A review of newer treatment approaches for type-2 diabetes: Focusing safety and efficacy of incretin based therapy

Abstract

Diabetes resulting from both genetic and lifestyle factors causes high insulin deficiency or its resistance. As hyperglycemia and decreased insulin secretion and/or its sensitivity appear to be the primary defects associated with diabetes, available treatments focus on reducing those defects. A novel approach of treatment is to target the incretin mimetic hormones, which are secreted by intestinal cells in response to food intake, provoking glucose-dependent insulin secretion from the pancreas. Efficacy and safety studies of dipetidyl peptidase inhibitors (DPP-IV), sitagliptin, vildagliptin and linagliptin provide similar improvements in HbA1c levels when compared with metformin, sulfonylureas or glitazones without contributing to weight gain and hypoglycemia. Caution is required when choosing the gliptin in people with renal or hepatic impairment and with a risk of pancreatitis. The glucagon like peptide (GLP-1) analogues Exenatide and Liraglutide also have positive impact on glycemic control especially when used as a combination therapy. Another upcoming approach is using sodium-glucose co transporter two inhibitors in kidney, by exploring pathophysiology of renal glucose re absorption in the proximal tubule.

Introduction

Even though diabetes is not a new born disease with a history since 1552 its prevalence is increasing day by day. As in other diseases newer drugs are getting added up and some become outdated or withdrawn. Even the most commonly used oral hypoglycemic agent (OHA) metformin is found to be ineffective in the long-term therapy for many patients. Sulfonylureas are used in case of patients who are not responding to metformin. But they can put patients at an increased risk of hypoglycemia, weight gain, heart attacks and strokes. Glitazones are also associated with cardiovascular risks. To avoid such pitfalls and to improve glycemic control with minimum side effects new therapeutic approaches are developed. Dipeptidyl peptidase (DPP)-4 inhibitors, which enhance postprandial levels of the incretin hormones glucagon like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), are newer therapeutic options with minimal side effects (Dicker, 2011).

The revised consensus algorithm accounts for the introduction of incretin-based therapies into clinical practice. The algorithm was authored in 2009 by the American Diabetes Association and European Association for the Study of Diabetes for the initiation and adjustment of therapy in Type 2 diabetes. The incretin hormones are gut borne and have clinically meaningful effects on glucose homeostasis, particularly in the postprandial period. So according to the algorithm their use can be emphasized in cases of hypoglycemia and increased body weight. Also 66% of the β-cell response during post prandial period is due to the incretin effect. The foundation of incretin-based therapies is to target this newly recognized feature of diabetes pathophysiology, resulting in sustained and powerful glycemic control and body weight control (Stonehouse et al., 2012; McIntosh et al., 2005).

The incretins are peptide hormones released into the circulation, in response to luminal nutrients, minutes after a meal. In humans, the major incretins are glucagon-like peptide-1 (GLP-1) secreted by the L cells in the ileum and colon and glucose-dependent insulinotropic polypeptide (GIP) secreted by the K cells in the duodenum. Hormonal effects on multiple organs are found to be exhibited by both GLP-1 and GIP and stimulate insulin secretion in a glucose-dependent manner along with appetite suppression and delayed gastric emptying. As a result of these combined effects, significant contribution has been made for the control of postprandial glucose resulting in a better glycemic control with relatively low risk of hypoglycemia. (Prins, 2008) The incretins are predominant gut borne mediators of insulin release, and GLP-1 deals with glucagon suppression. GLP-1 represents a clinically better therapeutic option over GIP as its insulinotropic effects are preserved in type 2 DM while GIP activity is impaired (Fujioka, 2007). However both incretins are rapidly inactivated in vivo by the enzyme DPP-IV. Two approaches considered to enhance the incretin effect in type 2 diabetes are to either administer GLP-1 receptor agonists that are resistant to cleavage by DPP4 or to inhibit DPP4 enzyme activity. These pharmacological approaches thereby effectively increase the half-life and circulating levels of the incretins (Prins, 2008).

