Basal Insulin Intensification in Patients with Type 2 Diabetes: A Review

Basal Insulin Intensification in Patients with Type 2 Diabetes: A Review Diabetes Ther (2018) 9:877–890 https://doi.org/10.1007/s13300-018-0395-3 REVIEW Basal Insulin Intensification in Patients with Type 2 Diabetes: A Review Jerry Meece Received: December 6, 2017 / Published online: March 24, 2018 The Author(s) 2018 can be administered via subcutaneous injection ABSTRACT once or twice daily, or weekly depending on formulation. More recently, two fixed-ratio As the number of people living with type 2 combinations of basal insulin and a GLP-1 RA diabetes (T2D) continues to rise, managing their that allow for once-daily dosing have been complex needs presents an increasing challenge approved. Each of these approaches has poten- to physicians. While treatment guidelines pro- tial benefits and drawbacks, particularly in vide evidence-based guidance, they are not terms of risk for hypoglycemia, weight change, prescriptive—rather they emphasize individu- convenience, and side effects. Understanding alization of management based on a patient’s these differences is central to guiding patient clinical needs and preferences. Physicians, and physician choice. This article discusses the therefore, need to be fully aware of the advan- rationale, advantages, disadvantages, and tages and disadvantages of the multiple and implementation of currently available strategies increasing treatment options available to them for basal insulin treatment intensification in at each stage of the disease. The progressive patients with T2D. nature of T2D means that treatment with basal Funding: Sanofi US, Inc. insulin will become inevitable for many patients, while for some patients basal insulin alone will eventually be insufficient for main- Keywords: Basal insulin; Diabetes type 2; taining glycemic targets. Recent guidelines rec- Fixed-ratio combinations; Glucagon-like ommend two basic approaches for intensifying peptide-1 receptor agonist; Treatment basal insulin: the use of rapid-acting insulin, intensification either as additional prandial injections or as part of premix (biphasic) insulin; and the addi- tion of glucagon-like peptide-1 receptor ago- INTRODUCTION nists (GLP-1 RAs) to the insulin therapy, which The number of people living with type 2 dia- Enhanced content To view enhanced content for this betes (T2D) is ever-growing. In 2017, it has been article go to https://doi.org/10.6084/m9.figshare. estimated that almost 425 million adults worldwide had diabetes, and this is projected to J. Meece (&) increase to 628 million by 2045 [1]. This Clinical Services, Plaza Pharmacy and Wellness alarming figure is a result of the aging popula- Center, Gainesville, TX, USA tion, which is more likely to develop T2D, e-mail: jmeece12@cooke.net 878 Diabetes Ther (2018) 9:877–890 together with population-wide lifestyle chan- Managing patients who do not achieve gly- ges, and also reflects the fact that T2D is being cemic goals despite uptitration of basal insulin diagnosed earlier and, with advances in man- provides a particular challenge, with a number agement strategies, patients are living longer of available options. Until recently, the recom- [1]. Managing the complex needs of patients mended strategy for intensifying insulin ther- with long-standing T2D is therefore an apy was the addition of rapid-acting insulins increasingly common clinical challenge for (RAIs) to the treatment regimen, either as primary healthcare practitioners. Current treat- additional prandial injection or as part of a ment guidelines provide evidence-based guid- premixed insulin formula. However, over recent ance for T2D management, but they are not years combining a GLP-1 RA with basal insulin prescriptive and emphasize the importance of has been shown to provide equal or slightly individualization of T2D management based on superior efficacy to the addition of prandial a patient’s clinical needs and preferences [2, 3]. insulin, with a beneficial effect on weight and If physicians are to achieve this, they need to be less hypoglycemia, as well as reduced regimen fully aware of the advantages and disadvantages complexity [5–9]. Based on this finding, the of the multiple treatment options and strategies most recent 2018 recommendations from the available to them at each stage of the disease. American Diabetes Association state that com- T2D is a progressive disease, and although pared with basal-plus insulin, ‘‘basal insulin plus some patients may manage it with oral medica- GLP-1 RAs are associated with less hypo- tions, most will eventually need to use insulin to glycemia and with weight loss instead of weight achieve glycemic control. Insulin treatment is gain but may be less tolerable and have a greater usually initiated when patients are no longer cost’’ [2]. meeting glycemic targets on combination ther- Treatment guidelines, therefore, give two apy using oral drugs, or present with a glycated potential approaches for intensifying insulin hemoglobin A (HbA1c) level of[ 9.0% with therapy: the addition of a RAI, either as an 1c symptomatic hyperglycemia [3]. Guidelines additional prandial injection or as part of a continue to be revised however, and basal insulin premixed insulin formula; or the addition of a therapy is now often used much sooner and fre- GLP-1 RA (Fig. 1). In review I discuss the ratio- quently in combination with oral agents or glu- nale and implementation of these two approa- cagon-like peptide-1 receptor agonists (GLP-1 ches and consider their advantages and RAs), rather than postponing insulin therapy disadvantages. until lifestyle modifications and oral agent This review article is based on previously treatment has failed [2, 3]. Guidelines for initial conducted studies and does not contain studies insulin therapy are straightforward. The first step with human participants or animals performed for most patients is the addition of a long-acting by any of the authors. basal insulin to oral therapy to control fasting plasma glucose (FPG) levels. In general, insulin THE PROBLEM OF OVER- analogs are favored over neutral protamine Hagedorn (NPH) insulin, largely because of their BASALIZATION better hypoglycemic profile due to their flat pharmacokinetic curve [2, 3]; however, NPH Uptitrating basal insulin is no longer having an HbA1c-lowering effect, while higher insulin insulin is associated with markedly lower costs and remains widely used in some settings, such as doses mean greater risk of weight gain and hypoglycemia. Treatment guidelines do not in resource-limited countries [4]. Many patients will successfully achieve and maintain glycemic give a definite upper limit for basal insulin dose, and there may be the temptation to continue goals on these regimens, but the disease of other patients may progress to the point at which basal with a familiar routine by increasing the basal insulin alone is insufficient, and these latter insulin dose despite the patient still not achieving glycemic targets—a situation known patients will require additional therapeutic sup- port to control postprandial glucose (PPG) levels. as ‘over-basalization’ [10]. The aim of basal Diabetes Ther (2018) 9:877–890 879 Fig. 1 Combination injectable therapy for type 2 diabetes. blood glucose. (Adapted with permission from American A1C Glycated hemoglobin (HbA1c), FBG fasting blood Diabetes Association 2017 guidelines. Reproduced with glucose, GLP-1 RA glucagon-like peptide-1 receptor permission from Inzucchi et al. [57]) agonist, hypo hypoglycemia, SMBG self-monitoring of insulin treatment to provide a steady level of assumes that beta-cell function is still sufficient insulin throughout the day, mimicking normal to help cover increased prandial insulin needs physiological production and controlling FPG in terms of insulin synthesis and secretion [10]. levels; its effects on PPG are limited. In T2D the Data from a recent study suggest that basal initial use of basal insulin alone therefore insulin has a ‘ceiling effect,’ whereby reductions 880 Diabetes Ther (2018) 9:877–890 in FPG become proportionally smaller with reductions in insulin dose, and/or carbohydrate increasing dose from 0.3 up to about 0.5 U/kg supplementation [16]. body weight (BW)/day, at which point FPG Efforts to improve lifestyle, however, should response does not increase despite increasing not delay changes in therapy; such changes can insulin levels [11]. Another study suggests that be done simultaneously and adjusted based on increasing basal insulin above 0.5 Units/kg patient response to lifestyle efforts [3]. Thera- BW/day may not improve glycemic control and peutically, there are two main guideline-rec- may also result in weight gain and increased risk ommended options for escalating basal insulin of hypoglycemia [12]. It is therefore important therapy [2, 3]. The first is to add a prandial to keep in mind (1) the risk of over-basalization insulin to the treatment regimen, either by and (2) guideline recommendations that basal adding a RAI prior to the largest meal of the day, insulin therapy should be escalated to combi- with addition at other meals in stages if nation injectables when the basal insulin dose required (basal-plus), adding