The incretin effect, incretin hormones and the safety, efficacy, and tolerability of incretin-based agents have been previously described.[10, 11] GLP-1RAs and DPP-4 inhibitors have different clinical profiles and, consequently, different patient-related outcomes.[10-12] Administration of GLP-1RAs results in pharmacological concentrations of these agents, stimulating GLP-1 receptor activity. Administration of DPP-4 inhibitors results in increased physiological levels of native GLP-1 and GIP by preventing the inactivation of these hormones by DPP-4 enzymes.[10-12] GLP-1RAs are associated with more potent glycaemic and extraglycaemic effects than DPP-4 inhibitors.[13-16]
Good glycaemic control is also associated with reduced risk of microvascular complications, such as retinopathy, neuropathy and nephropathy,[17, 18] and may contribute to cardiovascular risk and total mortality. Good glycaemic control, which is achievable with proper patient education, can lead to a high quality of life.
Treatment effects among head-to-head studies
Table 1[13, 14, 16, 20-31] lists treatment effects of GLP-1RAs and DPP-4 inhibitors in head-to-head studies of patients with T2D. Compared with exenatide, liraglutide significantly improves A1c and patient satisfaction.[20, 32] Greater A1c reduction and weight loss were achieved with liraglutide compared with exenatide-ER; however, gastrointestinal symptoms were less with exenatide-ER. Exenatide-ER demonstrated superior A1c reduction and less nausea but more injection site reactions than exenatide.[22-24, 33] Both agents led to similar reductions in weight and blood pressure.[23, 24] Liraglutide provided a greater and more sustained reduction of A1c and weight (up to 52 weeks), with minimal risk of hypoglycaemia and greater treatment satisfaction than sitagliptin.[26, 27, 34] Exenatide greatly reduces postprandial glucose (PPG) and glucagon secretion and increases insulin secretion compared with sitagliptin.[13, 14] Exenatide-ER provides better and more sustained glucose control and weight loss, with minimal hypoglycaemia and better treatment satisfaction than sitagliptin.[16, 30, 31] Saxagliptin + metformin was non-inferior to sitagliptin + metformin in improving glycaemic control in patients with T2D. There are no head-to-head studies with linagliptin.
Table 1. Glycaemic and extraglycaemic effects of treatment with GLP-1RAs and DPP-4 inhibitors in head-to-head studies in patients with T2D
|Drug/Study||Design & Duration (weeks)||Background Medication||∆A1c (%)||∆FPG (mmol/L)||∆2-h PPG (mmol/L)||∆BW (kg)||∆β-cell Function||∆ SBP (mm Hg)|
|Liraglutide vs. exenatide||R-CC (26)||MET, SU or both||−1·12a vs. −0·79||−1·61a vs. −0·60||NR vs. −1·33a,b||−3·24 vs. –2·87|| |
HOMA-B (%)a: +32·12 vs. +2·74
FIns (pm/L)c: 12·43 vs. −1·38
FCP (nm/L): 0·05 vs. −0·02
FPIns/Ins ratio: 0·0 vs. −0·02
FG (ng/L):−19·44 vs. −12·33
|−2·51 vs. −2·00|
|Liraglutide vs. exenatide-ER||R-CC (26)||MET, SU and/or TZD||−1·48 vs. −1·28||NR||NR||−3·58 vs. −2·68||NR||−3·5 vs. −2·5|
|Exenatide vs. exenatide-ER||R-CC (24)||None, 1 or combination: MET, SU, TZD||−0·9 vs. −1·6a||−0·67 vs. −1·94c||NR||−1·4 vs. −2·3d||NR||−1·2 vs. −2·9|
|Exenatide vs. exenatide-ER[23, 24]||R-CC (30)||None, 1 or 2: MET, SU, TZD||−1·5 vs. −1·9c||−1·4 vs. −2·3a||−6·9d vs. −5·3||−3·6 vs. −3·7||Increased ratio of insulin to glucosed||−3·4d vs. −4·7d|
|Sitagliptin vs. saxgliptin||R-DBCC (18)||MET||−0·60 vs. −0·52||−0·90 vs. −0·60||NR||−0·40 vs. −0·40|| |
HOMA-2B (%): +13·1 vs. +11·0
FIns (μm/L): −3·0 vs. −0·5
FPIns (pm/L): −3·4 vs. −2·4
FCP (nm/L): 0·01 vs. −0·05
|Liraglutide (1·8 mg) vs. sitagliptin||R-CC (26)||MET||−1·5a vs. −0·9||−2·14a vs. 0·83||NR||−3·38a vs. −0·96|| |
HOMA-B (%): +28·7a vs. +4·18
HOMA-IR (pm): −1·50 vs. −0·94
FIns (pm/L): 1·29 vs. −6·77
FCP (nm/L): 0·09c vs.−0·04
FPIns/Ins: −0·10c vs. −0·03
|−0·72 vs. −0·94|
