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Table of Contents
Year : 2011  |  Volume : 15  |  Issue : 4  |  Page : 298-308

Choosing a Gliptin

1 Department of Endocrinology, Jaslok Hospital and Research Centre, 15 - Deshmukh Marg, Mumbai 400026, India
2 Bharti Hospital and BRIDE, Karnal, India

Date of Web Publication30-Sep-2011

Correspondence Address:
Vishal Gupta
Department of Endocrinology, Jaslok Hospital and Research Centre, 15 - Deshmukh Marg, Mumbai 400 026
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2230-8210.85583

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The treatment of type 2 diabetes mellitus (T2DM) has included the use of metformin and sulfonylurea (SU) as first-line anti-diabetic therapies world over since years. This remains, despite the knowledge that the combination results in a progressive decline in [beta]-cell function and by 3 years up to 50% of diabetic patients can require an additional pharmacological agent to maintain the glycosylated hemoglobin (HbA1c) <7.0% (UKPDS). Gliptins represent a novel class of agents that improve beta cell health and suppress glucagon, resulting in improved post-prandial and fasting hyperglycemia. They function by augmenting the incretin system (GLP-1 and GIP) preventing their metabolism by dipeptidyl peptidase-4 (DPP-4). Not only are they efficacious but also safe (weight neutral) and do not cause significant hypoglycemia, making it a unique class of drugs. This review focuses on gliptins (sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin) discussing pharmacokinetics, pharmacodynamics, efficacy, and safety.

Keywords: Diabetes mellitus, dipeptidyl-dipeptidase, dipeptidyl peptidase-4-inhibitors, gliptins, GLP, incretins

How to cite this article:
Gupta V, Kalra S. Choosing a Gliptin. Indian J Endocr Metab 2011;15:298-308

How to cite this URL:
Gupta V, Kalra S. Choosing a Gliptin. Indian J Endocr Metab [serial online] 2011 [cited 2021 May 13];15:298-308. Available from: https://www.ijem.in/text.asp?2011/15/4/298/85583

   Introduction Top

The treatment of type 2 diabetes mellitus (T2DM) has included the use of metformin (particularly in the overweight patient) and sulfonyurea (SU) (in both lean and overweight patient), as first line anti-diabetic therapies world over. Prior to 1995, the use of SU was the most popular anti-diabetic therapy in the USA (United States). SU's act by increasing insulin secretion in a glucose-independent manner, thereby risking severe unpredictable hypoglycemia, particularly if the meal is delayed or if its carbohydrate quantity reduced. The use of metformin only became popular in the US post 1995. It only makes sense that they continue to remain mainstay therapy as despite their problems they are best suited to deal with the original pathogenic triumvirate theory for T2DM proposed by Ralf Defranzo, (qualitative and quantitative beta cell failure and insulin resistance at level of liver and peripheral tissue). This was particularly true since there was no agent that could help improve health of the beta cell and cause insulin release in a glucose dependant manner. This all changed once it was learnt that the incretin system was involved in the pathogenesis of T2DM. Failure of this incretin system has been implicated in progression of beta-cell failure and therefore any therapy that can augment this system has been shown to promote beta cell health and insulin release in a glucose-dependent manner. [1],[2],[3],[4],[5]

Although the use of metformin therapy has been associated with several advantages (non-hypoglycemic, weight-loss promoting, anti-ischemic to cardiac tissue, improvement in non-alcoholic hepatosteatosis, anti-neoplastic etc), its use has been associated with gastrointestinal adverse effects, precluding or limiting its use, particularly in the non-overweight patient. [2],[6] Use of SU's on the other hand although effective in lowering plasma glucose can be associated with variable severities of hypoglycemia, weight gain, beta-cell death, and possibly adverse cardiac outcomes as proposed originally by the UKPDS and later by other groups. [2],[7]

The UKPDS was the first to show that the combination of SU and metformin resulted in a progressive decline in [beta]-cell function and by 3 years up to 50% of diabetic patients can require an additional pharmacological agent to maintain the glycosylated hemoglobin (HbA1c) <7.0%. [2],[5] Moreover, the percentage of diabetic patients classified as adequately controlled while mostly on these therapies still remains a challenge with a majority (> 50%) of diabetic patients having a HbA1c > 7%. [8] From the above data it seems clear that existing popular therapies are not only ineffective but are associated with a significant amount of morbidity (weight gain and hypoglycemia). The need of the hour is a refreshing class of drugs whose effects on hyperglycemia can be sustained, without adversely affecting the survival of beta-cells, and are weight neutral and free of hypoglycemia, a true class of anti-hyperglycemics, a dream too good to be true. GLIPTINS might just fulfill that dream.

