**4. Incretin based therapies and their role in the management of type 2 diabetes**

Effects of incretin hormones on glucose metabolism and contribution of incretins in the pathogenesis of T2 DM, make these hormones ideal therapeutical targets. Decrease in apetite, reduction of body weight, improvement in insulin secretion and delay in gastric emptying are among several favorable effects of GLP-1 infusion [71]. Rapid degradation of bioactive GLP-1 by DPP-4 shortens half life, and limits anti-diabetic effects of GLP-1 [73]. Two treatment strategies has been developed to overcome this problem, first to develop DPP-4 resistant GLP-1 analogs, and the second to inhibit the degrading enzyme DPP-4. These two groups of medi‐ cations will be discussed in detail.

#### **4.1. Dipeptydyl peptidase-4 inhibitors**

These oral agents are approved for treatment of diabetes whose hyperglycemia do not improve with monotherapy with sullphonylurea, tiazolidinedione and metformin or their dual combinations. They exert their effects by inhibiting the enzyme which cleaves the incretins and increase GIP and GLP-1 levels. Sitagliptin, saxagliptin, linagliptin and alogliptin are available in US, and vildagliptin is used in outside US. They have the advantage of being weight neutral and do not cause hypoglycemia except for combinations with sulphonylureas. They have been shown to be effective and safe when combined with sulphonylurea, tiazolidinedione or metformin in patients with T2 DM [73]. Usual dose of sitagliptin is 100 mg once daily, and renal dysfunction necessitate dose reduction (50 mg for patients who have glomerular filtration rate 50 mL/min and 25 mg for patients with <30 mL/min) [74]. Saxagliptin is used 2.5-5 mg once a day and the dose should be reduced to 2.5 mg for moderate renal insufficiency. It is also an effective agent in combinations like sitagliptin [75, 76]. Vildagliptin is used 50 mg twice daily in T2 DM. Dose adjustment is not necessary in mild renal insufficency, 50 mg daily dose is suggested in case of modarate and severe renal dysfunction. Linagliptin is used 5 mg daily, and it differs from other DPP-4 inhibitors with its completely hepatic elimination, which makes it possible to use in renal dysfunction. Efficacy and safety of linagliptin have been proven in monotherapy and combination studies [78-80]. Alogliptin is used 25 mg daily and dose adjustment is necessary in renal dysfunction. It has similar efficacy and safety profiles with other DPP-4 inhibitors [80].

All of the members of DPP-4 inhibitors seem to have similar efficacy, but their enzymatic affinity may be different [81, 82]. Their side effects include headache, increased risk of nasopharyngitis, urinary tract infection, and skin reactions [83]. There are reports about hepatic dysfunction with alogliptin and vildagliptin. Although the incidence of pancreatitis is not increased, a population based data suggested an increased frequency of hospitalisation for pancreatitis among sitagliptin users [84]. There is concern about whether DPP-IV inhibitors cause panceratic cancer development or not, but a causal relationship has not been established yet.

Cardiovascular safety of DPP-4 inhibitors is the matter of concern, since cardiovascular diseases are the most common cause of death in T2 DM patient population and there are several antidiabetic drugs which have been withdrawn from marketing due to their cardivascular safety problems. In a study which cardiovascular events was an endpoint, saxagliptine and metformin showed similar cardiovascular safety pattern, but patients in saxagliptin group hospitalised more frequently for heart failure when compared with metformin group [85]. Two other studies showed that neither alogliptin, nor sitagliptin have beneficial or adverse cardiovascular effects in short term use [86, 87]. Although these studies showed increased or decreased risks for cardiovascular events with DPP-4 inhibitors in short term use, their long term cardiovascular safety need to be further evaluated in long term clinical trials.

#### **4.2. GLP-1 receptor agonists**

**3. Contribution of incretin system in the pathogenesis of diabetes**

replacement is possible and improve hyperglycemia [65, 66].

**diabetes**

278 Treatment of Type 2 Diabetes

cations will be discussed in detail.

