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GLP-1 RAs as compared to prandial insulin after failure of basal insulin in type 2 diabetes: lessons from the 4B and Get-Goal DUO 2 trials
Diabetes Metab. 2015 Dec;41(6 Suppl 1):6S16-20.
The add-on of a prandial (short-acting) GLP-1 RA to basal insulin in subjects with T2DM who fail to control A1C on basal insulin, stems from the physiological principles of post-prandial glucose homeostasis, and it is based on evidence from clinical trials. The 4B and GetGoal DUO 2 studies are the first to establish in head-to-head comparison, the efficacy and safety of short-acting GLP-1 RAs vs prandial insulin, when added-on to basal insulin glargine. In the 4B study (exenatide 2/d vs lispro 3/d) exenatide demonstrated similar efficacy vs lispro in reducing A1C to ~7.2%. However, exenatide reduced also body weight and hypoglycemia incidence as compared to lispro. In GetGoal DUO 2, the head-to-head comparison was between lixisenatide 1/d vs glulisine either 1/d (at the main meal, basal-plus) or 3/d (basal-bolus). Like in 4B, in GetGoal DUO 2 the A1C decreased to similar values with lixisenatide or glulisine 1/d (~7.2%), or glulisine 3/d (~7.0%). Again, as in the 4B, body weight and hypoglycemia incidence were lower with lixisenatide. In both studies a similar percentage of subjects reached the A1C <7.0% on GLP-1 RA or prandial insulin. A higher percentage of subjects reported adverse events on GLP-1 RAs, primarily gastrointestinal related. The studies 4B and GetGoal DUO 2 suggest that after failure of basal insulin in T2DM, the add-on of prandial GLP-1 RA is as effective as prandial insulin in lowering A1C, with added benefits of reducing body weight and risk for hypoglycemia. In addition, the GLP-1 RA + basal insulin is a simpler therapeutic option as compared to basal-plus and basal-bolus regimens.
Keywords: GLP-1 receptor agonists, exenatide, lixisenatide, basal insulin.
The modern idea of adding-on of GLP-1 RAs in subjects with type 2 diabetes (T2DM) who fail to control blood glucose on basal insulin (± oral agents)  stems from the lessons of physiology of post-prandial blood glucose regulation in normal, non-diabetic subjects.
In physiology, the post-prandial plasma glucose is highly controlled by multiple, integrated mechanisms which cooperate to limit excursions of plasma glucose above 120-130 mg/dL . Teleologically, this suggests the importance in nature of preventing even small increase of glucose after meals to avoid the cascade of metabolic, endothelial and vascular, deleterious consequences . In response to a mixed meal, a rapid rise in insulin (initially portal, later systemic as well), combined with an intra-islet paracrine suppression of glucagon, and systemic suppression of free fatty acids by insulin, cooperate to suppress endogenous glucose production and stimulate peripheral glucose utilization. Both these two mechanisms limit the increase of glucose in plasma. In addition, the meal directly stimulates the acute release of incretin hormones, the two primary being GIP and GLP-1. Indeed GLP-1 stimulates directly insulin secretion in a glucose-dependent manner, suppresses glucagon, either indirectly (via pancreatic islet hyperinsulinemia) and directly , and decelerates gastric emptying . The latter mechanism reduces the rate of entry of ingested glucose into the circulation, and contributes by at least 50% to the overall incretin effect to reduce post-prandial .
Post-prandial hyperglycemia is an early abnormality in the natural history of type 2 diabetes, as a consequence of impaired insulin secretion and relative hyperglucagonemia. However, although it is controversial whether plasma incretin concentrations are reduced in T2DM , the overall incretin effect is lower than normal . The recent availability of short-acting GLP-1 RAs, such as exenatide and lixisenatide, used either alone or in combination with oral agents, has made it possible to reduce post-prandial hyperglycemia in T2DM. Hence, the successfully tested hypothesis of adding GLP-1 RAs to reduce post-prandial hyperglycemia also in combination with basal insulin in those T2DM subjects who fail to control blood glucose on basal insulin only (± oral agents) [9, 10, and 11]. With such a combination, A1C decreases, body weight is reduced, and there is no increase in hypoglycemia. These observations have opened the door to a new paradigm treatment, i.e. add-on of prandial GLP-1 RAs in place of prandial insulin after failure of basal insulin to control hyperglycemia and A1C .
