Exenatide is the first among these molecules that gained approval from the United States Food and Drug Administration (FDA) in 2005[9]. The drug, isolated from saliva of the reptile Gila monster (Heloderma suspectum), has 39 aminoacids with a 53% structural homology to natural GLP-1[9,10]. It has a plasma half-life of 3-4 h, and is excreted by glomerular filtration with subsequent degradation[10].

Exenatide improved glycemic control in patients with T2DM, not responsive to lifestyle modification, and medications such as sulfonylureas, metformin and thiazolidinediones, either alone or in combinations[9,11]. Exenatide treatment showed improvements in both the fasting and post-prandial hyperglycemia in T2DM patients[12]. In a recent meta-analysis examining the efficacy of the drug compared to placebo from nine clinical trials, the weighted mean difference of mean variation of hemoglobin A1c (∆ HbA1c) for all included data for exenatide 5 μg twice daily or its equivalent long acting dosage form was -0.68% [95%CI: -0.89 to -0.48 (P < 0.0001)] and for exenatide 10 μg twice daily or its equivalent long-acting dosage was -0.99% [95%CI: -1.18 to -0.8 (P < 0.0001)][13]. The weighted mean difference of mean variation of BW (∆ BW) for 5 μg twice daily or its equivalent long acting dosage form in eight of the trials was -0.56 kg [95%CI: -0.07 to -0.06 (P = 0.0002)] and for exenatide 10 μg twice daily or its equivalent long-acting dosage form in twelve trials was -1.24 kg [95%CI: -1.69 to -0.78 (P < 0.0001)]. Other observed benefits were reduction of systolic and diastolic blood pressures, and total cholesterol and low density lipoprotein (LDL)[13].

Being structurally different from native GLP-1, development of antibodies to exenatide on long-term treatment is common. Low-titre anti-exenatide antibodies were observed in 32% of cases on twice daily regimen and in 45% cases on once weekly regimen[14]. However, a significant effect on therapeutic efficacy was not evident in most cases. Higher antibody titres were less common (5% and 12% respectively), and increasing titres were associated with a reduction in average efficacy that was statistically significant for exenatide once weekly preparation[14]. Apart from injection-site reactions, there were no observed safety issues with anti-exenatide antibodies.

The drug is manufactured using recombinant DNA technology, and is with a 97% structural homology to human GLP-1[15]. Therefore, the molecule can be used effectively in patients with reduced response to exenatide therapy after prolonged use because of antibody production. The estimated mean differences in HbA1c reduction with liraglutide 1.2 mg and 1.8 mg daily compared to placebo were -1.01% (95%CI: -1.18 to -0.85) and -1.18% (95%CI: -1.32 to -1.04) respectively in a recent meta-analysis[16]. The Liraglutide Effect and Action in Diabetes (LEAD) program trial showed that mono-therapy with 1.2 mg and 1.8 mg of the drug was associated with a mean 2.1 kg and 2.5 kg weight reduction respectively, compared with a mean 1.1 kg weight gain among patients on glimepiride (P < 0.001) treatment[17].

The other observed benefits were: a mean reduction in systolic blood pressure of 2.59 mmHg (P = 0.0008) and 2.49 mmHg (P = 0.003) from baseline for liraglutide 1.2 mg and 1.8 mg respectively at 26 wk of treatment[15], improvement of β-cell function[18], reduction of total cholesterol and LDL, improvement of non-alcoholic fatty liver disease (NAFLD)[19], and improvement of cardiovascular risk markers[15].

Plasma half-life of lixisenatide is 3 h similar to that of exenatide[20], although it can be used as a single daily subcutaneous injection. Treatment with the drug resulted in a HbA1c reduction of 0.9%, body weight reduction of -3.62 kg (95%CI: -5.86 to -1.36) without significant risk of hypoglycemia compared to insulin[21]. Lixisenatide was also shown to improve NAFLD (number needed to treat: 14 patients, P = 0.042)[22]. Although slightly less effective than exenatide in terms of lowering HbA1c levels and weight reduction, lixisenatide use can be more convenient in comparison to exenatide as it has less hypoglycemia risk and gastrointestinal side effects, and the ease of once-daily administration[23].

Albiglutide is a DPP4-resistant human GLP-1 manufactured by fusion of the molecule with recombinant human albumin[24]. With a plasma half-life of approximately 5 d, the drug has the advantage of being administered once weekly. The drug recently received FDA approval in the United States for management of T2DM. Albiglutide can be used as a monotherapy or as an add-on therapy to metformin, sulfonylureas, insulin glargine and thiazolidinediones. Superior clinical efficacy compared to sitagliptin, and glimepiride, and non-inferiority to insulins (glargine and lispro) with HbA1c reduction of 0.55% to 0.9% and weight reduction up to 1.21 kg were reported with the use in T2DM cases[25]. Although gastrointestinal side effects were less common, efficacy in reducing HbA1c and body weight were less pronounced compared to liraglutide.

