Curr Diab Rep (2017) 17:91 DOI 10.1007/s11892-017-0926-8

PHARMACOLOGIC TREATMENT OF TYPE 2 DIABETES (HE LEBOVITZ AND G BAHTIYAR, SECTION EDITORS)

New Basal Insulins: a Clinical Perspective of Their Use in the Treatment of Type 2 Diabetes and Novel Treatment Options Beyond Basal Insulin Patrick F. Frias 1 & Juan Pablo Frias 2

# Springer Science+Business Media, LLC 2017

Abstract Purpose of Review The purpose of this review was to review advances in basal insulin formulations and new treatment options for patients with type 2 diabetes not achieving glycemic targets despite optimized basal insulin therapy. Recent Findings Advances in basal insulin formulations have resulted in products with increasingly favorable pharmacokinetic and pharmacodynamic properties, including flatter, peakless action profiles, less inter- and intra-patient variability, and longer duration of activity. These properties have translated to significantly reduced risk of hypoglycemia (particularly during the night) compared with previous generation basal insulins. When optimized basal insulin therapy is not sufficient to obtain or maintain glycemic goals, various options exist to improve glycemic control, including intensification of insulin therapy with the addition of prandial insulin or changing to pre-mixed insulin and, more recently, the addition of a GLP-1 receptor agonist, either as a separate injection or as a component of one of the new fixed-ratio combinations of a basal insulin and GLP-1 RA. Summary New safer and often more convenient basal insulins and fixed ratio combinations containing basal insulin (and GLP-1 receptor agonist) are available today for patients with type 2 diabetes not achieving glycemic goals. Head-to-head studies comparing the latest generation basal insulins are This article is part of the Topical Collection on Pharmacologic Treatment of Type 2 Diabetes * Juan Pablo Frias [email protected] 1

Emory University School of Medicine, Atlanta, GA, USA

2

National Research Institute, 2010 Wilshire Boulevard, Suite 302, Los Angeles, CA 90057, USA

underway, and future studies assessing the fixed-ratio combinations will be important to better understand their differentiating features. Keywords Type 2 diabetes . Basal insulin . GLP-1 receptor agonists . Fixed-ratio combination

Introduction Insulin, which is produced and secreted by pancreatic beta cells, plays a critical role in glucose homeostasis [1]. It does so through multiple mechanisms including, but not limited to, stimulation of glucose uptake by peripheral tissues (e.g., skeletal muscle) and suppression of hepatic glucose production [1]. Normally, relatively small amounts of insulin are secreted continuously to maintain normoglycemia in the fasting and postabsorptive state, and discrete ‘boluses’ are secreted when nutrient is ingested to maintain normal postprandial glucose concentrations [1, 2]. The pathophysiology of type 2 diabetes (T2DM) is complex, with hyperglycemia resulting from defects in multiple organ systems and tissues, including pancreatic beta cells [3]. Abnormal insulin production and secretion is a cardinal feature of T2DM, and it has been estimated that up to 80% of beta cell function is already lost at the time a person has glucose concentrations diagnostic of T2DM [3, 4]. Importantly, this defect is progressive in nature, with a steady decline in beta cell function being a key characteristic of the disorder [3]. As such, T2DM is a progressive disease that inevitably requires therapy with multiple antihyperglycemic agents in order to obtain and/or maintain normal or near-normal glycemia [5]. The current T2DM treatment paradigm, based on both robust clinical data and expert opinion, calls for metformin

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therapy as the initial therapeutic agent, followed by sequential addition of medications with complementary mechanisms of action (oral or injectables) if individualized glycemic goals are not achieved after approximately 3 months of therapy [6, 7]. For patients whose initial glycemic control is very poor (i.e., A1C greater than 9.0%), and in which a single agent will unlikely result in adequate glycemic control, it is recommended to consider initiating combination therapy with two agents [6, 7]. Among the various therapeutic options available today, basal insulin is critically important and should be considered early in the course of therapy, particularly given the efficacy and safety profile of today’s basal insulin analogs. In patients with suboptimal glycemic control despite optimization of basal insulin therapy, numerous options exist including intensification of insulin therapy with the addition of rapid-acting insulin, changing to pre-mixed insulin, or the addition of a GLP-1 receptor agonist (GLP-1 RA) [6]. The initiation of a fixed-ratio combination of a basal insulin and a GLP-1 RA is a recently available novel option for optimization of glycemic control to also consider in this patient population [8•, 9•, 10•, 11•]. The present article reviews currently available basal insulins with a focus on their use in clinical practice for the treatment of patients with T2DM. It also discusses treatment options if glycemic control remains suboptimal after optimization of basal insulin therapy, with a focus on the new fixedratio combination products containing a basal insulin and a GLP-1 RA.