The initial randomized controlled studies of add-on of GLP-1 RAs to basal insulin have been conducted vs placebo [9, 10, and 11]. More recently, two studies have compared efficacy and safety of exenatide  and lixisenatide  vs prandial insulin, when either of these two GLP-1 RAs is added to basal insulin. These clinically meaningful comparisons have provided a number of relevant informations for the clinical decision as to when, if, and how to add-on prandial insulin or GLP-1 RA to basal insulin in T2DM failing to basal insulin only. In this short review, the 4B and GetGoal DUO 2 studies will be summarized and commented, and its practical messages highlighted.
2. The 4B Study
In the 4B study (Basal insulin glargine + exenatide BID vs Basal insulin glargine + Bolus insulin lispro) , the efficacy and safety of treatment of post-prandial hyperglycemia with either exenatide twice daily, or insulin lispro at each meal, in T2DM subjects inadequately controlled on titrated insulin glargine and metformin, were compared. This well performed study in a quite large number of subjects (n = 1036 screened, n = 917 enrolled) has several implications for clinical practice. First, the 4B study has examined the common subjects attending the diabetes clinic, i.e. age ~60 years, relatively long (known) diabetes duration (mean 12 years), and poor glycemic control despite treatment with basal insulin glargine and glucose lowering oral agents. Metformin was continued, and sulphonylurea, if any, withdrawn, and titration of insulin glargine optimized for 12 weeks (BIO-phase) before randomization to either exenatide (2/d) or lispro added at each meal (3/d) to glargine. Unfortunately, optimization of basal insulin was insufficient in 4B, since in the three month BIO phase period, the fasting plasma glucose and A1C decreased only from ~150 to ~130 mg/dL, and from 8.5±1% to 8.2±1%, respectively. At the end of this period, there were only 92 “responders” (A1C ≤7.0%) in whom A1C decreased from 7.9±0.7 to 6.7±0.4%, whereas 652 subjects were “failures” (A1C>7.0%) with A1C declining only from 8.6±0.8 to 8.4±0.9%. Interestingly, as compared to failures, the responders to optimization of basal insulin, tended to be younger, to have shorter diabetes duration, lower baseline A1C and fasting plasma glucose, and to use a smaller insulin glargine dose despite similar body weight. The failures were then randomized to add-on with fixed dose (10-20 μg/die based on tolerability), of exenatide twice daily (n = 315) or titrated prandial lispro (n = 312) while continuing insulin glargine (ongoing titration). The difference in A1C change from randomization to end point at 30 weeks between exenatide or lispro added to glargine (the primary outcome of the study) was -0.04 (95% CI: -0.18, 0.11), demonstrating non-inferiority for both margins of 0.4 and 0.3%. At end point of 30 weeks, A1C dropped from 8.3±1.0 to 7.2±1.0% with exenatide, and from 8.2±0.9 to 7.2±1.0% with insulin lispro. Proportions of subjects with A1C ≤7.0% were similar (~50% in both groups). Fasting plasma glucose decreased with exenatide (~11 mg/dL), but not with lispro. Post-prandial PG decreased at all daily meals with both treatments, but to a greater extent with insulin lispro at lunch. As expected, average weight decreased with exenatide (~-2.5 kg) while it increased with lispro (~2.1 kg). Insulin glargine dose was reduced more in the lispro group (~-10 U) vs exenatide (~-5 U). Incidence of hypoglycemia was greater with lispro for minor episodes (41 vs 30% for exenatide) and for confirmed non-nocturnal episodes (34 vs 15% for exenatide). As expected gastrointestinal-related adverse events, including nausea, vomiting, and diarrhea, were more common with exenatide as compared to lispro (47 vs 13%, respectively).