RAI at all meals exceeds 0.5 Units/kg BW/day. (basal-bolus), or by switching to a premixed (biphasic) insulin formulation of intermediate- and short-acting insulins. In general, RAIs are BEYOND BASAL INSULIN preferred over regular human insulin because of their more rapid onset and offset of action and When treatment is intensified beyond basal association with a lower incidence of hypo- insulin therapy, a number of factors should be glycemia [2, 3], although regular insulin may taken into account as part of the shared decision- represent a pragmatic choice where costs or lack making process, such as patient preference, of resources limit availability [17]. The second safety, tolerability, glycemic efficacy, risk of option is to add a GLP-1 RA to the treatment hypoglycemia, and other non-glycemic effects regimen. Each treatment regimen has advan- (e.g., weight change and/or impact on life-style) tages and disadvantages (Table 1), and these [13]. Continued basal insulin therapy should, should be taken into account when deciding on however, be considered an essential component a strategy with the patient. of future treatment strategies [2]. Initial discus- sions should also include issues around lifestyle (nutrition, weight loss, and physical activity) and ADDING PRANDIAL INSULIN the possible treatment of obesity, such as using the American Association of Clinical Endocri- The aim of injecting RAIs just before a meal is to nologists Obesity Treatment Algorithm, which support basal-insulin action on FPG by con- may include obesity pharmacotherapy [14]. The trolling PPG excursions. In effect, adding pran- effectiveness of lifestyle changes such as weight dial RAIs to the treatment regimen mimics the loss and exercise in decreasing the incidence and physiological meal-simulated insulin release, progression of T2D is well known. Although which is lost first as beta-cell function declines. generally considered an initial strategy, it is RAI analogs (lispro, aspart, or glulisine) are important that lifestyle optimization is ongoing preferred over regular human insulin because throughout the course of T2D [3]. In a cohort they have a more rapid onset and shorter study, almost half of overweight or obese duration of action, making them better suited patients with T2D who lost a mean of 4% of body for controlling PPG, and are associated with less weight were able to reduce their insulin dose; a hypoglycemia [18, 19]. The simplest and gen- mean reduction of 11% of initial body weight was erally most effective way of adding prandial to required to discontinue insulin [15]. Although basal insulin is to cover the largest (or most exercise has undoubted benefits for patients with carbohydrate-heavy) meal of the day with an T2D, those using insulin or insulin secretagogues injection of RAI, often termed basal-plus [7, 13]. should be made aware of the amplified risk of The initial mealtime dose of RAI should be 4 U, hypoglycemia during and after exercise and 0.1 U/kg BW, or 10% of the basal dose (possibly should be advised on blood-glucose monitoring, with a reduction in basal insulin dose by the Diabetes Ther (2018) 9:877–890 881 Table 1 Advantages and disadvantages of prandial insulin and glucagon-like peptide-1 receptor agonist regimens for insulin intensification Guideline- Advantages Disadvantages recommended options Prandial insulin Basal-plus Dosing/titration flexibility greater than basal- Risk of hypoglycemia bolus or premixed Weight gain Gradual introduction to multiple daily Progresses to multiple daily injections injections Basal-bolus Dosing/titration flexibility greater than Multiple daily injections immediately premixed Risk of hypoglycemia Weight gain Premixed Simplified regimen vs. basal-plus of basal-bolus Less flexibility than basal plus or basal bolus Less effective glycemic control vs. basal-plus of basal- bolus Greater risk of hypoglycemia and weight gain GLP-1 RAs Added to basal Weight neutral/weight loss Once/twice daily or once weekly (depending on GLP-1 insulin RA) injection in addition to basal insulin Lower incidence of hypoglycemia vs. addition of RAI Gastrointestinal side effects Fixed-ratio Simple, once-daily regimen Gastrointestinal side effects combination Decreased post-prandial glucose excursions without increased risk of hypoglycemia Reduced gastrointestinal side effects vs. GLP-1 RA alone Reduced weight gain vs. basal insulin GLP-1 RA glucagon-like peptide-1 receptor agonist, RAI rapid-acting insulin same amount in patients with a HbA1c level need for multiple daily injections and may also of\ 8% [64 mmol/mol]) [2]. The dose should be reduce the incidence of hypoglycemia com- titrated by 1–2 U or 10–15% every 2–3 days until pared with going straight to basal–bolus therapy targets are met (e.g., 2-h PPG or next pre-meal [20]. glucose is consistently[ 140 mg/dL) [3]. If tar- RAI can also be introduced by moving gets are not achieved, additional RAI should be straight to a basal-bolus regimen; in this case, added at one and then two other mealtimes guidelines recommend an initial dose of 50% (basal-bolus) as required, with titration as for basal/50% prandial daily, split over three doses the initial RAI [2, 3, 18]. This technique has the given before meals, with titration as for basal- benefit of a relatively simple, gradual, and plus [3]. There is a risk of hypoglycemia during structured titration, which may improve confi- titration of basal-plus and basal-bolus regimens, dence with and acceptance of an increasing and patients should be made fully aware of this 882 Diabetes Ther (2018) 9:877–890 risk and any reported symptoms correlated with endogenous glucose levels. Basal insulin acts in blood-glucose logs. If hypoglycemia does occur, a non-glucose-dependent manner predomi- the total daily basal and/or prandial insulin nantly on FPG levels, with a lesser effect on dose should be reduced by 10–20% if the blood PPG. Treatment with insulin is generally asso- glucose level was\ 70 mg/dL, or by 20–40% if ciated with an increase in body weight and a the patient experiences severe hypoglycemia risk of hypoglycemia [2, 25]. GLP-1 RAs act on (i.e., needed assistance from another person, or both FPG and PPG levels, to varying degrees, by blood glucose level is\ 40 mg/dL) [3]. For some enhancing glucose-dependent insulin secretion patients, multiple daily injections are inconve- by beta-cells and decreasing glucagon secretion nient and may be difficult to manage. The use by alpha-cells [26]. In addition, they have been of complex treatment regimens has been shown shown to inhibit gastric acid secretion, slow to be associated with intentional and accidental gastric emptying, and, by interactions with the nonadherence with medications in patients central nervous system, increase satiety, result- with T2D [21, 22]. Premixed (or biphasic) insu- ing in reduced food intake and therefore lins (NPH/regular 70/30; 70/30 aspart mix; reduced glucose input [26, 27]. There are two 75/25 or 50/50 lispro mix) provide less dosing general types of GLP-1 RAs, namely, short- and flexibility but do offer the advantage of a sim- long-acting [26, 28]. Short-acting GLP-1 RAs plified dosing regimen compared with basal- (e.g., exenatide, lixisenatide) have a more pro- bolus [3], which may make them particularly found effect on PPG than long-acting agents suitable for selected patients, such as those who (e.g., liraglutide, albiglutide) and are associated struggle to manage multiple daily injections with a slower, more sustained effect on gastric [23]. Overall, however, premixed insulins are emptying. Long-acting agents have a greater less effective than basal-bolus regimens in effect on FPG than on PPG and a lesser effect on achieving the target HbA1c [23], and their use gastric emptying which seems to be subjected to has been associated with a higher rate of tachyphylaxis [2, 28]. Treatment with GLP-1 hypoglycemia and with greater weight gain RAs is generally associated with weight loss due [3, 24]. The initial premix dose should be based to appetite suppression. This may make them on the current basal insulin dose, divided either particularly suitable for patients who are already into two-thirds AM and one-third PM, or one- overweight or those who fear weight gain with half AM and one-half PM, with once- or twice- additional insulin therapy. weekly titration [1–2 U or 10–15%) to target. Exenatide and liraglutide have been associ- The dose should be reduced by 2–4 U or 10–20% ated with slight increases in heart rate (\ 2 if hypoglycemia occurs [2]. Patients taking pre- beats/min) [29]. The mechanism behind these mixed insulins need to adhere to a regular meal increases in heart rate, but it is interesting to and exercise schedule to reduce the risk of note that the effect appears to be more evident hypoglycemia [23]. for long-acting GLP-1 RAs (liraglutide, exe- natide long-acting release) than for short-acting ones (exenatide twice daily) [30], and with ADDING GLP-1 RAS liraglutide compared with lixisenatide [31]. Overall, GLP-1 RAs as a class have demonstrated Combining drugs with complementary mecha- positive cardiovascular outcomes, with meta- nisms of action to target multiple aspects of analyses of clinical trial data showing no sig- disease