**4.1. Dipeptydyl peptidase-4 inhibitors**

Diabetes is the state of compromised insulin secretion which resulted with hyperglycemia. Incretin effect is reduced or almost absent in T2 DM [63]. Although the secretion of GIP is nearly normal, its insulinotropic effect has been shown to be lost in T2 DM [27]. Secretion of GLP-1 is decreased in contrast to GIP, but its favorable effects on endocrine pancreas and extrapanceratic sites are preserved in T2 DM [20, 64]. In conclusion, detoriation of both the effect and secretion of incretin hormones are involved in the pathogenesis of T2 DM. It is not clear wheter the detoriation of incretin effect is a primary defect in the pathogenesis of diabetes or not. Studies suggest that incretin hormone detoriation is a secondary defect during pro‐ gression of diabetes. Another important fact is the restoration of insulin secretion with GLP-1

There are several mechanisms of action of GLP-1 in T2 DM. The first one is the augmentation of glucose induced insulin secretion, resulting with improvement in hyperglycemia. Nearnormal improvement in β-cell response to glucose, improvement in the first phase insulin secretion and completely normalisation of second phase insulin secretion by GLP-1 has been exactly defined [67]. Although the induction of insulin secretion is lost during chronic GLP-1 administration, glucose lowering action with maintained insulin levels tend do persist. Reduction in glucagon secretion is another mechanism of antiglycemic effect of GLP-1 [68]. Administration of GLP-1 delays gastric emptying significantly, and results with reduced postprandial glucose levels [69, 70]. The latter mechanism seems to be lost in chronic fashion. Based upon these mentioned antiglycemic effects of GLP-1, several pharmacological agents are developed for the treatment of diabetes, which will be talked about elswhere in this chapter.

**4. Incretin based therapies and their role in the management of type 2**

Effects of incretin hormones on glucose metabolism and contribution of incretins in the pathogenesis of T2 DM, make these hormones ideal therapeutical targets. Decrease in apetite, reduction of body weight, improvement in insulin secretion and delay in gastric emptying are among several favorable effects of GLP-1 infusion [71]. Rapid degradation of bioactive GLP-1 by DPP-4 shortens half life, and limits anti-diabetic effects of GLP-1 [73]. Two treatment strategies has been developed to overcome this problem, first to develop DPP-4 resistant GLP-1 analogs, and the second to inhibit the degrading enzyme DPP-4. These two groups of medi‐

These oral agents are approved for treatment of diabetes whose hyperglycemia do not improve with monotherapy with sullphonylurea, tiazolidinedione and metformin or their dual combinations. They exert their effects by inhibiting the enzyme which cleaves the incretins and increase GIP and GLP-1 levels. Sitagliptin, saxagliptin, linagliptin and alogliptin are available There are two approved synthetic GLP-1R agonist molecules in the marketing. First one is Exenatide and the second one is Liraglutide. They are approved for T2 DM as an add-on drug for patients whom glycemic regulation is failed with one or two oral anti-diabetic medication [88]. Lower hypoglycemia risk is an important advantage of these molecules, which make them an excellent choice of therapy in patients whom hypoglycemia is of concern. Although they are as effective as other older anti-diabetic agents in comparison trials, data about their long term safety, effects on mortality and weight reduction is lacking [89]. Their effects on weight reduction has been proven by several studies, in which weight reducion was a secondary endpoint [90].

#### **4.3. Exenatide**

It is the synthetic analog of GLP-1, and it naturally occurs in the saliva of Gila monster (Heloderma spectum) as Exendin-4. It has 53% aminoacid homology with original GLP-1 molecule and has a long half-life beacuse of its resitance to DPP-4 mediated degradation. It is approved for T2 DM, as single or an add-on agent with other oral anti-diabetics in US. It can be combined with all of the oral anti-diabetics except for DPP-4 inhibitors.

It binds to GLP-1R and shows insulinotropic effects of GLP-1 on β-cells in the presence of glucose. It slows gastric emptying, lowers plasma glucose levels and reduces weight by inducing satiety like GLP-1 [91, 92]. Insulinotrophic effects has been shown in animal models [93, 94].