The 4B study adds important knowledges on how to progress the treatment of subjects with diabetes who do not meet the target despite basal insulin + metformin.
First of all, as is often the case, in the 4B study  we can learn from the results of the period of basal insulin optimization, the BIO phase period. In the total study population, after 3 months of titration of basal insulin, A1C decreased only to ~8.2%, suggesting not adequate titration of basal insulin. Previous studies indicate that when basal insulin is titrated optimally at the target in T2DM subjects, A1C decreases more as compared to what has been obtained in the 4B study [14 and 15].
As compared to prandial lispro 3 times/d, exenatide (2 times/d), similarly reduced A1C by end of studies by ~1.0% (from 8.2 to ~7.2% with both treatments). Interestingly, this occurred in a similar percentage of subjects (“responders” ~50% in both groups). As said, in 4B the comparison between exenatide and lispro occurred in the presence of suboptimal titration of basal insulin, thus generating the hypothesis that a more aggressive titration of basal insulin would result into even better (lower) A1C by end of the study. Add-on of exenatide to basal insulin was associated with additional benefits vs lispro, such as loss of body weight and lower incidence of non-nocturnal hypoglycemia. As expected, more gastrointestinal related adverse events were seen with exenatide, but apparently this did not translate into treatment discontinuation which did not differ beteween the two arms.
With the limitation of insufficient titration of basal insulin, the 4B study has proven non-inferiority of the prandial GLP-1 RA exenatide vs prandial insulin, thus substantiating the hypothesis that prandial insulin is no longer the exclusive option after failure of basal insulin.
3. The GetGoal DUO 2 study
The GetGoal DUO 2 study results have not been published yet, and therefore the comments are based on the presentation of the trial at the June 2015 ADA meeting in Boston . GetGoal DUO 2 follows the studies GetGoal-L  and GetGoal DUO 1 , which have both explored the efficacy and safety of once-a-day add-on of lixisenatide to basal insulin at fixed dose , or to insulin glargine with continuing titration  as compared to placebo. The originality of GetGoal DUO 2 is the comparison between add-on of lixisenatide and active treatment (prandial insulin).
Similarly to the 4B, the GetGoal DUO 2 study is a large head-to-head study comparing add-on of lixisenatide vs prandial insulin glulisine (either 1/d, i.e. “basal-plus”, or 3/d, i.e. “basal-bolus”) to optimized regimen of basal insulin glargine ± metformin. The enrolled population shares similar characteristics to that of 4B (~12 years diabetes duration, BMI ~32 kg/m2, uncontrolled A1C on basal insulin ± 1-3 oral agents). The oral agents except metfomin, were discontinued, and basal insulin optimized for 12 weeks. During the run-in period of GetGoal DUO 2, glargine insulin was more successfully titrated to target of fasting euglycemia (fasting PG decreased from 167±52 to 120±33 mg/dL) than in 4B, and therefore A1C decreased more (from 8.5±0.7 to 7.80.6%). Then, 894 subjects were randomized to add-on of lixisenatide (n = 298), or glulisine 1/d (n = 298) (both lixisenatide or glulisine given at main meal, either breakfast or dinner), or glulisine 3/d (n = 298) to basal insulin (with continued titration) for 26 weeks. Three co-primary end-points were assessed at the end of study: i) non-inferiority of A1C with lixisenatide vs glulisine once/d upper bound of the two-sided 95% confidence interval (CI) for treatment difference <0.4%]; ii) non-inferiority of lixisenatide vs glulisine 3/d; iii) superiority of lixisenatide vs glulisine in reducing body weight. At 26 weeks, all co-primary endpoints were met. Reductions in A1C from baseline to week 26 were non-inferior with lixisenatide vs glulisine 1/d and 3/d [least squares (LS) mean (95% CI) treatment difference for lixisenatide vs glulisine 1/d -0.05 [-0.170, 0.064%]; vs glulisine 3/d 0.21 [0.095, 0.328%]; lixisenatide was statistically superior (p < 0.0001) vs