Characteristics of Currently Available Basal Insulins Over the past 15 years, there have been significant advances in basal insulin formulations. Prior to 2001, the year insulin glargine 100 U/mL (IGlar U-100, Lantus®, Sanofi) became commercially available in the USA, the most commonly used basal insulin in T2DM was the intermediate-acting neutral protamine hagedorn (NPH) insulin. Insulin detemir (IDet, Levemir®, Novo Nordisk) became available in 2005, and within the past 2 years, two basal insulins with more favorable pharmacokinetic and pharmacodynamic profiles, insulin glargine 300 U/mL (IGlar U-300, Toujeo®, Sanofi) and insulin degludec 100 and 200 U/mL (IDeg U-100 and U-200, Tresiba®, Novo Nordisk), have launched in the USA [12–15]. These enhancements in formulations have resulted in longer-acting insulins with less intra- and interpatient variability and ultimately with reduced risk of hypoglycemia, particularly nocturnal hypoglycemia [16–20]. Key characteristics and resulting pharmacokinetic and pharmacodynamic properties of today’s commercially available basal insulins are detailed below and summarized in Table 1.

NPH Insulin NPH is an intermediate-acting insulin composed of a suspension of zinc-bound insulin and protamine that exists in a 5:1 molar ratio [21]. Upon injection, the solvent rapidly diffuses into the subcutaneous tissue, leaving behind slowly dissolving insulin crystals at the injection depot [22]. The absorption kinetics, and therefore glucose-lowering effects of NPH, can vary significantly from injection to injection. This may be due to both the variability in shape and size of subcutaneous insulin precipitates formed with each administration and potentially inadequate resuspension in its vial or pen, which is required before each injection [22, 23]. NPH insulin has an onset of action of 1–2 h, peaks at 4– 6 h, and has a duration of action of approximately 12– 14 h. It is marketed by multiple manufactures and is available in both insulin vial and pen presentations in 100 U/ mL concentration [24, 25]. Insulin Glargine 100 U/mL (IGlar U-100, Lantus®) Insulin glargine (IGlar) is formed by modifying the amino acid sequence on the A and B chain of human insulin (asparagine replaced by glycine at position A21 and two arginines added to the C-terminus of the B chain), resulting in a decrease in its isoelectric point [26, 27]. This allows it to be soluble in its slightly acidic injection solution (pH approximately 4) and precipitate once injected into the more neutral subcutaneous tissue. These micropercipitates slowly dissolve leading to protracted release of IGlar into the circulation, and a smooth and relatively peakless action profile [26, 27]. IGlar U-100 has a half-life of approximately 13.5 h and a duration of action of 22–24 h with a single dose and 24–25.6 h when at steady state [22]. It is available in a 10-mL vial (containing 1000 U of IGlar) and a 3-mL pen (SoloStar® disposable prefilled pen) containing 300 U of IGlar [12]. Of note, the first follow-on IGlar to Lantus, Basaglar® (Eli Lilly and Company and Boehringer Ingelheim), was approved by FDA in December 2015 and was made commercially available in the USA in late 2016 [28]. In clinical trials, it was found to have near equivalent pharmacokinetic and pharmacodynamic characteristics as well as efficacy and safety compared with Lantus [29]. It is available in a 3-mL pre-filled pen (KwikPen®) in 100 U/mL concentration [28]. Other IGlar U-100 products are in late stages of clinical development [30]. Insulin Detemir (IDet, Levemir®) Insulin Detemir (IDet) is a pH neutral insulin analog in which the amino acid threonine in position B30 has been removed and a C14 fatty acid chain has been attached to the amino acid B29. Protracted absorption is achieved through the formation of dihexamers at the injection depot, as well as reversible