Pathogenesis of type 2 diabetes mellitus

The natural history of T2DM as proposed originally of Ralph Defranzo (triumvirate theory) involved [9] :

  1. Insulin resistance at level of liver resulting in hepatic outpouring of glucose into the hepatic venous system
  2. Insulin resistance at peripheral tissue (skeletal muscles) resulting in inability in uptake of glucose
  3. Beta-cell failure (five stages) resulting in declining insulin secretion capacity [1]

Beta cells failure can be described in five stages:

Stage 1: Beta-cell compensation, where the beta cell mass increases. This causes increased basal insulin release so that plasma glucose can be kept within the normal range. This beta-cell compensation occurs because of increasing insulin resistance (obesity and genetic factors). At this stage, people are usually obese with normal glucose tolerance and reduced insulin sensitivity by approximately 29%. It has been shown that 66% of beta-cell function is lost when the 2-hour post-meal plasma glucose is between 120 and 139 mg/dl (normal glucose tolerance) suggesting that beta cell dysfunction starts very early .

Stage 2: Beta-cell adaptation, where in plasma glucose although higher than at stage 1 is associated with normal glucose tolerance, at the cost of increased workload. This stage is associated with a further decline in insulin sensitivity by 28% (as age advances and obesity worsens).

Stage 3: Beta-cell decompensation, where in glucose levels rise relatively rapidly. At this stage, 80% of [beta]-cell function is lost. Fasting hyperglycemia of approximately 140-200 mg/dl can result from basal hepatic glucose production of ~0.5 mg/kg/min due to associated insulin resistance. The liver of an 80-kg diabetic can add as much as 35 g of glucose to the systemic circulation following an overnight fast. [9],[10],[11]

Stage 4: Beta-cell decompensation (stable), once the plasma glucose rises it stays relatively stable.

Stage 5: Beta-cell failure, marked by severe hyperglycemia and progression to ketosis. [1],[2],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34]

Declining beta-cell function is the epitome phenomenon of worsening hyperglycemia over time. [2],[4],[25] Secretagogues (SU) have been shown to expedite beta-cell dysfunction. Defranzo in the Banting ADA lecture (2009) showed that after an initial decline of glycosylated hemoglobin (between 0.5% and 1.8%) in various studies using SU's (glyburide, glimerperide, gliclazide) time to failure of therapy (return of glycosylated hemoglobin to baseline) occurred as early as 1-2 years with glimerperide and 5-10 years with other SU's. [2] SU's have been shown to expedite beta-cell failure and induce apoptosis at rates greater by two- to

fourfold. [24],[35] Up to 80% of patients while on SU's, loose control of diabetes with need for insulin therapy, due to beta-cell exhaustion. [2]

Based on data from the UKPDS [25] and Weir [2] by the time patient develops impaired glucose tolerance, between 50% and 66% of [beta]-cell function is lost. Between 75% and 80% of beta-cell function is lost once hyperglycemia fulfilling the definition of diabetes mellitus develops. After 10-15 years of diabetes duration <10% of endogenous insulin is present and exogenous insulin therapy becomes necessary.