gulisine 3/d for body weight change at week 26, LS mean [95% CI] treatment difference, -1.99 [-2.593, -1.396 kg]. The decrease in A1C the 3 groups was from 7.8±0.6 to 7.2±0.8%, 7.7±0.6 to 7.2±0.8%, and 7.8±0.6 to 7.0±0.7% (lixisenatide, glulisine 1/d and 3/d, respectively). The percentage of patients who reached end-of-study A1C <7.0% was 42%, 38% and 49% (lixisenatide, glulisine 1/d and 3/d, respectively, treatment difference for lixisenatide vs glulisine was not statistically different). With lixisenatide there was a LS mean change of body weight of -0.6 kg, in contrast to increase in body weight with glulisine 1/d (increase of 1.0 kg), and 3/d (increase 1.4 kg). Post-prandial PG was similarly lower with lixisenatide vs glulisine 1/d in the overall group of 298 subjects. However, data of post-prandial plasma glucose in the 30% of subjects who had lixisenatide or glulisine at breakfast, separated from those of the 70% of subjects who had the treatment at dinner, are needed to examine the reduction of post-prandial hyperglycemia at the three meals as specific result of the treatment. So far, the plasma glucose data with lixisenatide or glulisine 1/d have been presented pooling all subjects toghether. With glulisine 3/d, as expected, post-prandial plasma glucose decreased at all meals. Although severe hypoglycemia was no different in the 3 groups, incidence of symptomatic hypoglycemia (plasma glucose <60 mg/dL) was numerically higher on glulisine vs lixisenatide, and statistically significantly higher on glulisine 3/d vs lixisenatide. As expected, more gastro-intestinal adverse events were seen on lixisenatide (~35%) as compared to glulisine 1/d (~7%) or 3/d (~9%), which lead to treatment discontinuation in 5% of patients (lixisenatide) as compared to 0.7-1.0% on glulisine.
GetGoal DUO 2 demonstrates that add-on of the GLP-1 RA lixisenatide to optimized basal insulin, controls A1C as well as glulisine 1/d given at the main meal (basal-plus), and improves A1C nearly at the values observed with glulisine 3/d (basal-bolus). Notably, additive benefits with lixisenatide as compared to glulisine for similar A1C, are the reduced body weight and less hypoglycemia. However, when add-on of lixisenatide is compared to glulisine 3/d, the A1C reduction is slightly but significantly lower than that of basal-bolus, suggesting superiority of basal-bolus regimen.
Taken together, the results of GetGoal DUO 2 suggest that in obese population with several years of diabetes duration, insufficiently controlled with basal insulin, add-on of lixisenatide may be a valid alternative as compared to once a day prandial insulin injection or full intensification of insulin regimen (basal-bolus). GetGoal DUO 2 adds new data to the existing evidence of efficacy and safety of add-on of GLP-1 RA as alternative to prandial insulin, to basal insulin.
No doubt after 4B and GetGoal DUO 2, the option of adding-on a prandial GLP-1 RA to basal insulin is no longer a theoretical choice based on patho-physiology, but a realistic possibility based on the evidence of the two studies.
In both studies 4B and GetGoal DUO 2, add-on of a prandial GLP-1 RA to basal insulin, not only improved glycemic control similarly to prandial insulin, but also reduced body weight without increasing the risk for hypoglycemia, as prandial insulin did instead. In addition to these benefits, the treatment regimen of GLP-1 RA (+ basal insulin) has the advantage of lower complexity as compared to the regimen of prandial insulin (+ basal insulin) in which need of titrating prandial insulin might be demanding.
Of course there are differences between the 4B and GetGoal DUO 2 studies. The GLP-1 RA administered is different (exenatide 2/d in the former, lixisenatide 1/d in the latter), although they both are “short-acting” GLP-1RAs targeting primarily post-prandial hyperglycaemia . In 4B the comparator prandial insulin is lispro 3/d, in GetGoal DUO 2 is glulisine either 1/d or 3/d. Interestingly, the absolute values of A1C reached at the end of these two different studies, are remarkably similar and close to ~7.0% both in the 4B and GetGoal DUO 2.