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Key pharmacodynamic characteristics of basal insulins

Type

Trade name

Onset of action (h)

Peak action (h)

Duration of action (h)

NPH Glargine 100 U/mL Detemir 100 U/mL

Humulin N Lantus Levemir

1–2 1–2 1–2

4–6 Relatively peakless Relatively peakless

Glargine 300 U/mL

Toujeo

1–2

Degludec 100 U/mL, 200 U/mL

Tresiba

1–2

Relatively peakless (flatter action profile than IGlar U-100) Relatively peakless (flatter action profile than IGlar U-100)

12–14 24 Up to 24 (dose dependent) 32

binding to albumin at both the injection depot and in the circulation [27, 31]. It has a half-life of approximately 5–7 h and a mean duration of action of approximately 23 h. It is available in a 10-mL vial (containing 1000 U of IDet) and a 3-mL pen (FlexTouch® disposable prefilled pen) containing 300 U of IDet [13, 22]. Insulin Glargine 300 U/mL (IGlar U-300, Toujeo®) Insulin glargine 300 U/mL (IGlar U-300) has a similar structure to IGlar U-100 but is three times more concentrated. This allows for insulin doses to be administered in smaller volumes. Because its more compact conglomerates result in extended release from the subcutaneous tissue, it has a smoother, less variable, and prolonged duration of action compared to IGlar U-100 [32]. At steady state, IGlar U-300 has a half-life of approximately 19 h and a duration of action of 32 h. It has less within-day and between-day variability in exposure when compared to IGlar U-100 [22]. Importantly, clinical studies have demonstrated that IGlar U-100 and U-300 are not bioequivalent. Approximately 12% more IGlar U-300 is needed for similar glycemic effect. This is thought to be due to longer residence time, thus prolonged exposure to tissue peptidases, in the subcutaneous tissue [18]. From a clinical perspective, this should be considered when switching between these two insulin formulations. IGlar U-300 is available only in a 1.5-mL disposable prefilled pen presentation (SoloStar®) containing 450 U of IGlar [14]. Insulin Degludec 100 and 200 U/mL (IDeg U-100 and U-200, Tresiba®) Insulin degludec (IDeg) exists as a soluble dihexamer in its formulation with phenol and zinc. Upon subcutaneous injection and the subsequent diffusion of phenol, multi-hexamer chains form at the injection site. As zinc diffuses from these multi-hexamer chains, IDeg monomers are released and absorbed into the circulation. The fatty acid side chain of

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IDeg allows it to reversibly bind albumin, increasing its plasma concentration [27, 33, 34]. IDeg U-100 and U-200 have been shown to be bioequivalent, with a half-life of approximately 25 h and a duration of action of approximately 42 h [22]. When compared to IGlar U-100, IDeg has a flatter action profile and four times lower day-to-day variability in glucose lowering effect [34]. Both the U-100 and U-200 concentrations of IDeg are available in a 3-mL pen (FlexTouch disposable prefilled pen) containing 300 and 600 U of IDeg, respectively [15].

Clinical Data of Basal Insulin Analogs Efficacy and safety findings from long-term clinical trials of basal insulin analogs (versus NPH and other analogs) are based in large part on the insulin’s pharmacokinetic and pharmacodynamic characteristics. Prolonged duration of activity, ‘flatter’ pharmacokinetic and pharmacodynamic profiles, and lower intra- and interpatient variability have resulted in lower rates of hypoglycemia (particularly during the night) as advances have been made in basal insulin formulations [16–19]. Randomized, controlled trials (RCT) of approximately 6-month duration assessing IGlar 100 U/mL or IDet versus NPH in insulin naïve patients with T2DM demonstrated similar glycemic control with significantly less hypoglycemia with the basal insulin analogs [35, 36]. With both the basal insulin analogs and NPH, patients achieved excellent glycemic control (60–70% achieving an A1C ≤ 7.0% by study end). The relative reduction in the event rates of nocturnal hypoglycemia with the insulin analogs versus NPH ranged from 42 to 55%, depending on the definition of hypoglycemia. Rosenstock et al. reported results of a 52-week RCT assessing once daily IGlar U-100 versus once or twice daily IDet in suboptimally controlled, insulin-naïve patients with T2DM [37]. In this study, titration of basal insulin to a fasting plasma glucose target of less than or equal to 108 mg/dL led to similar, clinically