Incretin-analogue based therapies

Glucagon-like peptide 1 (GLP-1) analogues are the foundation of incretin-based therapies and the main advantage is that they can be used as monotherapy, or in combination with other diabetic medications along with diet and exercise in adults with type 2 DM (Chiniwala and Jabbour, 2011) Emerging evidence suggests minimum risk of hypoglycemia with incretin-based treatments except in combination with insulin secretagogues. They also exhibit beneficial effects on cardiovascular and hepatic health, the central nervous system, inflammation and sleep (Stonehouse et al., 2012) The administration of incretin analogues resistant to cleavage by DPP4 was really appreciable. Two drugs exenatide and liraglutide are clinically used now, given as subcutaneous injection. Formulation developments are on going to check whether long-acting once-weekly injections are possible. Exendin, the clinical formulation of exenatide is a potent activator of the GLP-1 receptor with almost 50% homology to GLP-1, while liraglutide maintains normal activity at the GLP-1 receptor. Both are resistant to cleavage by DPP4 and have a long circulating half-life (Prins, 2008).

Dipeptidyl-peptidase IV inhibitors

Dipeptidyl-peptidase (DPP) IV is a ubiquitous enzyme that is responsible for the inactivation of both incretin hormones GLP-1 and GIP. DPP IV inhibitors are FDA approved oral medications in type 2 diabetes, which inhibit dipeptidyl peptidase-4 thereby increase circulating concentrations of incretin hormones and provide glycemic control with improved islet cell function (Pratley and Salsali, 2007) and by this mechanism of action they allow GLP1 to stay in the body for longer time which improves control of glucose as well as reduce appetite. They help the pancreas to secrete insulin in glucose dependent manner in post-prandial period and thereby reducing dramatic episodes of blood sugar spikes (Stonehouse et al., 2012) Also they are well tolerated, carry a low risk of hypoglycemia and weight gain (Stonehouse et al., 2012; Pratley and Salsali, 2007).

Another new approach is the use of sodium glucose co transporter-2 inhibitors which are in the phase III studies for the treatment of type 2 diabetes. Several specific SGLT2 inhibitors currently under development include dapagliflozin, canagliflozin, empagliflozin, ipragliflozin and tofogliflozin. They work independently and inhibit glucose re-absorption from the glomerular filtrate. Reduced renal threshold for glucose, glycosuria and net calorie loss are the results. Trials regarding long-term outcomes are ongoing (Isaji, 2007; Grempler et al., 2012).

In the present article, we discuss the attributes of new treatment strategies of diabetes and an attempt has been made to compare and elaborate various aspects of incretin based therapies including their efficacy and adverse reactions focused on GLP1 agonists and commonly used gliptins-vildagliptin, Sitagliptin and linagliptin.

Comparison of various efficacy studies of Sitagliptin, Vildagliptin and Linagliptin

A large number of clinical studies and extensive clinical experience demonstrate that gliptins provide unique therapeutic benefits that make them ideal for treatment of type 2 diabetes. They are available in combination pills with Metformin. All these medicines have been shown to significantly reduce HbA1c when used as monotherapy and in combination with other traditional agents. But they are comparatively more expensive. Several studies were designed and done to compare these drugs with other OHAs to clarify their efficacy in relation to traditional agents. Various meta analysis were done to study the safety issues also. They are found to be associated with minimum side effects like headache, nausea as well as mild skin reactions.