|Liraglutide (1·8 mg) vs. sitagliptin||R-CC (52)||MET||−1·51a,b vs. −0·88||−2·04a,b vs. 0·59||NR||−3·68a,b vs. −1·16|| |
HOMA-B (%): +25·76e vs. +3·98
HOMA-IR (pm): −1·36 vs. −0·41
FIns (pm/L): 1·63 vs. −2·27
FCP (nm/L): 0·09 vs. 0·01
FPIns/Ins:−0·09e vs. −0·01
|−2·55 vs. −1·03|
|Exenatide vs. sitagliptin||R-CC (4)||MET + Ins Glargine||−1·8d,f vs. −1·5f||−0·67g vs. −0·67g||−6·78d vs. 6·44d||−0·9d,g vs. 0·1||NR||NR|
|Exenatide vs. sitagliptin||R-CC (20)h||MET||−0·38 vs. −0·68g||0·06 vs. −0·55i,j||−1·55f,j vs. −2·10f,j||−2·58f vs. 2·20f||NR||NRk|
|Exenatide vs. sitagliptin||R-DBCC (2)||MET||NR||−0·83 vs. −1·05||−6·22a vs. −2·05||−0·8 vs. −0·3|| |
Insulinogenic index: 0·82d vs. 0·55
Ins secretion rate (0–30 min): 0·04c vs. 0·03c
|Exenatide vs. sitagliptin||R-DBCC (4)||MET or TZD||NR||−1·6f vs. −1·6f||−6·0d,f vs. −2·5f||−1·37d vs. −0·89||HOMA-B (%): +32·9c,f vs. +20·8f||−2·5 vs. −2·0|
|Exenatide-ER vs. sitagliptin||R-CC (26)||MET||−1·5a vs. 0·9||−1·8c vs. 0·9||NR||−2·3c vs. −0·8||NR||Values not reported|
|Exenatide-ER vs. sitagliptin||R-CC (26)||None||−1·53e vs. −1·15e||−2·3e vs. −1·1||Values not reported||−2·0e vs. −.8e|| |
HOMA-B (%): +1·8e vs. +1·3
HOMA-IS (%): +1·0 vs. +1·0
|−1·3 vs. −1·8|
|Exenatide-ER vs. sitagliptin||R-CC (26)||MET||−1·55d vs.−0·92d||−1·8d vs. −0·9||NR||−2·3d vs. −0·8d||NR||NR|
Cardiovascular effects among head-to-head studies
T2D increases the risk of cardiovascular disease; therefore, comprehensive cardiovascular risk reduction is a major focus in the treatment. Differences exist between GLP-1RAs and DPP-4 inhibitors with respect to their effects on blood and lipid profile. Head-to-head clinical trials comparing GLP-1RAs with insulin[36, 37] (Table 1) and treatment effects in combination with insulin (Table 2) demonstrated a small reduction in systolic blood pressure with GLP-1RAs that appears to be independent of weight loss. No significant change in diastolic blood pressure was observed.[20, 26, 30] Available data from trials with DPP-4 inhibitors suggest minimal effects on systolic and diastolic blood pressure.[26, 30, 38] Lipid profile, particularly triglyceride levels, was greatly improved with GLP-1RAs compared with DPP-4 inhibitors or insulin.[20, 26, 36] A meta-analysis of cardiovascular outcomes from 4 clinical trials[17, 39-41] suggested that every 1% reduction in A1c might be associated with a 15% relative risk reduction in non-fatal myocardial infarction. The currently available data suggest that the risk of cardiovascular disease is not increased and might be reduced with GLP-1RAs and DPP-4 inhibitors. Studies on the cardiovascular effects of DPP-4 inhibitors are underway and showing promising results.[43-49]
Table 2. Glycaemic and extraglycaemic effects of insulin plus GLP-1RAs or DPP-4 inhibitors in patients with T2D
|Drug/Study||Design & Duration (weeks)||Background Medication||∆A1c (%)||∆ FPG (mmol/L)||∆2-h PPG (mmol/L)||∆Insulin Dose (Units/day)||Hypoglycaemic episodes||∆BW (kg)||∆SBP (mm Hg)|
|Liraglutide + Ins Det + MET vs. liraglutide + MET||R-CC (26)||MET||−0·51a vs. +0·02||−2·1a vs. −0·4||Values not reported||NR||Minor events: 0·286 vs. 0·029 (event/person/year)||−0·16 vs. −0·95c||−3·13 vs. −1·65|
|Exenatide + Ins Glarg||R-PC (30)||Ins Glarg + MET or TZD or Both||−1·74b||−1·6||−2·0b||+13·0||Minor events: 1·4 vs. 1·2 (event/person/year)||−1·8b||−2·7c|
|Exenatide + Multiple Ins||Website questionnaire (12)||OAD||−0·51d||NR||NR||NR||9·2% of patientse||−4·1d||NR|
|Sitagliptin + Multiple Ins||R-CC (24)||Insulin, SU, MET, TZD||−0·6f||Not significant||−74·5 (mg/dL)||2·5|| |
Minor events: 7 events/person/yearf
Severe events: 0·88 events/person/yearf
|Sitagliptin + Multiple Ins||R-PC (24)||Insulin + MET||−0·6b||−0·8||−2·0||NC||16% incidence rate|| 0·1||NR|
|Saxagliptin + Ins or Ins + MET||R-PC (24)||Insulin, MET||−0·73h||−10·08 (mg/dL)||−27·2 (mg/dL)b||−1·7||18·4% of patients (5·3% confirmed events)||−0·39||NR|