This new long acting GLP-1 analogue received recent FDA approval for use in T2DM. The plasma half-life of dulaglutide is approximately 4 d, with a once weekly dosing advantage[26]. Efficacy of once weekly regimen was reported to be superior to: metformin monotherapy, sitagliptin as add-on to metformin, and exenatide as add-on to metformin and pioglitazone, with a safety profile similar to other GLP-1 analogues[27]. The plasma half-lives, dosage range and common side effects of GLP-1 analogues are shown in Table 1.

Sitagliptin is first among the DPP-4 inhibitors that received FDA approval in 2006. The drug has good oral bio-availability, a half-life of 10-12 h (with once daily dosing advantage), and is eliminated mainly through the kidneys necessitating dose reduction in renal impairment[28]. Sitagliptin improves both fasting and postprandial hyperglycemia in T2DM patients. HbA1c reduction of up to 0.94% has been reported when sitagliptin is used as a monotherapy and better reduction in combination regimens. A recent meta-analysis concluded that sitagliptin had comparable efficacy to metformin in reduction of HbA1c and body weight, and improvement of β-cell function, although inferior to metformin in improvement of insulin sensitivity[29].

When used as a monotherapy, this molecule showed glycemic control comparable to sulfonylureas and thiazolidinediones, with the advantages of fewer hypoglycemic episodes and lesser body weight gain[30]. Additional favorable effects on pancreatic alpha- and beta-cell function compared to sulphonylureas were noted with the drug. The plasma half-life of vildagliptin is 1.5-4.5 h and the elimination is mainly through hepatic hydrolysis[28]. HbA1c reduction of 0.5%-1% has been reported with the drug use in T2DM. Use in combination with metformin, further improves glycemic control when metformin monotherapy is insufficient, with good tolerability and safety[30]. Combination regimens with other oral anti-diabetic medications and insulins are also effective and well tolerated.

The drug received FDA approval in 2009 for use in patients with T2DM. When used as monotherapy at a maximum dose of 5 mg, saxagliptin caused a mean HbA1c reduction of 0.8% with significant improvement of fasting hyperglycemia, and with other categories of oral anti-diabetics, an additional mean HbA1c reduction by 0.6%-0.7%[31]. The plasma half-life is 2.5 h and elimination is mainly by hepatic and renal clearance[28].

Linagliptin is primarily excreted via bile and therefore safe to be used in T2DM patients with renal impairment. With a reasonable safety profile, low hypoglycemia risk, HbA1c reduction ranging from 0.6% to 0.8% and weight neutrality, the drug became popular in the recent years[32]. Additional benefits such as improvement of wound healing, reduction of hepatic steatosis, decrease in the infarct size following myocardial infarction and ischemic stroke, improvement of vascular function, and reduction of albuminuria are claimed with linagliptin use in pre-clinical studies that needs further research in large randomized controlled trials. Linagliptin has relatively low oral bio-availabilty compared to other DPP-4 molecules (15%-50%) and the plasma half-life of the drug is 12 h[32].

This new DPP-4 molecule has a plasma half-life of about 21 h, and can be administered once daily[33]. Elimination is mainly through kidneys that necessitates dose reduction in advanced renal disease. Alogliptin is safe and well tolerated. A mean HbA1c reduction of 0.6% is reported with monotherapy[28,33], and additional reduction in combination regimens with other anti-diabetics[33].

Teneligliptin is one of the latest additions to the class of DPP-4 inhibitors. A recent study revealed that the drug administration was associated with significant elevations of postprandial active GLP-1 and GIP levels, lowering of postprandial hyperglycemia, 24-h mean blood glucose levels, and mean amplitude of glycemic excursions without hypoglycemia[34]. A significant elevation in early-phase insulin release and a reduction in postprandial glucagon surge were also observed. Even short-term teneligliptin treatment was found to be beneficial in patients with T2DM. HbA1c reduction of about 1%, improvement of β-cell function, insulin sensitivity, and adverse lipid parameters are the benefits claimed in a clinical trial[35].

The drug is still being evaluated in phase III clinical trials and is expected to be available for clinical use soon. Mean HbA1c reduction of -0.85% ± 0.70%, reduction in the fasting proinsulin/ insulin ratio, and improvement of insulin secretion were observed when used as an add-on therapy to metformin (all effects comparable with sitagliptin) in a recent multi-center clinical trial[36]. Safety profile and efficacy were also comparable with sitagliptin.

The dosage ranges and common side effects of DPP-4 inhibitors are shown in Table 2.