pathophysiology has the potential to nificant differences or demonstrating improve- improve efficacy. Both insulin and GLP-1 RAs ments in the rates of major cardiovascular are in themselves effective glucose-lowering events between GLP-1 RAs and placebo or therapies, but they achieve this by different, comparator drugs [32, 33]. Since 2008, the U.S. and complimentary, mechanisms of action. The Food and Drug Administration (FDA) has aim of basal insulin therapy is to provide con- required that all antidiabetes medications sistent insulin levels to mimic the constant demonstrate cardiovascular safety [34]. To date, physiological release of insulin that regulates the results of four cardiovascular outcome trials Diabetes Ther (2018) 9:877–890 883 of GLP-1 RAs have been reported, all of which Furthermore, a recent FDA and European have demonstrated at least noninferiority of Medicines Agency assessment of evidence from treatment with GLP-1RAs compared with stan- clinical trials and observational studies con- dard care [35, 36], even though a direct com- cluded that ‘assertions concerning a causal parison between studies is difficult due to association between incretin-based drugs (i.e., different patient populations, length of trials, GLP-1 RAs and dipeptidyl peptidase 4 inhibi- dropout rates, and HbA1c lowering. The ELIXA tors) and pancreatitis or pancreatic cancer, as study of lixisenatide showed that in patients expressed recently in the scientific literature with T2D who have had a recent acute coronary and in the media, are inconsistent with the event (within 180 days), lixisenatide was non- current data’ [43]. The rates of pancreatitis and inferior to placebo regarding primary endpoint pancreatic cancer have been generally low in events, with no significant differences in rate of large long-term CVOT trials. For example, in the hospitalization for heart failure or rate of death ELIXA study in 6068 patients with T2D, pan- between the groups [37]. Even though there was creatitis occurred in five lixisenatide- and eight a very large dropout rate, similar findings were placebo-treated patients, and three lixisenatide- reported in the EXSCEL trial in patients with or and nine placebo-treated patients were diag- without previous cardiovascular disease, with nosed with pancreatic cancer [37]. In the SUS- no difference in major cardiovascular events TAIN-6 trial including 3297 patients, acute with extended-release exenatide compared with pancreatitis occurred in nine patients in the placebo [36]. In the LEADER trial of liraglutide semaglutide group and in 12 in the placebo in patients with T2D and high cardiovascular group; pancreatic cancer occurred in one and risk, primary outcome, death from cardiovas- four patients, respectively [38]. Similarly, fewer cular causes, and death from any cause, occur- patients treated with liraglutide in the LEADER red in significantly fewer liraglutide-treated trial experienced acute pancreatitis compared patients than in those on placebo, with no sig- with placebo (18 vs. 23 patients, respectively), nificant differences in rates of nonfatal although the incidence of pancreatic cancer was myocardial infarction, nonfatal stroke, and greater in the liraglutide group (13 vs. 5 hospitalization for heart failure between groups patients, respectively) [40]. In addition, a recent [38]. The SUSTAIN-6 trial, which also included large, multinational cohort study found that patients at high cardiovascular risk, reported the use of incretin-based drugs was not associ- significant reductions in major cardiovascular ated with an increased risk of pancreatic cancer events with semaglutide, largely driven by a compared with sulfonylureas [44]. Nevertheless, reduced incidence of nonfatal stroke [36], even guidelines recommend that GLP-1 RAs should though the trail was not pre-specified as a be used with caution in patients with a history superiority trial. of pancreatitis and discontinued if acute pan- The most commonly reported side effects of creatitis develops [3]. GLP-1 RA therapy are gastrointestinal ones The effectiveness of GLP-1 RAs combined (nausea, vomiting, and diarrhea). These are with basal insulins to treat T2D has been generally mild to moderate and typically demonstrated in a large number of clinical trials improve over time, resulting in discontinuation and in real-world studies [8]. In patients whose of therapy in \ 5% of patients in clinical trials; T2D is inadequately controlled on basal insulin, slow dose-titration helps to reduce these effects the addition of the GLP-1 RAs to the treatment [28]. Concerns have been expressed regarding regimen has consistently shown improvements the possible association between treatment with in HbA1c and PPG excursions, with reductions GLP-1 RA and acute pancreatitis and/or pan- in body weight, but without an increase in creatic cancer, based on a series of case reports hypoglycemic risk compared with placebo [39, 40]; however, no studies have confirmed [45–47] and RAIs (basal-plus and basal-bolus) that GLP-1 RAs cause pancreatitis [41], and no [6, 8, 48]. GLP-1 RAs are administered via sub- evidence of an increased risk was found in a cutaneous injection, with dosing varying large systematic review and meta-analysis [42]. depending on the agent (e.g., exenatide: twice 884 Diabetes Ther (2018) 9:877–890 Table 2 Randomized trials of fixed-ratio insulin/glucagon-like peptide-1 receptor agonist combinations Randomized Study HbA1c Patients Change in Hypoglycemia GI adverse trials population change achieving target body weight events of Patients Events/ from HbA1c (< 7.0% from nausea/ affected patient- baseline (56 mmol/mol) baseline vomiting (%) (%) year (%) (%) (kg) iGlarLixi studies LixiLan-O Insulin-naive; iGlarLixi: iGlarLixi: 74 iGlarLixi: iGlarLixi: iGlarLixi: iGlarLixi: 9.6/ [53] metformin - 1.6 - 0.3 25.6 1.4 3.2 Gla-100: 59 ± 2nd OAD Gla-100: Gla-100: Gla-100: Gla-100: Gla-100: 3.6/ Lixi: 33 - 1.3 ? 1.1 23.6 1.2 1.5 Lixi: Lixi: - 2.3 Lixi: 6.4 Lixi: 0.3 Lixi: 24.0/6.4 - 0.9 LixiLan-L Basal insulin ± iGlarLixi: iGlarLixi: 55 iGlarLixi: iGlarLixi: iGlarLixi: iGlarLixi:10.4/ [54] B 2OADs - 1.1 - 0.7 40.0 3.0 3.6 Gla-100: 30 Gla-100: Gla-100: Gla-100: Gla-100: Gla-100: 0.5/ - 0.6 ? 0.7 42.5 4.2 0.5 IDegLira studies DUAL-I Insulin-naive; IDegLira: IDegLira: 81 IDegLira: IDegLira: IDegLira: IDegLira: 9.0/ [50] - 1.9 - 0.5 32.0 1.8 4.0 Metformin ± IDeg: 65 pioglitazone IDeg: IDeg: ? 1.6 IDeg: IDeg: 2.6 IDeg: 4.0/1 Lira: 60 - 1.4 39.0 Lira: - 3.0 Lira: 0.2 Lira: 20.0/8 Lira: Lira: 7.0 - 1.3 DUAL-II Basal insulin IDegLira: IDegLira: 60 IDegLira: IDegLira: IDegLira: IDegLira: 6.5/ [52] ? - 1.9 - 2.7 24.0 1.5 nr IDeg: 23 metformin IDeg: IDeg: 0.0 IDeg: IDeg: 2.6 IDeg: 3.5/nr ± other - 0.9 25.0 OAD DUAL-III Previous GLP- IDegLira: IDegLira: 75 IDegLira: IDegLira: IDegLira: IDegLira: 3.1/ [55] 1RA ? - 1.3 ? 2.0 32.0 2.8 nr GLP-1 :36 b b b b b metformin GLP-1 : GLP-1 : GLP-1 : GLP-1 : GLP-1 : 4.1/ ± other - 0.3 - 0.8 2.8 0.1 nr OAD DUAL-IV Insulin-naive; IDegLira: IDegLira: 79 IDegLira: IDegLira: IDegLira: IDegLira: 4.5/ [56] sulphoylurea - 1.45 ? 0.5 41.7 3.5 2.4 Placebo: 29 Placebo: Placebo: Placebo: Placebo: Placebo: 3.4/ metformin - 0.46 - 1.0 17.1 1.4 2.7 Diabetes Ther (2018) 9:877–890 885 Table 2 continued Randomized Study HbA1c Patients Change in Hypoglycemia GI adverse trials population change achieving target body weight events of Patients Events/ from HbA1c (< 7.0% from nausea/ affected patient- baseline (56 mmol/mol) baseline vomiting (%) (%) year (%) (%) (kg) DUAL-V Gla-100 ? IDegLira: IDegLira: 72 IDegLira: IDegLira: IDegLira: IDegLira: 9.4/ [51] metformin - 1.8 - 1.4 28.4 2.2 nr Gla-100: 47 Gla-100: Gla-100: Gla-100: Gla-100: Gla-100: 1.1/ - 1.1 ? 1.8 49.1 5.1 nr GI Gastrointestinal, Gla-100 insulin glargine 100 U, HbA1c glycated hemoglobin A1c, IDeg insulin degludec, Lira liraglutide, Lixi lixisenatide, nr not reported, OAD oral antidiabetes drug DUAL studies: confirmed or severe hypoglycemia (\ 56 mg/dL); LixiLan studies: documented symptomatic hypo- glycemia (B 70 mg/dL) Unchanged from previous therapy daily before meals; liraglutide: once daily [in- Recently, two new titratable fixed-ratio combi- dependent of meals]; lixisenatide: once daily nation (FRC) formulations of a basal insulin and [within 1 h before any meal of the day]; exe- a GLP-1 RA have been approved by the FDA for natide extended-release, albiglutide, and the treatment of adults with T2D. iGlarLixi is a dulaglutide: once weekly) [49]. FRC of insulin glargine 100 Units/ml (iGlar) and A benefit of GLP-1 RAs in terms of the the short-acting GLP-1 RA lixisenatide (Lixi). patient’s perspective is that these are not insulin IDegLira is an FRC of insulin degludec (IDeg) in preparations, and therefore the patient may not combination with the long-acting GLP-1 RA have the negative perceptions of weight gain liraglutide (Lira). In clinical trials, both FRCs and hypoglycemia. The positive effects of GLP-1 have been shown to result in greater reductions RAs on both of these parameters may be seen as in HbA1c compared with either basal insulins or a particular benefit by some patients. The side- GLP-1 RAs given alone, with the benefit of effect profile, particularly the risk of gastroin- mitigation