Beneficial effects on hyperglycemia, weight reduction, lipids and blood pressure has been shown with clinical trials, which has less than 30 weeks of duration [71, 95-99]. Exenatide reduces a1c levels by aproximately 1%, has lower hypoglycemia risk and hypoglycemia risk is increased with concurrent use of sulphonylurea. Exenatide causes a significant weight loss, which seems independent from its nausea inducing effect. Of note, patients experience nause lose more weight compared with patients who do not have [83, 100]. Preceding type of of drug is another important factor on weight loss during exenatide use. Patients using metformin show much more weight loss when compared with patients using sulphonylurea and tiazolidinedions [100-103].

The most common side effect of exenatide is gastrointestinal, predominantly nausea and rarely vomitting, which wane with ongoing therapy. Starting with 5 mcg and increasing the dose after one month to 10 mcg help to overcome nausea. Although risk of pancreatitis among patients who use incretin based drugs has been shown to be similar to the diabetic patients who do not use incretin based therapy, hospitalisation for acute pancreatitis may be increased [84, 104-106]. Insulinotrophic effects of GLP-1 raised concerns about the possibilty of pancreatic cancer and neuroendocrine tumor risk among patients using incretin-based therapies [107-110]. There is no data which prove or unprove these issues, so it is suggested to monitor patients for possible adverse effects affecting pancreas [111]. Although acute renal failure following exenatide use has been reported, it is difficult to prove direct relationship with exenatide use and renal failure in this patient population, which is prone to develop acute renal failure because of concurrent use of nephrotoxic drugs and underlying diabetic nephropathy [112]. Exenatide is conraindicated in severe renal impairment (creatinine clearance below 30 mL/min), and close follow up for serum creatinine is suggested when initiating therapy and after the dose titration from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min. Gastroparesis and history of past acute pancretitis are the other contraindications for exenatide use.

Although Exendin-4 is a GLP-1R analog, it shares a %53 homology with human GLP-1, which leads to development of anti-exendin antibody. It has been shown that anti-exenatide antibody development occur in about %40-57 of treated group [103, 113]. In one study the frequency of anti-exenatide antibody was reported to be more than %70 at the end of 24 weeks, and %40 of these antibody positive patients did not show further a1c reduction [114].. Although these mentioned studies have some limitations, ineffectiveness of exenatide due to blocking antibodies in long term use is possible.

The usual administarion schedule is starting with 5 mcg sc twice a day within 1 hours before breakfast and diner, and titration to 10 mcg twice a day 1 month later. Exenatide once weekly sc formulation is also available in US and Europe, and efficacy on hyperglycemia has been shown [115]. There are studies which compare the efficacy of daily and weekly formulations of exenatide. The improvement in a1c level seem to be better achieved with weekly formulation when compared with daily formulation, with similar body weight reduction [116, 117].

### **4.4. Liraglutide**

reduction has been proven by several studies, in which weight reducion was a secondary

It is the synthetic analog of GLP-1, and it naturally occurs in the saliva of Gila monster (Heloderma spectum) as Exendin-4. It has 53% aminoacid homology with original GLP-1 molecule and has a long half-life beacuse of its resitance to DPP-4 mediated degradation. It is approved for T2 DM, as single or an add-on agent with other oral anti-diabetics in US. It can

It binds to GLP-1R and shows insulinotropic effects of GLP-1 on β-cells in the presence of glucose. It slows gastric emptying, lowers plasma glucose levels and reduces weight by inducing satiety like GLP-1 [91, 92]. Insulinotrophic effects has been shown in animal models

Beneficial effects on hyperglycemia, weight reduction, lipids and blood pressure has been shown with clinical trials, which has less than 30 weeks of duration [71, 95-99]. Exenatide reduces a1c levels by aproximately 1%, has lower hypoglycemia risk and hypoglycemia risk is increased with concurrent use of sulphonylurea. Exenatide causes a significant weight loss, which seems independent from its nausea inducing effect. Of note, patients experience nause lose more weight compared with patients who do not have [83, 100]. Preceding type of of drug is another important factor on weight loss during exenatide use. Patients using metformin show much more weight loss when compared with patients using sulphonylurea and