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significant improvements in A1C (− 1.5% at week 52 with both insulins) with similarly low rates of hypoglycemia. Patients treated with IDet experienced less body weight gain compared with IGlar U-100 treated patients (2.7 vs 3.5 kg, p = 0.03). This was driven primarily by patients treated with once daily IDet [37]. More recently, RCTs comparing the newest basal insulin analogs, IGlar U-300 and IDeg U-100 and U-200, to IGlar U-100 have been reported [18, 19, 38•, 39, 40, 41•, 42, 43]. Some of these trials were the basis for the FDA approval of IGlar U-300 and IDeg U-100 and U-200. They demonstrated that the new basal insulin analogs have similar glycemic efficacy (fasting plasma glucose and A1C) with less hypoglycemia compared with IGlar U-100 in insulin-naïve and insulin-experienced patients with T2DM treated with basal or basal-bolus insulin therapy [18, 19]. A 26-week study in patients with T2DM suboptimally controlled with oral agents or basal insulin (with or without orals agents) demonstrated that flexible dosing of IDeg, which consisted of rotating between morning and evening dosing every day (creating a minimum of 8 h and a maximum of 40 h between doses) was equivalent with respect to efficacy and safety as daily IDeg or IGlar U-100 dosing at the same time each day [44]. This study was the basis for the label recommendation to instruct patients who forget a dose of IDeg to take it once they realize it has been missed, if it is administered in the waking hours and the patient ensures that at least 8 h elapse before the next dose [15]. The recently published DEVOTE Study, assessing the long-term cardiovascular safety of IDeg in high-risk patients with T2DM, demonstrated non-inferiority with respect to major cardiovascular events compared with IGlar U-100 [45••]. In this trial, patients treated with IDeg also experienced significantly less severe hypoglycemia compared with IGar U-100 (3.7 vs 6.2 events per 100 patient-years, p < 0.0001) [45••]. Based on these and other studies, the key differentiating feature with advances in basal insulin formulations has been a reduction in hypoglycemia, due presumably to the “flatter” and more predictable pharmacokinetic and pharmacodynamic profiles. Head-to-head trials assessing the efficacy and safety of IGlar U-300 versus IDeg U-100 in patients with T2DM are currently being conducted [46]. Results of these studies should be available in 2018. Of note, there is limited data assessing the basal insulin analogs in pregnant women with T2DM. Relatively small prospective and retrospective studies have not indicated that their use increases fetal or maternal risk relative to human insulin, but these trials are not powered to make definitive conclusions [47, 48]. As such, the basal insulin labels state that they should be used in pregnancy only if the potential benefits outweigh the potential risks.

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Use of Basal Insulin in the Treatment of Type 2 Diabetes Given the role of progressive beta cell dysfunction in the pathogenesis and natural history of T2DM, most patients with the disorder will eventually require insulin therapy to maintain and/or sustain adequate glycemic control. Basal insulin has had a role as an add-on to oral antidiabetic agents in patients with T2DM for over 2 decades. Shank et al. demonstrated the utility of bedtime insulin added to the regimen of patients suboptimally controlled on a sulfonylurea in 1995 [49]. In this small but impactful RCT, the addition of bedtime NPH to sulfonylurea therapy was shown to be superior to bedtime insulin or sulfonylurea alone, and it was demonstrated that the improvement in fasting glucose was related to reduction in overnight hepatic glucose production. Subsequent studies also demonstrated the value of adding dinner time NPH-based pre-mixed insulin to “failing” sulfonylurea therapy. The “treat-to-target” studies briefly described above, in which IGlar U-100 and IDet were compared to NPH insulin using a protocol-defined insulin titration algorithm based on specific fasting glucose targets, not only demonstrated the superior safety profiles of these new basal insulin analogs, but also significantly increased the use of basal insulin in patients with T2DM suboptimally controlled by oral agent therapy [35, 36]. Subsequent to the publication of these initial treat-to-target trials, Holman et al. published the 1- and 3-year results of the 4-T Study [50, 51]. This study assessed the efficacy and safety of initiation of rapid-acting (prandial) versus basal versus premixed insulin in insulin-naïve patients with T2DM suboptimally controlled on metformin and sulfonylurea therapy. Although the A1C-lowering was least favorable with basal insulin versus prandial and pre-mixed insulin, the more favorable effects of basal insulin on hypoglycemia and body weight led the authors and other experts to conclude that initiation of insulin with basal rather than prandial or pre-mixed insulin should be the preferred choice for most patients. Given the relatively low percentage of patients that achieved an A1C of less than 7% after 1 year in each of the 4-T study treatment groups (prandial 48.7%, basal 27.8%, and pre-mixed 41.7%), this study highlighted that most patients with T2DM initiated on one insulin formulation will likely need intensification of antidiabetic therapy to obtain or sustain glycemic goals [50]. Based on these and other trials, the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) and the American Association of Clinical Endocrinologists (AACE) T2DM treatment guidelines recommend basal insulin as a treatment consideration early in their treatment recommendations [5–7]. With medical nutrition therapy, physical activity, and weight loss, if needed, as the cornerstone of treatment, metformin is recommended as first line therapy if there