of weight loss without a higher risk testinal effects, may be a concern for some of hypoglycemia compared with basal insulin patients, but these can be ameliorated by slow, alone [50–57] (Table 2). In insulin-experienced controlled dose escalation. More regular blood- patients, iGlarLixi resulted in greater reductions glucose monitoring during titration can also in HbA1c from baseline compared with insulin help further reduce the likelihood of hypo- glargine (-1.1% vs. -0.6%, p \ 0.0001), with a glycemia and can be reassuring for patients with greater proportion of patients achieving HbA1c a particular fear of this complication. \ 7.0% (53 mmol/mol) (55% vs. 30%, respec- tively) [54]. Mean body weight decreased by 0.7 kg with iGlarLixi and increased by 0.7 kg with BASAL INSULIN/GLP-1 RA FIXED- iGlar. Rates of documented symptomatic RATIO COMBINATIONS hypoglycemia (PG B 70 mg/dL) were similar between groups (40.0% in the iGlarLixi group Adding a GLP-1 RA to basal insulin as a separate and 42.5% in the iGlar group) [54]. treatment adds to the injection burden and Similar results were achieved using IDegLira. regimen complexity for patients (although to a Insulin-experienced patients treated with IDe- lesser degree than basal-bolus regimens), as well gLira showed greater reductions in HbA1c as potentially introducing GI adverse events. compared with insulin degludec alone (-1.9 vs. 886 Diabetes Ther (2018) 9:877–890 -0.9%, respectively; p\ 0.0001) [50] or insulin Units, the starting dose should be 15 Units; glargine alone (-1.8 vs. -1.1, respectively; p \ where the insulin dose is 30–60 Units, starting 0.001) [56]. Treatment with IDegLira was also dose should be 30 Units. iGlarLixi should be associated with weight loss compared with titrated to individualized FPG goals, with dose weight gain/no change with basal insulin alone adjustments of 2–4 Units every week as required (-2.7 kg vs. no change with insulin degludec; based on the patient’s metabolic needs, blood -1.4 kg vs. ?1.8 kg with insulin glargine). Rates glucose monitoring results, and glycemic con- of confirmed hypoglycemia with IDegLira were trol goal. The maximum dose of iGlarLixi is 60 similar to insulin degludec alone (36–51%, and Units/20 lg; for those patients requiring [ 60 lower than with insulin glargine alone Units alternative separate antidiabetes products (45–57%) [54]. Interestingly, the use of a FRC such as iGlar and lixisenatide should be used. appears to mitigate the side effects of its indi- For IDegLira, the pre-filled pen shows dose vidual components, with a reduction in gas- steps, equivalent to units of insulin; each dose trointestinal side effects compared with the step consists of 1 Unit of insulin degludec and GLP-1 RA component alone due to slow titra- 0.036 mg liraglutide. The pre-filled pen can tion [50, 53, 54, 58]. For example, in the Lix- provide from 1 up to 50 dose steps in one iLan-O trial, 9.6% of patients treated with injection, in increments of one dose step. IDe- iGlarLixi experienced nausea, the most com- gLira can be administered, once daily, at any monly reported gastrointestinal event, com- time but at the same time each day, and does pared with 24.0% of patients treated with Lixi not need to be used with a meal. Patients who alone [53]. Similarly, in the DUAL-1 trial, nau- are switching to IDegLira from a basal insulin sea was experienced by 9% of patients treated analog should stop using their current insulin, with IDegLira compared with 20% of those and all patients should initiate treatment with treated with Lira alone [50]. 16 Units (16 Units of insulin degludec and 0.58 Titration of basal insulin/GLP-1 RA FRCs is mg of liraglutide) regardless of whether they based on the insulin component, and follows a were previously receiving basal insulin. Dose similar titration schedule for that used for adjustments should be made based on target titrating insulin. It is important to note that FPG, with the dose being titrated upwards or these are fixed-ratio, not fixed-dose combina- downwards by 2 Units every 3–4 days. The tions; iGlarLixi is approved in a 100 Units maximum dose of IDegLira is 50 dose steps (50 iGlar:33 lg lixisenatide ratio combination and Units insulin degludec and 1.8 mg liraglutide); IDegLira a 100 Units IDeg:3.6 mg liraglutide patients requiring [ 60 Units would need to ratio combination. Both components are titra- administer separate injections of IDeg and ted based on the patient’s insulin needs, with liraglutide. IDegLira currently carries a black- the GLP-1 RA component rising in ratio with box warning for risk of thyroid c-cell tumors the insulin dose, at an amount depending on related to liraglutide, and is contraindicated in the formulation. patients with a personal or family history of iGlarLixi is supplied premixed in a modified medullary thyroid carcinoma and in patients SoloStar pen [59], which contains a fixed ratio with multiple endocrine neoplasia syndrome of 100 Units of iGlar to 33 lg of lixisenatide type 2. (doses range from 15 Units/5 lg to 60 Units/20 lg of iGlar/lixisenatide); only the insulin dose is shown in the pen window. iGlarLixi is admin- ACKNOWLEDGEMENTS istered subcutaneously once daily within 1 hour before the first meal of the day. Patients who are switching to iGlarLixi from a basal insulin Funding. This study was funded by Sanofi analog should stop their current insulin, and US, Inc. including funding of the journal’s their iGlarLixi dose should be calculated from article processing charge. their current insulin dose. For those switching from basal insulin where the insulin dose is\ 30 Diabetes Ther (2018) 9:877–890 887 approaches to glycemic treatment. Diabetes Care. Medical Writing Assistance. The author 2017;40[Suppl 1]:S64–74. received writing and editorial support in the preparation of this manuscript provided by 3. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Con- Rasilaben Vaghjiani, PhD, of Excerpta Medica, sensus statement by the American Association of Clinical Endocrinologists and American College of funded by Sanofi US, Inc. Endocrinology on the comprehensive type 2 dia- betes management algorithm—2017 executive Authorship. The named author meets the summary. Endocr Pract. 2017. https://doi.org/10. International Committee of Medical Journal 4158/ep161682.cs. Editors (ICMJE) criteria for authorship for this 4. Gill GV, Yudkin JS, Keen H, Beran D. The insulin article, takes responsibility for the integrity of dilemma in resource-limited countries. A way for- the work as a whole, and has given his approval ward? Diabetologia. 2011;54:19–24. for this version to be published. The author had full access to all of the data in this study and 5. Diamant M, Nauck MA, Shaginian R, 4B Study Group, et al. Glucagon-like peptide 1 receptor ago- takes complete responsibility for the integrity of nist or bolus insulin with optimized basal insulin in the data and accuracy of the data analysis. type 2 diabetes. Diabetes Care. 2014;37:2763–73. Disclosures. Jerry Meece is a consultant for 6. Mathieu C, Rodbard HW, Cariou B, et al. A com- Astra Zeneca, Eli Lilly, Johnson and Johnson, parison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in sub- Novo Nordisk, and Sanofi. jects with type 2 diabetes (BEGIN: VICTOZA ADD- ON). Diabetes Obes Metab. 2014;16:636–44. Compliance with Ethics Guidelines. This article is based on previously conducted studies 7. Eng C, Kramer CK, Zinman B, Retnakaran R. Glu- cagon-like peptide-1 receptor agonist and basal and does not contain studies with human par- insulin combination treatment for the manage- ticipants or animals performed by the author. ment of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014;384:2228–34. Data Availability. Data sharing is not applicable in this article as no datasets were 8. Rosenstock J, Guerci B, Hanefeld M, et al. Prandial options to advance basal insulin glargine therapy: generated or analyzed during the current study. testing lixisenatide plus basal insulin versus insulin glulisine either as basal-plus or basal-bolus in type 2 Open Access. This article is distributed diabetes: the GetGoal Duo-2 trial. Diabetes Care. under the terms of the Creative Commons 2016;39:1318–28. Attribution-NonCommercial 4.0 International 9. Balena R, Hensley IE, Miller S, Barnett AH. Combi- License (http://creativecommons.org/ nation therapy with GLP-1 receptor agonists and licenses/by-nc/4.0/), which permits any non- basal insulin: a systematic review of the literature. commercial use, distribution, and reproduction Diabetes Obes Metab. 2013;15:485–502. in any medium, provided you give appropriate 10. LaSalle JR, Berria R. Insulin therapy in type 2 dia- credit to the original author(s) and the source, betes mellitus: a practical approach for primary care provide a link to the Creative Commons license, physicians and other health care professionals. and indicate if changes were made. J Am Osteopath Assoc. 2013;113:152–62. 11. Shaefer C, Traylor L, Gao L, Dex T, Sepe P, Skolnik N. Exploratory study of a dose-response curve for basal insulin. Presented at 75th Scientific Sessions REFERENCES of the American Diabetes Association. Boston MA. June 5–9, 2015. 1. International Diabetes Federation. IDF diabetes 12. Reid T, Gao L, Gill J, et al. How much is too much? atlas. Eighth edition 2017. http://www. Outcomes in patients using high-dose insulin glar- diabetesatlas.org/resources/2017-atlas.html. Acces- gine. Int J Clin Pract. 2016;70:56–65. sed 3 Jan 2018. 13. Nathan DM, Buse JB, Davidson MB, et al. Medical 2. American Diabetes Association. 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Basal Insulin Intensification in Patients with Type 2 Diabetes: A Review