Monotherapy
Drug	Duration (weeks)	Number of subjects (N)	Baseline HbA1c (%)	Reduction in HbA1c (%)
Sitagliptin
100 mg (Hanefeld et al., 2007; Scott et al., 2007; Barzilai et al., 2009) 100 mg & 200 mg (Raz et al., 2006)	12	555	7.7	0.6
		743	7.8	0.8
	24	123	7.8	0.7 (Elderly)
	18	521	8.1	0.6 & 0.5, respectively
100 mg & 200 mg (Aschner et al., 2006)	24	741	8	0.8 & 0.9, respectively
50 mg (moderate renal insufficiency) 25 mg (severe insufficiency) (Chan et al., 2008)
	54	65	7.7	0.6
Vildagliptin
25 mg BD vs Placebo (Pratley et al., 2006)	12	70 & 28, respectively	8	0.6 ± 0.2
50 mg BID, 50 mg OD & 100 mg OD (Dejager et al., 2007)	24	632	8.4	0.8 ± 0.1,0.8 ± 0.1 & 0.9 ± 0.1, respectively
50 mg BID,50 mg OD & 100 mg OD (Pi-Sunyer et al., 2007)	24	354	8.4	0.7 ± 0.2, 0.5 ± 0.2 & 0.9 ± 0.2, respectively
50 mg & 100 mg (Kalra, 2011)	12	279 & 98	8	0.43 & 0.6, respectively
10 mg, 25 mg & 50 mg BID vs Placebo (Kikuchi et al., 2009)	12	291	7.4	0.8%, 1.0% & 1.2% respectively (placebo adjusted mean change)
50 mg BID compared with voglibose (Iwamato et al., 2010)	12	188 & 192, respectively	7.6	<6.5% in 50.8% & 24.2% patients respectively
100 mg compared with rosiglitazone 8 mg (Rosenstock et al., 2007a)	24	519 & 267, respectively	8.7	1.1 & 1.3, respectively
Linagliptin
5MG vs Placebo (Del Prato et al., 2011)	24	336 & 167, respectively	⩾ 9.0	1.01% (placebo adjusted reduction)
5 mg OD &10 mg OD vs voglibose 0.2 mg tid (Kawamori et al., 2012)	26	561	7.63,7.50 & 7.91, respectively	0.32% & 0.39%, respectively (adjusted mean difference)
5 mg OD &10 mg OD vs Placebo (Kawamori et al., 2012)	12	–	7.58%, 7.48% and 8.34%, respectively	0.87% & 0.88% respectively (adjusted mean difference)
As add on to metformin
Sitagliptin
100 mg + metformin 2G BD, 100 mg + metformin 1G BD, metformin 2G BD, metformin 1G BD, 100 mg OD & placebo (Goldstein et al., 2007)	24	1091	8.8	2.07%, 1.57%, 1.30%, 0.99% & 0.83%, respectively (placebo subtracted change)
100 mg vs Placebo (Charbonnel et al., 2006)	24	701	8	<7% in 47% & 18.3% patients respectively
100 mg vs 5 mg (Glipizide) (Nauck et al., 2007)	52	1172	7.5	0.67 in both (63% and 59% patients respectively)
100 mg vs 8 mg (Rosiglitazone) (Scott et al., 2008)	18	273	7.7	0.7 & 0.8, respectively
100 mg (As add on to metformin + glimepiride) (Hermansen et al., 2007)	24	441	8.3	0.89
Vildagliptin
50 mg OD (Ahren et al., 2004)	12	107	7.7 ± 0.1	0.6 ± 0.1
50 mg OD vs placebo (Ahren et al., 2005)	52	31& 26, respectively	7.7	1.0 ± 0.2% (between group difference)
50 mg OD & 50 mg BID vs Placebo (Bosi et al., 2007)	24	n = 177, 185 and 182, respectively	7.5–11%	0.7 ± 0.1% & 1.1 ± 0.1%, respectively (between group difference)
50 mg BID vs 30 mg OD pioglitazone (Bolli et al., 2008)	24	295 & 281, respectively	7.5–11%	0.9 & 1.0, respectively
Linagliptin
Compared with Placebo (Taskinen et al., 2011)	24	524 & 177, respectively	8.1	0.49 & +0.15, respectively
Compared with glimepiride (Gallwitz et al., 2012a)	2 year	777 & 775, respectively	7.69	0.16 & 0.36, respectively