It therefore makes sense that a paradigm shift to newer therapies is required that can help conserve beta-cell function. Until a few years ago only thiazolidinedione (TZD) therapy was shown to conserve beta-cell function [26],[27] apart from its overwhelming insulin sensitizing benefits (at the level of liver and periphery/skeletal muscle). Incretin-based therapies have been shown to outscore all other anti-diabetic therapies in that regard. Any therapeutic strategy that helps improve plasma incretin concentration following a carbohydrate meal, improves beta-cell function (increased insulin biosynthesis and secretion). It has also been shown by some studies that improvement in beta-cell health occurs more following a morning meal compared to an afternoon meal. [30]

From the triumvirate theory, Ralf Defranzo in the Banting and Best Lecture at the 2009 American Diabetes Association suggested there is much more to the pathogenesis of T2DM and proposed the "ominous octet." [1],[2],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34]

Lipotoxicity (disharmonious quartet, fourth component)

Fat cells are resistant to the insulin's anti-lipolytic effect resulting in increased plasma free fatty acids (FFA). Increased FA have been shown to competitively inhibit insulin-mediated glucose uptake, transport and metabolism in muscle and liver, stimulate hepatic glucose production, impair first and second phases of insulin release, and reduce insulin secretory rate. [12],[13]

Incretin (quintessential quintet, fifth component)

Glucose disposal is more efficient following an oral glucose meal as compared to an intravenous glucose infusion. This led some scientists to believe that the gastrointestinal tract was responsible for release of hormones that aided in glucose disposal. This theory was entertained more than 100 years ago. [14],[15],[16],[17],[18],[19] These hormones were later identified as gut derived "incretins" (glucagons like peptide {GLP-1}and gastric insulotropic peptide {GIP}) which are responsible for > 99% of this incretin effect (enhanced glucose disposal following oral load). Out of the two hormones it is GLP-1 that is the more active peptide in human beings. Patients with T2DM experience a blunting or even total loss of this incretin effect. Amplification of this incretin effect forms the basis of several incretin-based therapies. [14],[15],[16],[17],[18],[19]

GIP is secreted by neuro-endocrine K-cells present in stomach and proximal small intestine. It has an amino acid sequence that is highly conserved across species, with over 90% homology. It has a half life of approximately 7 min in healthy individuals and 5 min in patients with T2DM. GIP is cleared through the kidney.

GLP-1 is a peptide that is secreted by neuro-endocrine L-cells present in the distal small intestine. GLP-1 circulates as two equipotent forms, GLP1 7-37 and GLP1 7-36 amide. GLP-1 (7-36) constitutes 80% of circulating GLP-1. The half-life of circulating native bioactive GLP1 is less than 2 min mostly because it is cleared by the kidney and degraded by dipeptidyl peptidase (DPP)-4. DPP-4 represents a single polypeptide chain of 766 amino acids and consists of four domains: an N-terminal cytoplasmic domain, a trans-membrane domain, an [alpha]/[beta]-hydrolase domain, and a [beta]-propeller domain. It is also called adenosine deaminase (ADA) binding protein, or CD26 (T-cell activation antigen). [14],[15],[16],[17],[18],[19],[31]

GIP and GLP-1 have distinct yet overlapping actions and act through specific G-protein receptor complexes, gastric inhibitory peptide receptor (GIP-R), and GLP-1 receptor (GLP-1R), respectively. Both GLP-1 and GIP are susceptible to cleavage at amino-terminus, position 2 (alanine), by the DPP-4. DPP-4 is a type II membrane peptidase resembling CD26 (marker of activated T-lymphocyte). It is the canonical representative of a family of genetically related peptidases. The DPP-4 gene family includes four enzymes DPP-4, DPP-8, DPP-9, fibroblast activation protein (FAP) and catalytically inactive proteins DPP-6 and DPP-10. DPP-4 has a widespread organ distribution (liver; gut; endothelial capillaries; acinar cells of mucous and salivary glands, pancreas; uterus; and immune organs such as thymus, spleen and lymph node) with the highest levels found in the kidney. DPP-4 regulates the activity of secretory hormones glucagon-like peptide (GLP)-1, and glucose-dependent insulinotropic peptide (GIP) to maintain glucose homeostasis (enhanced insulin secretion and glucagons suppression), thereby improving post-prandial and fasting hyperglycemia. [14],[18],[19],[29] Other physiological substrates of DPP-4 include neuropeptide-Y (NPY) (role in appetite, energy homeostasis, and blood pressure control), substance P (role in pain and inflammation). [33]