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Diabetes Ther (2018) 9:877–890 https://doi.org/10.1007/s13300-018-0395-3 REVIEW Basal Insulin Intensification in Patients with Type 2 Diabetes: A Review Jerry Meece Received: December 6, 2017 / Published online: March 24, 2018 The Author(s) 2018 can be administered via subcutaneous injection ABSTRACT once or twice daily, or weekly depending on formulation. More recently, two fixed-ratio As the number of people living with type 2 combinations of basal insulin and a GLP-1 RA diabetes (T2D) continues to rise, managing their that allow for once-daily dosing have been complex needs presents an increasing challenge approved. Each of these approaches has poten- to physicians. While treatment guidelines pro- tial benefits and drawbacks, particularly in vide evidence-based guidance, they are not terms of risk for hypoglycemia, weight change, prescriptive—rather they emphasize individu- convenience, and side effects. Understanding alization of management based on a patient’s these differences is central to guiding patient clinical needs and preferences. Physicians, and physician choice. This article discusses the therefore, need to be fully aware of the advan- rationale, advantages, disadvantages, and tages and disadvantages of the multiple and implementation of currently available strategies increasing treatment options available to them for basal insulin treatment intensification in at each stage of the disease. The progressive patients with T2D. nature of T2D means that treatment with basal Funding: Sanofi US, Inc. insulin will become inevitable for many patients, while for some patients basal insulin alone will eventually be insufficient for main- Keywords: Basal insulin; Diabetes type 2; taining glycemic targets. Recent guidelines rec- Fixed-ratio combinations; Glucagon-like ommend two basic approaches for intensifying peptide-1 receptor agonist; Treatment basal insulin: the use of rapid-acting insulin, intensification either as additional prandial injections or as part of premix (biphasic) insulin; and the addi- tion of glucagon-like peptide-1 receptor ago- INTRODUCTION nists (GLP-1 RAs) to the insulin therapy, which The number of people living with type 2 dia- Enhanced content To view enhanced content for this betes (T2D) is ever-growing. In 2017, it has been article go to https://doi.org/10.6084/m9.figshare. estimated that almost 425 million adults worldwide had diabetes, and this is projected to J. Meece (&) increase to 628 million by 2045 [1]. This Clinical Services, Plaza Pharmacy and Wellness alarming figure is a result of the aging popula- Center, Gainesville, TX, USA tion, which is more likely to develop T2D, e-mail: jmeece12@cooke.net 878 Diabetes Ther (2018) 9:877–890 together with population-wide lifestyle chan- Managing patients who do not achieve gly- ges, and also reflects the fact that T2D is being cemic goals despite uptitration of basal insulin diagnosed earlier and, with advances in man- provides a particular challenge, with a number agement strategies, patients are living longer of available options. Until recently, the recom- [1]. Managing the complex needs of patients mended strategy for intensifying insulin ther- with long-standing T2D is therefore an apy was the addition of rapid-acting insulins increasingly common clinical challenge for (RAIs) to the treatment regimen, either as primary healthcare practitioners. Current treat- additional prandial injection or as part of a ment guidelines provide evidence-based guid- premixed insulin formula. However, over recent ance for T2D management, but they are not years combining a GLP-1 RA with basal insulin prescriptive and emphasize the importance of has been shown to provide equal or slightly individualization of T2D management based on superior efficacy to the addition of prandial a patient’s clinical needs and preferences [2, 3]. insulin, with a beneficial effect on weight and If physicians are to achieve this, they need to be less hypoglycemia, as well as reduced regimen fully aware of the advantages and disadvantages complexity [5–9]. Based on this finding, the of the multiple treatment options and strategies most recent 2018 recommendations from the available to them at each stage of the disease. American Diabetes Association state that com- T2D is a progressive disease, and although pared with basal-plus insulin, ‘‘basal insulin plus some patients may manage it with oral medica- GLP-1 RAs are associated with less hypo- tions, most will eventually need to use insulin to glycemia and with weight loss instead of weight achieve glycemic control. Insulin treatment is gain but may be less tolerable and have a greater usually initiated when patients are no longer cost’’ [2]. meeting glycemic targets on combination ther- Treatment guidelines, therefore, give two apy using oral drugs, or present with a glycated potential approaches for intensifying insulin hemoglobin A (HbA1c) level of[ 9.0% with therapy: the addition of a RAI, either as an 1c symptomatic hyperglycemia [3]. Guidelines additional prandial injection or as part of a continue to be revised however, and basal insulin premixed insulin formula; or the addition of a therapy is now often used much sooner and fre- GLP-1 RA (Fig. 1). In review I discuss the ratio- quently in combination with oral agents or glu- nale and implementation of these two approa- cagon-like peptide-1 receptor agonists (GLP-1 ches and consider their advantages and RAs), rather than postponing insulin therapy disadvantages. until lifestyle modifications and oral agent This review article is based on previously treatment has failed [2, 3]. Guidelines for initial conducted studies and does not contain studies insulin therapy are straightforward. The first step with human participants or animals performed for most patients is the addition of a long-acting by any of the authors. basal insulin to oral therapy to control fasting plasma glucose (FPG) levels. In general, insulin THE PROBLEM OF OVER- analogs are favored over neutral protamine Hagedorn (NPH) insulin, largely because of their BASALIZATION better hypoglycemic profile due to their flat pharmacokinetic curve [2, 3]; however, NPH Uptitrating basal insulin is no longer having an HbA1c-lowering effect, while higher insulin insulin is associated with markedly lower costs and remains widely used in some settings, such as doses mean greater risk of weight gain and hypoglycemia. Treatment guidelines do not in resource-limited countries [4]. Many patients will successfully achieve and maintain glycemic give a definite upper limit for basal insulin dose, and there may be the temptation to continue goals on these regimens, but the disease of other patients may progress to the point at which basal with a familiar routine by increasing the basal insulin alone is insufficient, and these latter insulin dose despite the patient still not achieving glycemic targets—a situation known patients will require additional therapeutic sup- port to control postprandial glucose (PPG) levels. as ‘over-basalization’ [10]. The aim of basal Diabetes Ther (2018) 9:877–890 879 Fig. 1 Combination injectable therapy for type 2 diabetes. blood glucose. (Adapted with permission from American A1C Glycated hemoglobin (HbA1c), FBG fasting blood Diabetes Association 2017 guidelines. Reproduced with glucose, GLP-1 RA glucagon-like peptide-1 receptor permission from Inzucchi et al. [57]) agonist, hypo hypoglycemia, SMBG self-monitoring of insulin treatment to provide a steady level of assumes that beta-cell function is still sufficient insulin throughout the day, mimicking normal to help cover increased prandial insulin needs physiological production and controlling FPG in terms of insulin synthesis and secretion [10]. levels; its effects on PPG are limited. In T2D the Data from a recent study suggest that basal initial use of basal insulin alone therefore insulin has a ‘ceiling effect,’ whereby reductions 880 Diabetes Ther (2018) 9:877–890 in FPG become proportionally smaller with reductions in insulin dose, and/or carbohydrate increasing dose from 0.3 up to about 0.5 U/kg supplementation [16]. body weight (BW)/day, at which point FPG Efforts to improve lifestyle, however, should response does not increase despite increasing not delay changes in therapy; such changes can insulin levels [11]. Another study suggests that be done simultaneously and adjusted based on increasing basal insulin above 0.5 Units/kg patient response to lifestyle efforts [3]. Thera- BW/day may not improve glycemic control and peutically, there are two main guideline-rec- may also result in weight gain and increased risk ommended options for escalating basal insulin of hypoglycemia [12]. It is therefore important therapy [2, 3]. The first is to add a prandial to keep in