(As add on to metformin ± OAD) 1 mg, 5 mg, 10 mg vs Glimepiride (1–3 mg) or Placebo (Forst et al., 2010)	12	333	8.2%, 8.5%, 8.4%, 8.2%, and 8.4%, respectively	0.4,0.73,0.67 & 0.9 respectively (treatment difference vs placebo)
(As add on to metformin + sulfonylurea) 5 mg vs Placebo (Owens et al., 2011)	24	793 & 265, respectively	7–10%	0.72 & 0.1, respectively
As add on to sulfonylurea
Sitagliptin
100 mg (Hermansen et al., 2007)	6 MONTH	441	8.3	0.7
Vildagliptin
50 mg OD, BID vs 4 mg (Glimepiride + Placebo) (Garber et al., 2008)	24	515	7.5–11	−0.6 ± 0.1%, & −0.7 ± 0.1%, respectively (between group difference)
Linagliptin
5 mg OD vs Placebo (Lewin et al., 2010)	18	161 & 84, respectively	8.6	0.47 (Placebo adjusted change)
As add on to glitazones
Sitagliptin
Compared with placebo (Rosenstock et al.)	24	175 & 178, respectively	8.1 & 8, respectively	7.2 & 7.8, respectively (HbA1c at end point)
Vildagliptin
50 mg OD, BD vs 45 mg Pioglitazone + Placebo (Garber et al., 2007)	24	463	8.7	0.8, 1.0 & 0.3, respectively
100 mg OD vs 30 mg Pioglitazone OD) (Rosenstock et al., 2007b	24	150 & 157, respectively	8.7	1.1 & 1.4, respectively
100 mg + 30 mg Pioglitazone & 50 mg + 15 mg Pioglitazone (Rosenstock et al., 2007b)	24	146 & 139, respectively	8.7	1.9 & 1.7, respectively
Linagliptin
5 mg or Placebo (Gomis et al., 2011)	24	259 & 130, respectively	8.6 & 8.58, respectively	1.25 & 0.75, respectively
Comparison of safety studies
Drug	Body weight	Hypoglycemia	More reported events	Rare events
Sitagliptin	Neutral (monotherapy) Increasing (With insulin and sulfonylureas) (Scott et al., 2007; Raz et al., 2006; Rosenstock et al., 2007a; Charbonnel et al., 2006; Hermansen et al., 2007; Arjona Ferreira et al., 2008)	None (monotherapy) (Barzilai et al., 2009; Raz et al., 2006; Rosenstock et al., 2007a; Rosenstock et al.) Increasing (with insulin and sulfonylureas) (Nauck et al., 2007; Hermansen et al., 2007; Vilsboll et al., 2010)	Headache, upper respiratory tract infection, nasopharyngitis. (Chan et al., 2008)	Pancreatitis, hypersensitivity reactions (Ahrén, 2010)
Vildagliptin	Neutral (Bosi et al., 2007; Bolli et al., 2008; Garber et al., 2007; Pratley et al., 2006; Scherbaum et al., 2008; Schweizer et al., 2007)	None (monotherapy) Increasing (with insulin) Kalra, 2011	Nausea, headache nasopharyngitis, dizziness, cough, constipation (Pratley et al., 2006; Scherbaum et al., 2008)	Mild liver enzyme elevation (Kothny et al., 2009)
Linagliptin	Neutral or decreased (monotherapy) Del Prato et al., 2011; Taskinen et al., 2011; Forst et al., 2010; Owens et al., 2011; Lewin et al., 2010; Kawamori et al., 2011 Increasing (with glitazones) Gomis et al., 2011	Increasing (with insulin, sulfonylureas and insulin secretagogues) (Forst et al., 2010; Owens et al., 2011; Lewin et al., 2010; Gallwitz et al., 2011)	Urticaria, angioedema or bronchial hyperreactivity (Del Prato et al., 2011; Taskinen et al., 2011; Forst et al., 2010; Owens et al., 2011; Gomis et al., 2011; Tradjenta, 2011)	-