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are no contraindications. Subsequent to metformin, other classes of oral agents as well as injectables, including GLP-1 RAs and basal insulin, should be considered in patients not achieving individualized treatment targets. In general, when initiated, basal insulin is started after a patient has “failed” 2–3 oral agents with or without a GLP-1 RA. The use of GLP-1 RA as the first injectable in patients suboptimally controlled on oral agents is becoming increasingly more common with the advent of once weekly GLP-1 RA formulations [52]. In patients not achieving adequate glycemic control with oral agents, with or without a GLP-1 RA, today’s basal insulin analogs can be conveniently initiated as a once daily injection. Recommendations both on the initial insulin dose and subsequent titration to achieve individualized glycemic targets vary depending on the insulin formulation as well as healthcare provider and patient preferences. Per the prescribing information, the recommended initiation dose of IGlar U-100 in patients with T2DM who are not currently treated with insulin is 0.2 U/kg or up to 10 U once daily, and for IDet, it is 0.1 or 0.2 U/ kg once daily in the evening or 10 U once or twice daily [12]. In patients previously treated with basal insulin and switching to IGlar U-100, a unit-to-unit conversion is recommended if the patient is being treated with a once daily basal insulin regimen, except for patients converting from IGlar U-300 in which case the initial dose of IGlar U-100 should be 80% of the total IGlar U-300 dose that is being discontinued. A similar 20% dose reduction is recommended for patients switching from twice daily NPH insulin to IGlar U-100. For patients switching from another basal insulin to IDet, a unit-to-unit conversion is recommended [13]. The recommended starting doses of IGlar U-300 and IDeg U-100 and U-200 in insulin-naïve patients with T2DM are 0.2 U/kg and 10 U once daily, respectively [14, 15]. In patients currently treated with a basal insulin once daily, the starting dose of IGlar U-300 should be the same as the dose of the insulin that is being discontinued (one-to-one conversion). As with IGlar U-100, in patients currently treated with twice daily NPH insulin, the initial dose of IGlar U-300 should be 80% of the total NPH dose that is being discontinued [14]. For IDeg, a one-to-one unit conversion is recommended for patients already treated with basal insulin [15]. Each of these initial dose recommendations are generally fairly conservative in order to mitigate the risk of hypoglycemia. To further mitigate this risk, consideration should also be given to adjusting the dose of concomitant oral antidiabetic agents, particularly insulin secretagogues (e.g., sulfonylureas and meglitinides). Additionally, patients should be educated about the symptoms and treatment of hypoglycemia and the use of a glucose meter for self-monitoring of blood glucose.

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After initiation, it is critical that the dose of basal insulin be titrated to achieve desired fasting plasma glucose (FPG) targets. There are several commonly used titration schemes that have been assessed for IGlar U-100 and IDet. Making dose adjustments either daily by 1 U (based on that day’s FPG) or every 3 days (based on the mean, median, or the lowest of the 3 preceding day’s FPG readings) are safe and effective methods to titrate. For IGlar U-300 and IDeg, it is recommended that dose adjustments not be made more frequently than every 3–4 days, to minimize the risk of hypoglycemia [14, 15]. Clearly, any hypoglycemia should prompt evaluation of potential precipitating events and consideration to reduce the insulin dose and/or adjust concomitant antidiabetic therapy.