mind (1) the risk of over-basalization insulin to the treatment regimen, either by and (2) guideline recommendations that basal adding a RAI prior to the largest meal of the day, insulin therapy should be escalated to combi- with addition at other meals in stages if nation injectables when the basal insulin dose required (basal-plus), adding RAI at all meals exceeds 0.5 Units/kg BW/day. (basal-bolus), or by switching to a premixed (biphasic) insulin formulation of intermediate- and short-acting insulins. In general, RAIs are BEYOND BASAL INSULIN preferred over regular human insulin because of their more rapid onset and offset of action and When treatment is intensified beyond basal association with a lower incidence of hypo- insulin therapy, a number of factors should be glycemia [2, 3], although regular insulin may taken into account as part of the shared decision- represent a pragmatic choice where costs or lack making process, such as patient preference, of resources limit availability [17]. The second safety, tolerability, glycemic efficacy, risk of option is to add a GLP-1 RA to the treatment hypoglycemia, and other non-glycemic effects regimen. Each treatment regimen has advan- (e.g., weight change and/or impact on life-style) tages and disadvantages (Table 1), and these [13]. Continued basal insulin therapy should, should be taken into account when deciding on however, be considered an essential component a strategy with the patient. of future treatment strategies [2]. Initial discus- sions should also include issues around lifestyle (nutrition, weight loss, and physical activity) and ADDING PRANDIAL INSULIN the possible treatment of obesity, such as using the American Association of Clinical Endocri- The aim of injecting RAIs just before a meal is to nologists Obesity Treatment Algorithm, which support basal-insulin action on FPG by con- may include obesity pharmacotherapy [14]. The trolling PPG excursions. In effect, adding pran- effectiveness of lifestyle changes such as weight dial RAIs to the treatment regimen mimics the loss and exercise in decreasing the incidence and physiological meal-simulated insulin release, progression of T2D is well known. Although which is lost first as beta-cell function declines. generally considered an initial strategy, it is RAI analogs (lispro, aspart, or glulisine) are important that lifestyle optimization is ongoing preferred over regular human insulin because throughout the course of T2D [3]. In a cohort they have a more rapid onset and shorter study, almost half of overweight or obese duration of action, making them better suited patients with T2D who lost a mean of 4% of body for controlling PPG, and are associated with less weight were able to reduce their insulin dose; a hypoglycemia [18, 19]. The simplest and gen- mean reduction of 11% of initial body weight was erally most effective way of adding prandial to required to discontinue insulin [15]. Although basal insulin is to cover the largest (or most exercise has undoubted benefits for patients with carbohydrate-heavy) meal of the day with an T2D, those using insulin or insulin secretagogues injection of RAI, often termed basal-plus [7, 13]. should be made aware of the amplified risk of The initial mealtime dose of RAI should be 4 U, hypoglycemia during and after exercise and 0.1 U/kg BW, or 10% of the basal dose (possibly should be advised on blood-glucose monitoring, with a reduction in basal insulin dose by the Diabetes Ther (2018) 9:877–890 881 Table 1 Advantages and disadvantages of prandial insulin and glucagon-like peptide-1 receptor agonist regimens for insulin intensification Guideline- Advantages Disadvantages recommended options Prandial insulin Basal-plus Dosing/titration flexibility greater than basal- Risk of hypoglycemia bolus or premixed Weight gain Gradual introduction to multiple daily Progresses to multiple daily injections injections Basal-bolus Dosing/titration flexibility greater than Multiple daily injections immediately premixed Risk of hypoglycemia Weight gain Premixed Simplified regimen vs. basal-plus of basal-bolus Less flexibility than basal plus or basal bolus Less effective glycemic control vs. basal-plus of basal- bolus Greater risk of hypoglycemia and weight gain GLP-1 RAs Added to basal Weight neutral/weight loss Once/twice daily or once weekly (depending on GLP-1 insulin RA) injection in addition to basal insulin Lower incidence of hypoglycemia vs. addition of RAI Gastrointestinal side effects Fixed-ratio Simple, once-daily regimen Gastrointestinal side effects combination Decreased post-prandial glucose excursions without increased risk of hypoglycemia Reduced gastrointestinal side effects vs. GLP-1 RA alone Reduced weight gain vs. basal insulin GLP-1 RA glucagon-like peptide-1 receptor agonist, RAI rapid-acting insulin same amount in patients with a HbA1c level need for multiple daily injections and may also of\ 8% [64 mmol/mol]) [2]. The dose should be reduce the incidence of hypoglycemia com- titrated by 1–2 U or 10–15% every 2–3 days until pared with going straight to basal–bolus therapy targets are met (e.g., 2-h PPG or next pre-meal [20]. glucose is consistently[ 140 mg/dL) [3]. If tar- RAI can also be introduced by moving gets are not achieved, additional RAI should be straight to a basal-bolus regimen; in this case, added at one and then two other mealtimes guidelines recommend an initial dose of 50% (basal-bolus) as required, with titration as for basal/50% prandial daily, split over three doses the initial RAI [2, 3, 18]. This technique has the given before meals, with titration as for basal- benefit of a relatively simple, gradual, and plus [3]. There is a risk of hypoglycemia during structured titration, which may improve confi- titration of basal-plus and basal-bolus regimens, dence with and acceptance of an increasing and patients should be made fully aware of this 882 Diabetes Ther (2018) 9:877–890 risk and any reported symptoms correlated with endogenous glucose levels. Basal insulin acts in blood-glucose logs. If hypoglycemia does occur, a non-glucose-dependent manner predomi- the total daily basal and/or prandial insulin nantly on FPG levels, with a lesser effect on dose should be reduced by 10–20% if the blood PPG. Treatment with insulin is generally asso- glucose level was\ 70 mg/dL, or by 20–40% if ciated with an increase in body weight and a the patient experiences severe hypoglycemia risk of hypoglycemia [2, 25]. GLP-1 RAs act on (i.e., needed assistance from another person, or both FPG and PPG levels, to varying degrees, by blood glucose level is\ 40 mg/dL) [3]. For some enhancing glucose-dependent insulin secretion patients, multiple daily injections are inconve- by beta-cells and decreasing glucagon secretion nient and may be difficult to manage. The use by alpha-cells [26]. In addition, they have been of complex treatment regimens has been shown shown to inhibit gastric acid secretion, slow to be associated with intentional and accidental gastric emptying, and, by interactions with the nonadherence with medications in patients central nervous system, increase satiety, result- with T2D [21, 22]. Premixed (or biphasic) insu- ing in reduced food intake and therefore lins (NPH/regular 70/30; 70/30 aspart mix; reduced glucose input [26, 27]. There are two 75/25 or 50/50 lispro mix) provide less dosing general types of GLP-1 RAs, namely, short- and flexibility but do offer the advantage of a sim- long-acting [26, 28]. Short-acting GLP-1 RAs plified dosing regimen compared with basal- (e.g., exenatide, lixisenatide) have a more pro- bolus [3], which may make them particularly found effect on PPG than long-acting agents suitable for selected patients, such as those who (e.g., liraglutide, albiglutide) and are associated struggle to manage multiple daily injections with a slower, more sustained effect on gastric [23]. Overall, however, premixed insulins are emptying. Long-acting agents have a greater less effective than basal-bolus regimens in effect on FPG than on PPG and a lesser effect on achieving the target HbA1c [23], and their use gastric emptying which seems to be subjected to has been associated with a higher rate of tachyphylaxis [2, 28]. Treatment with GLP-1 hypoglycemia and with greater weight gain RAs is generally associated with weight loss due [3, 24]. The initial premix dose should be based to appetite suppression. This may make them on the current basal insulin dose, divided either particularly suitable for patients who are already into two-thirds AM and one-third PM, or one- overweight or those who fear weight gain with half AM and one-half PM, with once- or twice- additional insulin therapy. weekly titration [1–2 U or 10–15%) to target. Exenatide and liraglutide have been associ- The dose should be reduced by 2–4 U or 10–20% ated with slight increases in heart rate (\ 2 if hypoglycemia occurs [2]. Patients taking pre- beats/min) [29]. The mechanism behind these mixed insulins need to adhere to a regular meal increases in heart rate, but it is interesting to and exercise schedule to reduce the risk of note that the effect appears to be more evident hypoglycemia [23]. for long-acting GLP-1 RAs (liraglutide, exe- natide long-acting release) than for short-acting