EXENATIDE: Exenatide is the first drug that mimics the activity of incretins, the natural glucoregulatory peptides. In April 2005 it was approved by the US FDA as an adjunctive therapy in patients with type 2 diabetes. Exenatide is a subcutaneously injected, peptide GLP-1 receptor agonist that has been shown to improve glycemic control, promote weight loss, and improve some cardiovascular risk markers in patients with T2DM (Klonoff et al., 2008; Aroda and DeYoung, 2011).

LIRAGLUTIDE: Liraglutide is another glucagon-like-peptide-1 (GLP-1) receptor agonist, taken as once daily injection. It was approved by FDA on January 25, 2010. It is designed not only to improve 24-h glycemic control in a glucose-dependent manner by increasing insulin secretion and decreasing glucagon secretion (Chang et al., 2003; Degn et al., 2004) but also accompanied by a delay in gastric emptying and weight loss (Juhl et al., 2002).

Many researchers have demonstrated that both exenatide and liraglutide are well tolerated and produce clinically meaningful reduction of HbA1c when used alone and in combination with other drugs.

Comparison of various efficacy studies of exenatide and liraglutide

Monotherapy
Dose	Duration	No. of patients	Reduction in HbA1c (%)
Exenatide
2 mg once weekly vs 100 mg Sitagliptin or 45 mg Pioglitazone (Bergenstal et al., 2012)	26	160, 166 & 165, respectively	0.6 & 0.3, respectively (treatment difference of exenatide vs Sitagliptin or Pioglitazone)
Once weekly vs metformin, pioglitazone and Sitagliptin
(Jones et al., 2012)	26	–	1.53, 1.48, 1.63 & 1.15, respectively
Liraglutide
1.2 mg & 1.8 mg vs Glimepiride (Garber et al., 2009)	52	746	0.84%, 1.14% & 0.51%, respectively
1.2 mg & 1.8 mg vs Glimepiride 8 mg (Garber et al., 2011)	2 year	–	0.9, 1.1 & 0.6, respectively
0.65 mg, 1.25 mg, 1.90 mg & Placebo (Vilsboll et al., 2007)	14	–	0.98, 1.40, 1.45 & +0.29, respectively
As combination therapy
Exenatide
10 μg, 5 μg, and placebo (as add on to sulfonyl urea) (Buse et al., 2004)	30	377	0.86 ± 0.11%, 0.46 ± 0.12%, and 0.12 ± 0.09%, respectively
10 μg, 5 μg, and placebo (as add on to metformin) (DeFronzo et al., 2005)	30	272	0.78 ± 0.10, 0.40 ± 0.11 & +0.08 ± 0.10
10 μg, 5 μg, and placebo (as add on to metformin & sulfonylurea) (Kendall et al., 2005)	30	733	0.8 ± 0.1, 0.6 ± 0.1 & +0.2 ± 0.1, respectively
Liraglutide
1.8 mg & 1.2 mg (as add on to metformin, vs sitagliptin) (Pratley et al., 2010)	26	225,221 & 219, respectively	1.5 & 1.24, respectively vs 0.9
(As add on to metformin + Rosiglitazone vs placebo) (Zinman et al., 2009)	26	533	1.5% ± 0.1%vs 1.5% ± 0.1%
(As add on to metformin + glimepiride, vs insulin glargine) (Russell-Jones et al., 2009)	26	581	1.33% vs 1.09%
(As add on to metformin + sulfonyl urea, vs exenatide) (Buse et al., 2009)	26	233 & 231, respectively	1.12% vs 0.79%, respectively

Comparison of safety studies
Drug	Body weight	Hypoglycemia	More reported events	Rare events
Exenatide	Decreased (Bergenstal et al., 2012; Gallwitz et al., 2012b)	Mild episodes (Bergenstal et al., 2012; Buse et al., 2004)	Nausea, diarrhea and upper-respiratory-tract infection (Bergenstal et al., 2012; Gallwitz et al., 2012b)	Injection-site erythema, pruritus, urticaria and rash (Buse et al., 2004)
Liraglutide	Neutral or decreased (Pratley et al., 2010; Zinman et al., 2009; Russell-Jones et al., 2009; Nauck et al., 2009; Marre et al., 2009)	None Garber et al., 2009; Zinman et al., 2009; Buse et al., 2009; Nauck et al., 2009; Marre et al., 2009; Seino et al., 2010; Kaku et al., 2010	Nausea, vomiting, diarrhea and constipation (Garber et al., 2009; Pratley et al., 2010; Zinman et al., 2009; Russell-Jones et al., 2009; Nauck et al., 2009; Marre et al., 2009; Seino et al., 2010; Kaku et al., 2010)	Acute pancreatitis and increase in calcitonin level (Russell-Jones et al., 2009; Nauck et al., 2009; Marre et al., 2009)

Sodium glucose co-transporters 2 (SGLT2) inhibitors

They represent a new strategy in the treatment of diabetes with a unique mechanism of action. They promote urinary glucose excretion by inhibiting glucose reabsorption from renal tubules and thus decrease plasma glucose levels. A significant proportion of glucose reabsorption is facilitated by SGLT-2, a member of the SGLT family and other members include SGLT-1, 3, 4, 5, and 6. Inhibition of SGLT-2 has been shown to block the body’s capacity to reabsorb glucose via the kidney and thereby reduce blood glucose levels (Isaji, 2007).