|Linagliptin + Ins + glucose-lowering drugs||R-PC (52)||Insulin, SU, glitazone, alpha-glucosidase inhibitor + glinide||−0·72h||−0·30||NR||−6·2|| |
Symptomatic: 33·5% of patients
Asymptomatic: 55·9% of patients
Overall:63·2% of patients
Treatment effects in combination with basal insulin
Dual and triple recommendations from the ADA/EASD include incretin-based therapy and/or insulin to safely reach glycaemic targets. Table 2 lists results from studies that combined incretin-based therapy and basal insulin.[50-56] Addition of incretins to basal insulin can decrease insulin dose[57-61] or minimize a necessary increase, while still reducing A1c without increasing the incidence of hypoglycaemia.[28, 50, 51, 57, 58, 62-66] Incretins + basal insulin are generally weight neutral (DPP-4 inhibitors) or result in weight loss (GLP-RAs)[28, 51, 57, 58, 62, 63, 66]
Detemir + liraglutide is well tolerated and easy to titrate. A novel treatment intensification sequence (metformin then liraglutide, followed by titration of detemir) results in good glycaemic control, sustained weight loss and minimal hypoglycaemia. Glargine + exenatide improves glycaemic control without increased hypoglycaemia or weight gain and lowers PPG, fasting plasma glucose (FPG) and fasting lipids.[28, 51, 62, 64] Adding exenatide to glargine or detemir reduces the rate of hypoglycaemia compared with basal insulin alone.
Combining sitagliptin with a variety of insulin regimens results in reduction of A1c and is associated with less hypoglycaemia and weight gain. Sitagliptin lowers A1c and PPG; however, sitagliptin + insulin ± metformin is associated with higher rates of hypoglycaemia compared with placebo + insulin ± metformin. Similar results were reported when sitagliptin was added to agents associated with hypoglycaemia (e.g. sulfonylureas); results were similar to placebo when added to agents not associated with hypoglycaemia (e.g. metformin). When added to basal insulin therapy (± metformin), saxagliptin reduces A1c and PPG levels compared with placebo. Linagliptin + basal insulin + glucose-lowering agents in the presence of renal impairment reduce A1c without drug-related renal failure.
Patient-centred management selection
There is good evidence to support the importance of the shared decision-making approach between patients and clinicians. The first step is setting an individualized A1c target by using individualized glucose-lowering therapies. Several factors are considered when choosing an A1c target, including stringent (6·0–6·5%) vs. relaxed glycaemic goals (7·5–8·0%) because not everyone benefits from aggressive glycaemic control, desire for weight loss, risk of hypoglycaemia, tolerability, cost, adherence and safety. In older patients and patients with comorbid conditions, therapy should focus on drug safety with protection against hypoglycaemia and drug–drug interactions. GLP-1RAs and DPP-4 inhibitors in combination with basal insulin have been recommended to minimize the risk of hypoglycaemia. GLP-1RAs or DPP-4 inhibitors should be considered in patients with T2D, particularly obese patients who fail to reach glycaemic targets on metformin. Patients (and physicians) who are reluctant to transition to insulin due to concerns about weight gain and hypoglycaemia may be candidates for incretin therapy. In addition, evidence suggests that incretins may lead to β-cell preservation, a desired goal earlier in the disease.
Generally, clinicians prefer GLP-1RAs over DPP-4 inhibitors because of their greater efficacy in glycaemic control. In clinical practice, however, DPP-4 inhibitors tend to be used more than GLP-1RAs due to the convenience of oral administration. When deciding whether GLP-1RAs or DPP-4 inhibitors best fit individual patient needs, a number of patient characteristics must be considered.
