5 The LanScape and 4-T trials included patient populations with very similar baseline characteristics (duration of diabetes, A1C, age, sex, BMI, race). The primary difference between the study populations was that the 4-T trial only included patients who were insulin-naïve prior to enrollment; whereas, the LanScape trial required participants to have at least 3 months of previous insulin exposure.

Although both trials evaluated similar therapeutic agents, the two studies utilized slightly different protocols. Following the run-in period, LanScape participants began either a twice daily biphasic insulin regimen, or a once daily basal-plus regimen. The 4-T trial design was slightly more complicated. In the first phase following the run-in period, participants were assigned to one of three intervention groups; biphasic twice daily, basal once/twice daily (depending on dose required), or prandial thrice daily. Participants with an A1C >10% (or >8% on two measurements) then had their regimen intensified by adding an insulin product with different time-action profiles (prandial or basal) to their base regimen.  Because the LanScape and 4-T trials collectively encompass the bulk of available evidence available to date comparing insulin intensification regimens, the results of both studies are compared side-by-side in Table 2.

Table 2. Study Results

The LanScape trial largely confirms conclusions from previous studies. Biphasic and basal-plus insulin regimens are roughly equivalent with respect to A1C reduction and incidence of adverse events. The most interesting difference is patient satisfaction — which favors basal-plus.  It is worth noting that only 3 of the 5 measures of patient satisfaction were statistically different and only 1 (the DTSQc) represents a clinically meaningful (difference of 3.16 on a scale of -3 to +3). Although patient satisfaction was higher with basal-plus therapy in LanScape, this regimen was also associated with a higher incidence of nocturnal hypoglycemia. One explanation for the increased incidence of nocturnal hypoglycemia with basal-plus treatment seen in LanScape may be the more aggressive prandial insulin protocol used (additional 6 units of prandial insulin for BG > 180 mg/dL compared to 4 units for BG > 171 mg/dL in the 4-T trial). Total daily insulin requirements were similar in both treatment arms.

Patient preference for basal-plus therapy may be related to decreased dosing frequency with basal-plus therapy. Although biphasic and basal-plus groups were both required to administer two injections per day, the basal-plus group had the option of giving both injections at the same time with the largest meal. Many studies have demonstrated that decreased medication dosing frequency (once daily compared with two or three times daily) results in improved patient adherence.^6,7 Improved patient satisfaction resulting from once-daily injections is therefore a reasonable consideration and may increase the likelihood of adherence.

The LanScape trial does have several limitations worth noting. First, the trial was open label and this may have influenced the patient satisfaction results. Also, by using 5 different measures of quality of life and patient satisfaction, the researchers increased the chance of a false positive due to a family-wise error. Lastly, the study population was predominantly Caucasian, a demographic sampling not representative of most patients with type 2 diabetes in the United States.⁸ Despite these limitations, the LanScape trial does have several strengths. It utilized a relatively large study population, investigated pertinent endpoints, and utilized insulin regimens and protocols that are consistent with current standards of care.

Diabetes treatment guidelines endorse individualization of therapy. When considering insulin intensification, we recommend using the “STEPS” acronym. “STEPS” stands for safety, tolerability, efficacy, price, and simplicity.⁹ With regards to safety, basal-plus and biphasic insulin have similar rates of adverse events including hypoglycemia and weight gain. Basal-plus may be a better option for patients who only eat one or two meals each day, due to the greater risk of hypoglycemia with biphasic insulin during times of fasting. Tolerability may favor a basal-plus regimen due to findings of increased patient satisfaction; however, patients who do not want to give themselves two injections at once may prefer the biphasic option. Efficacy appears to be equivalent with respect to A1C reduction. The cash price is currently very comparable between the different types of insulin, but insured individuals would likely pay an additional copay for basal-plus compared to biphasic. Lastly, simplicity likely favors basal-plus because patients need only remember to inject themselves at one time each day.  Ultimately, the choice between insulin regimens should be based on a shared decision making process.

Data from the LanScape trial depict biphasic and basal-plus insulin regimens as equally efficacious, but suggest higher patient satisfaction with basal-plus. Additionally, the rigid nature of premixed biphasic insulin can be challenging and limits the ability to match insulin doses with carbohydrate intake with meals.  Progressive beta cell failure is an inevitable feature of type 2 diabetes. Patients who require insulin to achieve their glycemic goals nearly always advance to basal bolus therapy. Although the results from the LanScape trial do not eliminate biphasic insulin as a treatment option, it is not superior to basal-plus. But if basal-plus works equally well and patients like it better, perhaps it should be more firmly established as first-line for insulin intensification in patients with type 2 diabetes. Does biphasic insulin still have a role in contemporary practice? What do you think?