In the 4B study, exenatide 2/d is as effective as basal-bolus insulin. Similarly in the GetGoal DUO 2, lixisenatide 1/d is non-inferior to basal-plus, an increasingly popular insulin regimen after failure of basal insulin [16 and 17]. In addition, lixisenatide 1/d closely mimics also the basal-bolus regimen in reducing A1C, although with basal-bolus the decrease in A1C at the end of the study is slightly greater (~7.0% vs ~7.2%, basal-bolus vs lixisenatide, respectively).
The new information deriving from 4B and GetGoal DUO 2 studies has implications for clinical practice.
After failure of basal insulin, we should consider the option of adding GLP-1 RA in place of prandial insulin. We should identify the best patient profile for the treatment with GLP-1 RA in place of prandial insulin. Unfortunately, so far the studies have not identified the clinical characteristics of responders to GLP-1 RAs, and we definitely need more data to better understand who will be a responder, and how long the response will be maintained over time in individual subjects. Of course, this is not a question with prandial insulin since everybody is responder to prandial insulin depending on dose. Obese subjects are considered candidates to GLP-1 RAs. Likely, short diabetes duration is a condition with higher chances of response to GLP-1 RA, but more data are needed in this regard. Although the response to GLP-1 RAs seems to be independent from baseline rate of gastric emptying , rapid gastric emptying might be an indication. Unfortunately so far we miss a simple and feasible method for measuring gastric emptying.
A minority of subjects do not tolerate GLP-1 RAs because of gastro-intestinal side effects. In these subjects prandial insulin is needed to improve post-prandial hyperglycemia.
Additional questions should be discussed. The 4B and GetGoal DUO 2 studies have examined subjects on basal insulin who were naïve to prandial insulin. Could T2DM persons already treated with basal-bolus insulin, be switched to basal insulin + GLP-1 RAs, thus reducing treatment complexity? Also, is it possible to combine a prandial GLP-1 RA with prandial insulin to mimic the sophisticated physiological mechanisms of post-prandial glucose homeostasis? Another unanswered question is “which” GLP-1 RA should we combine with basal insulin. Should we prefer a prandial short acting GLP-1 RA, like in the 4B and GetGoal DUO 2 studies? Or rather a basal, long-acting GLP-1 RA such as liraglutide once a day [19 and 20], or exenatide  or albiglutide  once a week? And if the long-acting GLP-1 RAs, which improve primarily fasting hyperglycemia, are chosen, should we then still add it to basal insulin which acts on fasting hyperglycemia as well, or rather withdraw basal insulin and treat prandial hyperglycemia with rapid-acting insulin ? This question should be answered by head-to-head studies comparing directly short-acting vs long-acting GLP-1 RAs both combined with basal insulin. So far we have only indirect comparisons from different studies which are suggestive, not evidences.
The attractive combination of GLP-1 RAs and basal insulin is now a legitimated, real treatment option in T2DM after failure of basal insulin. However, it is an expensive treatment, and reimbursement issues limit its use in the majority of countries, allthough we should keep in mind the lower incidence of hypoglycemia and the less stringent need of blood glucose control, as both of these aspects may impact costs as well. Like for other expensive treatments in diabetes, it is important that the advantageous combination GLP-1 RAs + basal insulin is given to selected subjects expected and proven to be responders, and timely discontinued in the failures.
The authors thank Prof. Julio Rosenstock for his warm contribution to discussion.
Disclosure of interests
F. Porcellati has received honoraria for advising and lecturing, and travel grants from BD, Eli Lilly, Sanofi and Menarini.
G. B. Bolli has received honoraria for advising and lecturing from Sanofi, Eli Lilly and Menarini.
P.L. received travel grants for scientific meetings from Sanofi and Menarini. C.G.F. has served on scientific advisory panels for Sanofi and received honoraria for speaker fees and/or travel grants from Bristol-Myers Squibb, Merck & Co., and Menarini.
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Section of Internal Medicine, Endocrinology and Metabolism, Department of Medicine, Perugia University School of Medicine, Italy
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