ones (exenatide twice daily) [30], and with ADDING GLP-1 RAS liraglutide compared with lixisenatide [31]. Overall, GLP-1 RAs as a class have demonstrated Combining drugs with complementary mecha- positive cardiovascular outcomes, with meta- nisms of action to target multiple aspects of analyses of clinical trial data showing no sig- disease pathophysiology has the potential to nificant differences or demonstrating improve- improve efficacy. Both insulin and GLP-1 RAs ments in the rates of major cardiovascular are in themselves effective glucose-lowering events between GLP-1 RAs and placebo or therapies, but they achieve this by different, comparator drugs [32, 33]. Since 2008, the U.S. and complimentary, mechanisms of action. The Food and Drug Administration (FDA) has aim of basal insulin therapy is to provide con- required that all antidiabetes medications sistent insulin levels to mimic the constant demonstrate cardiovascular safety [34]. To date, physiological release of insulin that regulates the results of four cardiovascular outcome trials Diabetes Ther (2018) 9:877–890 883 of GLP-1 RAs have been reported, all of which Furthermore, a recent FDA and European have demonstrated at least noninferiority of Medicines Agency assessment of evidence from treatment with GLP-1RAs compared with stan- clinical trials and observational studies con- dard care [35, 36], even though a direct com- cluded that ‘assertions concerning a causal parison between studies is difficult due to association between incretin-based drugs (i.e., different patient populations, length of trials, GLP-1 RAs and dipeptidyl peptidase 4 inhibi- dropout rates, and HbA1c lowering. The ELIXA tors) and pancreatitis or pancreatic cancer, as study of lixisenatide showed that in patients expressed recently in the scientific literature with T2D who have had a recent acute coronary and in the media, are inconsistent with the event (within 180 days), lixisenatide was non- current data’ [43]. The rates of pancreatitis and inferior to placebo regarding primary endpoint pancreatic cancer have been generally low in events, with no significant differences in rate of large long-term CVOT trials. For example, in the hospitalization for heart failure or rate of death ELIXA study in 6068 patients with T2D, pan- between the groups [37]. Even though there was creatitis occurred in five lixisenatide- and eight a very large dropout rate, similar findings were placebo-treated patients, and three lixisenatide- reported in the EXSCEL trial in patients with or and nine placebo-treated patients were diag- without previous cardiovascular disease, with nosed with pancreatic cancer [37]. In the SUS- no difference in major cardiovascular events TAIN-6 trial including 3297 patients, acute with extended-release exenatide compared with pancreatitis occurred in nine patients in the placebo [36]. In the LEADER trial of liraglutide semaglutide group and in 12 in the placebo in patients with T2D and high cardiovascular group; pancreatic cancer occurred in one and risk, primary outcome, death from cardiovas- four patients, respectively [38]. Similarly, fewer cular causes, and death from any cause, occur- patients treated with liraglutide in the LEADER red in significantly fewer liraglutide-treated trial experienced acute pancreatitis compared patients than in those on placebo, with no sig- with placebo (18 vs. 23 patients, respectively), nificant differences in rates of nonfatal although the incidence of pancreatic cancer was myocardial infarction, nonfatal stroke, and greater in the liraglutide group (13 vs. 5 hospitalization for heart failure between groups patients, respectively) [40]. In addition, a recent [38]. The SUSTAIN-6 trial, which also included large, multinational cohort study found that patients at high cardiovascular risk, reported the use of incretin-based drugs was not associ- significant reductions in major cardiovascular ated with an increased risk of pancreatic cancer events with semaglutide, largely driven by a compared with sulfonylureas [44]. Nevertheless, reduced incidence of nonfatal stroke [36], even guidelines recommend that GLP-1 RAs should though the trail was not pre-specified as a be used with caution in patients with a history superiority trial. of pancreatitis and discontinued if acute pan- The most commonly reported side effects of creatitis develops [3]. GLP-1 RA therapy are gastrointestinal ones The effectiveness of GLP-1 RAs combined (nausea, vomiting, and diarrhea). These are with basal insulins to treat T2D has been generally mild to moderate and typically demonstrated in a large number of clinical trials improve over time, resulting in discontinuation and in real-world studies [8]. In patients whose of therapy in \ 5% of patients in clinical trials; T2D is inadequately controlled on basal insulin, slow dose-titration helps to reduce these effects the addition of the GLP-1 RAs to the treatment [28]. Concerns have been expressed regarding regimen has consistently shown improvements the possible association between treatment with in HbA1c and PPG excursions, with reductions GLP-1 RA and acute pancreatitis and/or pan- in body weight, but without an increase in creatic cancer, based on a series of case reports hypoglycemic risk compared with placebo [39, 40]; however, no studies have confirmed [45–47] and RAIs (basal-plus and basal-bolus) that GLP-1 RAs cause pancreatitis [41], and no [6, 8, 48]. GLP-1 RAs are administered via sub- evidence of an increased risk was found in a cutaneous injection, with dosing varying large systematic review and meta-analysis [42]. depending on the agent (e.g., exenatide: twice 884 Diabetes Ther (2018) 9:877–890 Table 2 Randomized trials of fixed-ratio insulin/glucagon-like peptide-1 receptor agonist combinations Randomized Study HbA1c Patients Change in Hypoglycemia GI adverse trials population change achieving target body weight events of Patients Events/ from HbA1c (< 7.0% from nausea/ affected patient- baseline (56 mmol/mol) baseline vomiting (%) (%) year (%) (%) (kg) iGlarLixi studies LixiLan-O Insulin-naive; iGlarLixi: iGlarLixi: 74 iGlarLixi: iGlarLixi: iGlarLixi: iGlarLixi: 9.6/ [53] metformin - 1.6 - 0.3 25.6 1.4 3.2 Gla-100: 59 ± 2nd OAD Gla-100: Gla-100: Gla-100: Gla-100: Gla-100: 3.6/ Lixi: 33 - 1.3 ? 1.1 23.6 1.2 1.5 Lixi: Lixi: - 2.3 Lixi: 6.4 Lixi: 0.3 Lixi: 24.0/6.4 - 0.9 LixiLan-L Basal insulin ± iGlarLixi: iGlarLixi: 55 iGlarLixi: iGlarLixi: iGlarLixi: iGlarLixi:10.4/ [54] B 2OADs - 1.1 - 0.7 40.0 3.0 3.6 Gla-100: 30 Gla-100: Gla-100: Gla-100: Gla-100: Gla-100: 0.5/ - 0.6 ? 0.7 42.5 4.2 0.5 IDegLira studies DUAL-I Insulin-naive; IDegLira: IDegLira: 81 IDegLira: IDegLira: IDegLira: IDegLira: 9.0/ [50] - 1.9 - 0.5 32.0 1.8 4.0 Metformin ± IDeg: 65 pioglitazone IDeg: IDeg: ? 1.6 IDeg: IDeg: 2.6 IDeg: 4.0/1 Lira: 60 - 1.4 39.0 Lira: - 3.0 Lira: 0.2 Lira: 20.0/8 Lira: Lira: 7.0 - 1.3 DUAL-II Basal insulin IDegLira: IDegLira: 60 IDegLira: IDegLira: IDegLira: IDegLira: 6.5/ [52] ? - 1.9 - 2.7 24.0 1.5 nr IDeg: 23 metformin IDeg: IDeg: 0.0 IDeg: IDeg: 2.6 IDeg: 3.5/nr ± other - 0.9 25.0 OAD DUAL-III Previous GLP- IDegLira: IDegLira: 75 IDegLira: IDegLira: IDegLira: IDegLira: 3.1/ [55] 1RA ? - 1.3 ? 2.0 32.0 2.8 nr GLP-1 :36 b b b b b metformin GLP-1 : GLP-1 : GLP-1 : GLP-1 : GLP-1 : 4.1/ ± other - 0.3 - 0.8 2.8 0.1 nr OAD DUAL-IV Insulin-naive; IDegLira: IDegLira: 79 IDegLira: IDegLira: IDegLira: IDegLira: 4.5/ [56] sulphoylurea - 1.45 ? 0.5 41.7 3.5 2.4 Placebo: 29 Placebo: Placebo: Placebo: Placebo: Placebo: 3.4/ metformin - 0.46 - 1.0 17.1 1.4 2.7 Diabetes Ther (2018) 9:877–890 885 Table 2 continued Randomized Study HbA1c Patients Change in Hypoglycemia GI adverse trials population change achieving target body weight events of Patients Events/ from HbA1c (< 7.0% from nausea/ affected patient- baseline (56 mmol/mol) baseline vomiting (%) (%) year (%) (%) (kg) DUAL-V Gla-100 ? IDegLira: IDegLira: 72 IDegLira: IDegLira: IDegLira: IDegLira: 9.4/ [51] metformin - 1.8 - 1.4 28.4 2.2 nr Gla-100: 47 Gla-100: Gla-100: Gla-100: Gla-100: Gla-100: 1.1/ - 1.1 ? 