Clinical Considerations in Patients Not Achieving Glycemic Targets Despite Optimized Basal Insulin Therapy Although many patients can achieve glycemic targets with the addition of basal insulin to oral antidiabetic agents, others require further intensification of therapy despite appropriate basal insulin titration [53, 54]. These patients may have elevated A1C levels despite normal or near normal FPG concentrations, indicating that they likely have significant postprandial hyperglycemia. Additionally, it is well accepted that if the daily basal insulin dose is above approximately 0.5 U/kg and the A1C is not at target, consideration should be given to initiating combination injectable therapy. The three general options recommended by the ADA to further intensify therapy in these situations are to add rapid-acting insulin (usually once daily initially before the largest meal of the day and subsequently advancing to two or more injections if needed), to switch from basal insulin to twice daily premixed insulin before breakfast and dinner (subsequently adding a lunchtime injection if needed), or to add a GLP-1 RA [6, 55, 56]. The options each have pros and cons. With intensification of insulin therapy, there is greater risk of hypoglycemia and weight gain as well as the need to increase frequency of selfmonitoring of blood glucose. The addition of a GLP-1 RA to ongoing insulin therapy is well-established and compared with “basal-bolus” insulin therapy generally results in similar A1C reductions, with less hypoglycemia and significantly less weight gain. Gastrointestinal-related side effects are more common with the addition of a GLP-1 RA and these agents are contraindicated and/or should be used with caution in certain patient populations, including patients with history of pancreatitis, severe renal impairment and, with long-acting GLP-1 RAs, personal or family history of medullary thyroid cancer.

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Full prescribing information should be consulted prior to use and, as with any medication, clinical judgment should be exercised when using these compounds

Degludec 100 U per mL Liraglutide 3.6 mg per mL Degludec U-100 and liraglutide

XULTOPHY® 100/3.6

3-mL disposable pen (FlexPen®)

Adults with T2DM suboptimally controlled with basal insulin (< 50 U) or liraglutide, with or without oral agents

▪ Titrate every 3–4 days by + 2 U in order to achieve individualized fasting plasma glucose target ▪ Reduce dose by 2 U if patient experiences hypoglycemia

▪ Titrate weekly by + 2 U to + 4 U in order to achieve individualized fasting plasma glucose target ▪ Reduce dose by 2 U to 4 U if patient experiences hypoglycemia

▪ If basal insulin dose 15-29 U, start with 15 U SOLIQUA™ 100/33 ▪ If basal insulin dose 30-60 U, start with 30 U SOLIQUA™ 100/33 ▪ Administer SC daily within 1 h of the first meal of the day ▪ Start with 16 U XULTOPHY® 100/3.6 ▪ Administer SC daily once daily at same time each day with or without food 3-mL disposable pen (SoloStar®) Glargine 100 U per mL Lixisenatide 33mcg per mL Glargine U-100 and lixisenatide