The roles of other SGLT family members in glycemic control are not well understood. SGLT-1 is highly expressed in the heart and also has an important role in normal intestinal glucose absorption. But its inhibition may lead to diarrhea and severe dehydration, symptoms observed in those with inherited mutations in the SGLT-1 gene. SGLT-3 is expressed in neurons of the small intestine and in neuromuscular junctions of skeletal muscle, transports sodium upon glucose binding, but not capable of monosaccharide transport. SGLT-4, 5 and 6 are expressed in the kidney and play an important role in renal monosaccharide and/or sodium reabsorption (Grempler et al., 2012).

SGLT-2 inhibitors fall into 2 classes. C-glucosides (empagliflozin, dapagliflozin, canagliflozin, ipragliflozin and tofogliflozin) and O-glucosides (sergliflozin, remogliflozin, T-1095A and phlorizin). All SGLT inhibitors are structurally similar, with different selectivity profile. Among the inhibitors tested for SGLT-2 over SGLT-1, Empagliflozin was shown to have the highest selectivity with fewer gastrointestinal side effects than the other less selective SGLT-2 inhibitors (Grempler et al., 2012). Preclinical studies and clinical trials have revealed that SGLT2 inhibition offers benefits to diabetic patients by reducing plasma glucose levels, decreasing glucotoxicity and lowering glycosylated hemoglobin levels. Some studies of O-glucosides showed unfavorable pharmacokinetic profile too. The therapeutic potential and safety concerns of these new drugs are currently under clinical development.

Summary and discussion

All the people never respond in the same way to treatments. Innovative and safe options with better treatment outcomes are greatly needed for the current generation of patients worldwide who are struggling with glycemic control problems, cardiovascular issues and obesity. Traditional oral anti-diabetic drugs achieve only limited glycemic control and are accompanied by weight gain or hypoglycemia except for biguanides and alpha-glycosidase inhibitors. Many randomized, double-blind, placebo or active comparator controlled, multicentre trials in patients with T2DM have proved that gliptins produce clinically meaningful reduction of HbA1c and are well tolerated in patients who are inadequately controlled with Metformin, sulfonylureas or glitazones or even with insulin.

Unique mechanism of action and oral dosing certainly position gliptins to be a first line option. But high cost and relative lack of long-term safety and efficacy studies like impact on cardiovascular disease are the major constraints at this point. Data from clinical trials suggest that one gliptin is not superior over another with regard to efficacy. But particularly some factors have to be in mind for safe use of each gliptin. Renal function assessment is needed prior to initiating and periodically during the treatment with sitagliptin. A dosage adjustment is recommended in moderate or severe renal insufficiency and in end-stage renal disease and dialysis cases (Ahrén, 2010) Also observe patients carefully for signs and symptoms if pancreatitis or a hypersensitivity reaction is suspected. The important clinical concern with vildagliptin is liver enzyme monitoring before and after its initiation since some hepatic enzyme elevation cases were reported with the vildagliptin therapy. While initiating linagliptin, one should be aware of the potential risk for acute pancreatitis (Tradjenta, 2011) Investigators have examined the use of linagliptin in patients with compromised renal function (Sloan et al., 2011; Graefe-Mody et al., 2011) and concluded that dose adjustments based on renal function are not required. Exenatide and liraglutide are subcutaneously injected, peptide GLP-1 receptor agonists that have been shown to improve glycemic control, promote weight loss, and improve some cardiovascular risk markers in patients with T2DM (Klonoff et al., 2008; Aroda and DeYoung, 2011).