1.8 49.1 5.1 nr GI Gastrointestinal, Gla-100 insulin glargine 100 U, HbA1c glycated hemoglobin A1c, IDeg insulin degludec, Lira liraglutide, Lixi lixisenatide, nr not reported, OAD oral antidiabetes drug DUAL studies: confirmed or severe hypoglycemia (\ 56 mg/dL); LixiLan studies: documented symptomatic hypo- glycemia (B 70 mg/dL) Unchanged from previous therapy daily before meals; liraglutide: once daily [in- Recently, two new titratable fixed-ratio combi- dependent of meals]; lixisenatide: once daily nation (FRC) formulations of a basal insulin and [within 1 h before any meal of the day]; exe- a GLP-1 RA have been approved by the FDA for natide extended-release, albiglutide, and the treatment of adults with T2D. iGlarLixi is a dulaglutide: once weekly) [49]. FRC of insulin glargine 100 Units/ml (iGlar) and A benefit of GLP-1 RAs in terms of the the short-acting GLP-1 RA lixisenatide (Lixi). patient’s perspective is that these are not insulin IDegLira is an FRC of insulin degludec (IDeg) in preparations, and therefore the patient may not combination with the long-acting GLP-1 RA have the negative perceptions of weight gain liraglutide (Lira). In clinical trials, both FRCs and hypoglycemia. The positive effects of GLP-1 have been shown to result in greater reductions RAs on both of these parameters may be seen as in HbA1c compared with either basal insulins or a particular benefit by some patients. The side- GLP-1 RAs given alone, with the benefit of effect profile, particularly the risk of gastroin- mitigation of weight loss without a higher risk testinal effects, may be a concern for some of hypoglycemia compared with basal insulin patients, but these can be ameliorated by slow, alone [50–57] (Table 2). In insulin-experienced controlled dose escalation. More regular blood- patients, iGlarLixi resulted in greater reductions glucose monitoring during titration can also in HbA1c from baseline compared with insulin help further reduce the likelihood of hypo- glargine (-1.1% vs. -0.6%, p \ 0.0001), with a glycemia and can be reassuring for patients with greater proportion of patients achieving HbA1c a particular fear of this complication. \ 7.0% (53 mmol/mol) (55% vs. 30%, respec- tively) [54]. Mean body weight decreased by 0.7 kg with iGlarLixi and increased by 0.7 kg with BASAL INSULIN/GLP-1 RA FIXED- iGlar. Rates of documented symptomatic RATIO COMBINATIONS hypoglycemia (PG B 70 mg/dL) were similar between groups (40.0% in the iGlarLixi group Adding a GLP-1 RA to basal insulin as a separate and 42.5% in the iGlar group) [54]. treatment adds to the injection burden and Similar results were achieved using IDegLira. regimen complexity for patients (although to a Insulin-experienced patients treated with IDe- lesser degree than basal-bolus regimens), as well gLira showed greater reductions in HbA1c as potentially introducing GI adverse events. compared with insulin degludec alone (-1.9 vs. 886 Diabetes Ther (2018) 9:877–890 -0.9%, respectively; p\ 0.0001) [50] or insulin Units, the starting dose should be 15 Units; glargine alone (-1.8 vs. -1.1, respectively; p \ where the insulin dose is 30–60 Units, starting 0.001) [56]. Treatment with IDegLira was also dose should be 30 Units. iGlarLixi should be associated with weight loss compared with titrated to individualized FPG goals, with dose weight gain/no change with basal insulin alone adjustments of 2–4 Units every week as required (-2.7 kg vs. no change with insulin degludec; based on the patient’s metabolic needs, blood -1.4 kg vs. ?1.8 kg with insulin glargine). Rates glucose monitoring results, and glycemic con- of confirmed hypoglycemia with IDegLira were trol goal. The maximum dose of iGlarLixi is 60 similar to insulin degludec alone (36–51%, and Units/20 lg; for those patients requiring [ 60 lower than with insulin glargine alone Units alternative separate antidiabetes products (45–57%) [54]. Interestingly, the use of a FRC such as iGlar and lixisenatide should be used. appears to mitigate the side effects of its indi- For IDegLira, the pre-filled pen shows dose vidual components, with a reduction in gas- steps, equivalent to units of insulin; each dose trointestinal side effects compared with the step consists of 1 Unit of insulin degludec and GLP-1 RA component alone due to slow titra- 0.036 mg liraglutide. The pre-filled pen can tion [50, 53, 54, 58]. For example, in the Lix- provide from 1 up to 50 dose steps in one iLan-O trial, 9.6% of patients treated with injection, in increments of one dose step. IDe- iGlarLixi experienced nausea, the most com- gLira can be administered, once daily, at any monly reported gastrointestinal event, com- time but at the same time each day, and does pared with 24.0% of patients treated with Lixi not need to be used with a meal. Patients who alone [53]. Similarly, in the DUAL-1 trial, nau- are switching to IDegLira from a basal insulin sea was experienced by 9% of patients treated analog should stop using their current insulin, with IDegLira compared with 20% of those and all patients should initiate treatment with treated with Lira alone [50]. 16 Units (16 Units of insulin degludec and 0.58 Titration of basal insulin/GLP-1 RA FRCs is mg of liraglutide) regardless of whether they based on the insulin component, and follows a were previously receiving basal insulin. Dose similar titration schedule for that used for adjustments should be made based on target titrating insulin. It is important to note that FPG, with the dose being titrated upwards or these are fixed-ratio, not fixed-dose combina- downwards by 2 Units every 3–4 days. The tions; iGlarLixi is approved in a 100 Units maximum dose of IDegLira is 50 dose steps (50 iGlar:33 lg lixisenatide ratio combination and Units insulin degludec and 1.8 mg liraglutide); IDegLira a 100 Units IDeg:3.6 mg liraglutide patients requiring [ 60 Units would need to ratio combination. Both components are titra- administer separate injections of IDeg and ted based on the patient’s insulin needs, with liraglutide. IDegLira currently carries a black- the GLP-1 RA component rising in ratio with box warning for risk of thyroid c-cell tumors the insulin dose, at an amount depending on related to liraglutide, and is contraindicated in the formulation. patients with a personal or family history of iGlarLixi is supplied premixed in a modified medullary thyroid carcinoma and in patients SoloStar pen [59], which contains a fixed ratio with multiple endocrine neoplasia syndrome of 100 Units of iGlar to 33 lg of lixisenatide type 2. (doses range from 15 Units/5 lg to 60 Units/20 lg of iGlar/lixisenatide); only the insulin dose is shown in the pen window. iGlarLixi is admin- ACKNOWLEDGEMENTS istered subcutaneously once daily within 1 hour before the first meal of the day. Patients who are switching to iGlarLixi from a basal insulin Funding. This study was funded by Sanofi analog should stop their current insulin, and US, Inc. including funding of the journal’s their iGlarLixi dose should be calculated from article processing charge. their current insulin dose. For those switching from basal insulin where the insulin dose is\ 30 Diabetes Ther (2018) 9:877–890 887 approaches to glycemic treatment. Diabetes Care. Medical Writing Assistance. The author 2017;40[Suppl 1]:S64–74. received writing and editorial support in the preparation of this manuscript provided by 3. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Con- Rasilaben Vaghjiani, PhD, of Excerpta Medica, sensus statement by the American Association of Clinical Endocrinologists and American College of funded by Sanofi US, Inc. Endocrinology on the comprehensive type 2 dia- betes management algorithm—2017 executive Authorship. The named author meets the summary. Endocr Pract. 2017. https://doi.org/10. International Committee of Medical Journal 4158/ep161682.cs. Editors (ICMJE) criteria for authorship for this 4. Gill GV, Yudkin JS, Keen H, Beran D. The insulin article, takes responsibility for the integrity of dilemma in resource-limited countries. A way for- the work as a whole, and has given his approval ward? Diabetologia. 2011;54:19–24. for this version to be published. The author had full access to all of the data in this study and 5. Diamant M, Nauck MA, Shaginian R, 4B Study Group, et al. Glucagon-like peptide 1 receptor ago- takes complete responsibility for the integrity of nist or bolus insulin with optimized basal insulin in the data and accuracy of the data analysis. type 2 diabetes. Diabetes Care. 2014;37:2763–73. Disclosures. Jerry Meece is a consultant for 6. Mathieu C, Rodbard HW, Cariou B, et al. A com- Astra Zeneca, Eli Lilly, Johnson and Johnson, parison of adding liraglutide versus a single daily dose of insulin aspart to insulin degludec in sub- Novo Nordisk, and Sanofi. jects with type 2 diabetes (BEGIN: VICTOZA ADD- ON). Diabetes Obes Metab. 2014;16:636–44. Compliance with Ethics Guidelines. This article is based on previously conducted studies 7. Eng C, Kramer CK, Zinman B, Retnakaran R. Glu- cagon-like peptide-1 receptor agonist and basal and does not contain studies with human par- insulin combination treatment for the manage- ticipants or animals performed by the author. ment of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014;384:2228–34. Data Availability. Data sharing is not applicable in this article as no datasets were 8. Rosenstock J, Guerci B, Hanefeld M, et al. Prandial options to advance basal insulin glargine therapy: generated or analyzed during the current study. testing lixisenatide plus basal insulin versus insulin glulisine either as basal-plus or basal-bolus in type 2 Open Access. This article is distributed diabetes: the GetGoal Duo-2 trial. Diabetes Care. under the terms of the Creative Commons 2016;39:1318–28. Attribution-NonCommercial 4.0 International 9. Balena R, Hensley IE, Miller S, Barnett AH. Combi- License (http://creativecommons.org/ nation therapy with GLP-1 receptor agonists and licenses/by-nc/4.0/), which permits any non- basal insulin: a systematic review of the literature. commercial use, distribution, and reproduction Diabetes Obes Metab. 2013;15:485–502. in any medium, provided you give appropriate 10. LaSalle JR, Berria R. 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One-year efficacy and safety of a fixed combination of insulin

Journal

Diabetes TherapySpringer Journals

Published: Mar 24, 2018

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