SOLIQUA™ 100/33

Labeled indication Presentation Trade name Concentrations Composition

Table 2

The most recently approved agents for the treatment of T2DM are the so-called “fixed-ratio combinations,” which contain a basal insulin and a GLP-1RA, and are administered as a single daily subcutaneous injection. The two currently available fixed-ratio combinations, IGlarLixi and IDegLira, received FDA approval in November 2016. IGlarLixi (Soliqua™ 100/33, Sanofi) is a combination of IGlar U-100 and lixisenatide, a short-acting GLP-1 RA. Each milliliter of IGlarLixi contains 100 U of IGlar and 33 mcg of lixisenatide. It is available in a 3-mL SoloStar pen [57]. IDegLira (Xultophy® 100/3.6, Novo Nordisk) combines IDeg U-100 and liraglutide, a longacting GLP-1 RA. Each milliliter of IDegLira contains 100 U of IDeg and 3.6 mg of liraglutide. It is available in a 3-mL FlexTouch pen [58]. See Table 2 for key characteristics and dosing recommendations of the available fixedratio combination products. In the USA, both agents are approved for use in patients suboptimally controlled on basal insulin (less than 60 U for IGlarLixi and less than 50 U for IDegLira). IGlarLixi and IDegLira are also approved for patients not achieving glycemic targets with lixisenatide or liraglutide, respectively. In Europe, the product’s labels are broader, and include use as the first injectable in patients “failing” oral antidiabetic agents [59, 60]. With both agents, studies assessing patients suboptimally controlled on both oral agents alone or basal insulin (with or without oral agents) demonstrated that the fixed-ratio combinations versus the individual components, resulted in significant improvements in glycemic control (55–75% of patients achieving A1C < 7.0%), mitigation of weight gain seen with basal insulin alone, less gastrointestinal side effects compared with GLP-1 RA alone, and no increased risk of hypoglycemia versus basal insulin [8•, 9•, 10•, 11•]. In patients suboptimally controlled on basal insulin, the recommended starting dose of IGlarLixi depends on the current basal insulin dose. If the patient is on less than 30 U of basal insulin, IGlarLixi should be started at 15 U (which contains 15 U IGlar and 5 mcg lixisenatide). In patients on 30 U or more of basal insulin, the recommended starting dose is 30 U (30 U IGlar and 10 mcg lixisenatide). The dose should be administered once daily anytime within 1 h of starting the first meal of the day [57]. The starting dose of IDegLira is 16 U, which contains 16 U IDeg and approximately 0.6 mg liraglutide. It is also a once daily subcutaneous injection that can be given at any time of the day, irrespective of meals, but should be administered at approximately the same time every day [58]. With the fixed-ratio combinations, as with basal insulin alone, subsequent titration based on self-monitored FPG is critical to achieve glycemic targets. The maximal dose

Key characteristics of fixed-ratio combinations of basal insulin and GLP-1 receptor agonist

Fixed-Ratio Combinations of Basal Insulin and GLP-1 RA Agonists

Adults with T2DM suboptimally controlled with basal insulin (< 60 U) or lixisenatide, with or without oral agents

Label recommended titration

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Starting dose and administration

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of IGlarLixi is 60 U and IDegLira is 50 U. At these doses, the maximally approved doses of the GLP-1 RA components are reached: 20 mcg lixisenatide and 1.8 mg of liraglutide for IGlarLixi and IDegLira, respectively. For patients who are not achieving glycemic targets with less than 50–60 U basal insulin, switching to one of these fixed-ratio combinations is an important option. Not only have they been shown to be efficacious, but they also have excellent safety profiles and are convenient, with one daily subcutaneous injection providing both basal insulin and a GLP-1 RA. Head-to-head trials have not yet been conducted to assess whether the differences in basal insulin and/or GLP-1 RA components (short-acting versus long-acting) of the two fixed-ratio combinations will result in clinically meaningful differences between the two agents.

Conclusions Basal insulin is an important therapeutic option for patients with T2DM. Over the past two decades, significant advances have been made in basal insulin formulations, resulting in insulins with properties that result in longer and flatter action profiles. From a clinical perspective, this has translated to lessened risk of hypoglycemia, an important barrier to insulin intensification, which can result in significant morbidity. Intensification of therapy in patients not achieving glycemic targets despite optimized basal insulin therapy is often required, primarily to address postprandial hyperglycemia. This can be accomplished with addition of prandial insulin, changing to pre-mixed insulin, or addition of a GLP-1 RA. The latter is associated with more favorable effects on body weight, less hypoglycemia, but with increased gastrointestinal-related side effects. Initiating a fixed-ratio combination product containing a basal insulin and a GLP-1 RA is a recently available option in this patient population. This novel option reduces injection burden, may improve compliance and adherence, and has been shown to be safe and effective in appropriate patients. Compliance with Ethical Standards

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References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

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Conflict of Interest Patrick F. Frias declares no conflict of interest. Juan Pablo Frias reports grants and personal fees from Sanofi, grants and personal fees from Novo Nordisk, and grants from Eli Lilly, Merck, and Mylan. Human and Animal Rights and Informed Consent All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable standards (including the Helsinki declaration and its amendments, instructional/national research committee standards, and international/national/institutional guidelines).

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