First the patient's current A1c level, their A1c target and which blood glucose level to control (e.g. FPG, PPG, or both) should be considered.[74, 75] GLP-1RAs will likely help achieve a tighter A1c target (6·0–6·5%), whereas a conservative A1c target (7·5–8·0%) may be sufficiently addressed with DPP-4 inhibitors. At A1c closer to 9%, FPG has a greater contribution to A1c. A 3-agent combination regimen, including longer-acting incretin agents liraglutide and exenatide-ER, plus basal insulin may be needed. At an A1c closer to 7%, PPG has a greater contribution to A1c,[74, 75] and a short-acting agent (e.g. exenatide) may be a better choice. DPP-4 inhibitors might be more suitable for elderly patients as monotherapy when A1c ≤7·6% and as combination therapy when A1c <9%, if the patient is frail, and/or has long disease duration and short life expectancy. If A1c >10%, basal insulin should be added to incretin-based therapy to offer better coverage of dysfunctional organs and FPG and PPG. This combination produces greater glycaemic control without the increase in hypoglycaemia or weight gain associated with increased insulin dose.
Second is the patient's preferred route of administration, dosing frequency and side-effect tolerability. DPP-4 inhibitors are preferred for patients who are unwilling or unable to use an injection device or uninformed about the availability of devices. Liraglutide once daily, exenatide-ER or DPP-4 inhibitors are better options for patients who prefer less frequent dosing compared with exenatide. Elderly patients might prefer DPP-4 inhibitors over GLP-1RAs because they are not associated with gastrointestinal symptoms. However, gastrointestinal symptoms are transient, dose dependent and less persistent with liraglutide and exenatide-ER compared with exenatide.[20, 22, 23] Sharing this information with patients is important when initiating therapy with GLP-1RAs to improve patient adherence.
Third, if renal insufficiency exists, consider reducing the dose of sitagliptin and saxagliptin.[76-78] Caution is advised with liraglutide, but no dose adjustment is required. Exenatide and exenatide-ER are not recommended if severe renal insufficiency or end-stage renal disease is present.[80, 81]
Adherence is an important component of patient-centred management, and data from clinical trials are based on a higher level of adherence than might be reasonably expected in a general patient population. Patients will not benefit from the demonstrated efficacy of diabetes agents if they do not take the prescribed medication or do not take it correctly. Efficacy shown in clinical trials represents the mean response, and non-responders often meet trial withdrawal criteria and are removed from evaluation. Weight gain and symptoms of hypoglycaemia have been shown to influence adherence. Other causes of decreased adherence include: forgetfulness, changes in daily behaviour or medication schedules, and cost. However, unlike patients who participate in clinical studies, patients seen in clinical practice may skip/miss medical appointments and/or have long intervals between appointments, and they incur the medication cost. This likely results in loss of adherence to the treatment plan.
Clinical pharmacists must assess adherence; however, there is no ‘ideal’ way to identify non-adherence. Pharmacist can assess adherence by using various open-ended questions and/or patient self-reported surveys, for example, ‘How is the patient taking the medication?’, ‘When does the patient skip or forget their medication? Which days and why?’, ‘If a caregiver(s) is involved in the administration of medications, what is he/she willing and able to do?’ Also, there are possible issues of continuity of care if caregivers rotate. Every 6 months, the pharmacist should ask self-injecting patients to demonstrate their technique for using the injection device. Patients may develop unique habits related to injection technique that interfere with appropriate dosing. A team-based approach to assess medication adherence/compliance, drug interactions and all drug- and disease-related concerns is needed. The team should include a nurse, clinician (physician, nurse practitioner or physician assistant) and a pharmacist, among many other healthcare professionals. The nurse (triages the patient), the clinician (conducts medical/office visit) and the pharmacist (ensures appropriate medication therapy and assesses adherence) can be part of a 1-stop shopping experience. The team provides follow-up instructions and medication review/education.
If GLP-1RAs were selected as the optimal dual combination therapy for a patient, the identification of the best-matched specific GLP-1RA for an individual patient should be guided by the adherence-related issues seen in clinical practice. Many patients skip, forget or purposely do not take the second dose of exenatide to avoid the feeling of nausea during or after dinner. Adherence may be improved with liraglutide once-daily and exenatide-ER due to less nausea and fewer injections. Approximately 47% of patients with T2D reported once-weekly dosing helped improve adherence, while other patients prefer to establish the habit of once-daily dosing. If a dose is missed, the next dose should be taken at the next regularly scheduled time. However, patients should be made aware that liraglutide may be taken at any time of day. Encourage patients to schedule a distraction-free time for exenatide-ER dosing to avoid interruptions that may delay injection immediately after mixing. Discuss with patients ways to make the dosing schedule a habit, suggesting linking exenatide-ER with a weekly activity such as attending religious services.