The most common side effect of exenatide is gastrointestinal, predominantly nausea and rarely vomitting, which wane with ongoing therapy. Starting with 5 mcg and increasing the dose after one month to 10 mcg help to overcome nausea. Although risk of pancreatitis among patients who use incretin based drugs has been shown to be similar to the diabetic patients who do not use incretin based therapy, hospitalisation for acute pancreatitis may be increased [84, 104-106]. Insulinotrophic effects of GLP-1 raised concerns about the possibilty of pancreatic cancer and neuroendocrine tumor risk among patients using incretin-based therapies [107-110]. There is no data which prove or unprove these issues, so it is suggested to monitor patients for possible adverse effects affecting pancreas [111]. Although acute renal failure following exenatide use has been reported, it is difficult to prove direct relationship with exenatide use and renal failure in this patient population, which is prone to develop acute renal failure because of concurrent use of nephrotoxic drugs and underlying diabetic nephropathy [112]. Exenatide is conraindicated in severe renal impairment (creatinine clearance below 30 mL/min), and close follow up for serum creatinine is suggested when initiating therapy and after the dose titration from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min. Gastroparesis and history of past acute pancretitis are the other

Although Exendin-4 is a GLP-1R analog, it shares a %53 homology with human GLP-1, which leads to development of anti-exendin antibody. It has been shown that anti-exenatide antibody

be combined with all of the oral anti-diabetics except for DPP-4 inhibitors.

endpoint [90].

280 Treatment of Type 2 Diabetes

**4.3. Exenatide**

[93, 94].

tiazolidinedions [100-103].

contraindications for exenatide use.

Liraglutide is a GLP-1 analog which is produced by a recombinant DNA technology. Substi‐ tution of lysine at position 34 by arginine, and attachment of palmitic acid side chain to lysine group at position 26 of original GLP-1 produce liraglutide. The lipid side chain lead to formation of a non-covalent bond with albumin, which in turn slows degredation of the molecule, allowing it to be used once a day sc. Liraglutide shares 97% aminoacid homology with GLP-1.

Clinical indications are similar with exenatide. Once daily administration of 0.6 mg sc for one week reduce gastrointestinal side effects. The dose should be increased to 1.2 mg once daily for one week, and to 1.8 mg once daily if blood glucose remains above the goals [118]. Liraglutide monotherapy and comibination with one or two oral agents are efficacous in reducing blood glucose and a1c, causing significant weight reduction compared with placebo, glimepride and sitagliptin [119-121].

Nausea, vomiting and diarrhea are the most common adverse events [119]. The relationship between liraglutide use and pancreatitis is controversial. Animal studies have shown a relationship between liraglutide use and benign and mallignant parafollicular C-cell tumors [122]. It may be a species specific effect and GLP-1R expression of human C-cell has been shown to be very low [122]. Short term human studies did not show any elevation in calcitonin levels with liraglutide, but this issue need further evaluation, since it takes a long time for a mallig‐ nant transformation. Liraglutide is not recommended for use in patients who have medullary thyroid carcinoma or a related syndrome, or a family history of these diseases.

#### **4.5. Is one GLP-1 receptor agonist superior to the other?**

In a 26 week trial comparing the effects of liraglutide and exenatide showed a beter glycemic control with liraglutide compared with exenatide, with similar weight loss and adverse effects [123]. In another study the effects of both analogs on hyperglycemia was similar, with slightly better weight reduction in liraglutide group [124]. One potential superiority of liraglutide to exenatide may be its molecular homology to GLP-1, which is not associated with development of blocking antibodies causing drug ineffectiveness during chronic use.

Besides their beneficial effects like weight reduction and low frequency of hypoglycemia, longterm safety data, effect on diabetic macro and microvascular complications and mortality of these GLP-1R analogs are still lacking.