DPP-8 and DPP-9 enzyme levels are less well studied compared to DPP-4. Although DP8 and DP9 have no confirmed physiological substrates there is a growing body of evidence to suggest that they are actively involved in healing processes (skin, liver etc), play an important role in immune function (cleave chemokines), and hematopoiesis. They have been shown to predominate over DPP-4 in testis and brain tissue and have a wide area of organ distribution (gastrointestinal tract, skin, lymph node, spleen, liver and lung, as well as in pancreatic acinar cells, adrenal gland, spermatogonia and spermatids of testis, and in Purkinje cells and in the granular layer of cerebellum). Unlike DPP4, DPP8/9 are intracellular proteases responsible for T-cell activation and therefore off-target inhibition by selective DPP4 inhibitors can cause undesirable and serious side-effects (immune dysfunction, impaired healing, reticulocytopenias, skin manifestations). [33],[34]

Following secretion, GLP-1 and GIP are both rapidly degraded by DPP-4. GLP-1 is degraded even before leaving the gut because of the presence of DPP-4 molecules anchored to the luminal surface of the endothelial cells of the mucosal capillaries. GIP is less susceptible to DPP-4 and leaves the gut un-degraded.

Hyperglucagonemia (setaceous sextet, sixth component)

The sixth member in the pathogenesis of T2DM is the pancreatic [alpha]-cell. Glucagon being a counter regulatory hormone contributes to fasting hyperglycemia via enhanced hepatic glucose production (neoglucogenesis) and to some extent via glycogenolysis. There is evidence that the liver may be hypersensitive to the stimulatory effect of glucagon. The incretins, particularly GLP-1, functions by augmenting insulin secretion and suppressing glucagon, thereby reducing post-prandial and fasting hyperglycemia. GIP on the other hand, although complementary to GLP-1 with regards insulin secretion, may antagonize GLP-1-mediated glucagon suppression. [2],[20],[22],[23]

Kidney (septicidal septet, seventh component)

The seventh member in the pathogenesis of T2DM is the kidney. It filters approximately 162 g of plasma glucose of which 90% is reabsorbed by the high capacity SGLT2 (sodium-glucose like transporter type 2) transporter in the proximal convoluted and 10% is reabsorbed from the descending proximal tubule. Diabetic patients exhibit markedly up-regulated SGLT2 mRNA resulting in greater glucose reabsorption contributing to hyperglycemia so its exact importance in humans in not really known. [2],[21]

Brain (ominous octet, eighth component)

The eighth member implicated in the pathogenesis of type 2 diabetes is the brain. GLP-1 is synthesized in the caudal part of the nucleus of the solitary tract and its receptors are widespread throughout the brain, particularly in the paraventricular nucleus of hypothalamus. The hypothalamus is the centre of feeding and satiety and it only seems logical that GLP-1 potentiation via any means will influence these responses of feeding. It has been shown that GLP-1 augmentation results in an anorexigenic effect. This occurs directly via its influence on the hypothalamus and indirectly via taste receptors. Humans GLP-1 is found in mammalian taste cells (type 2 and type 3). The weight loss observed with GLP receptor agonists have been associated with reduction in food intake and weight loss in rats. It has also been seen that GLP-1 helps modulate taste sensation, which might help with the possible anorexigenic effect of GLP-1 potentiation strategies. Obese subjects with T2DM have been associated with increased appetite, accounting for the usefulness of GLP-1 augmentation in this subset of patients. [2],[36],[37],[38]

   What Should be the Ideal Anti-Hyperglycemic Drug? Top

From the above pathogenetic discussion it would only seem logical that one chooses therapy that seems to address the ominous octet ie. a drug that can improve beta-cell health (TZD, incretin bases therapies {GLP analogues, DPP-4 inhibitors/Gliptins}, biguanides, alfa-glucosidase inhibitors), improve insulin resistance (biguanides, TZD's, possibly incretin based therapies) suppress glucagon secretion (incretin based therapies), suppress appetite (GLP-1 analogues, biguanides), improve lipid health (TZD), and suppress renal glucose reabsorption. The drug combination that seems most logical is incretin-based therapies (addressing 4 out of the 8 pathophysiological mechanisms) with biguanide (metformin) or TZD (addressing insulin resistance at liver and skeletal muscle). [2],[26],[27],[39]

   Dipeptidyl Peptidase-4 Inhibitors (Gliptins) Top

This new class of anti-diabetic agents seems like they have revolutionized the treatment of diabetes. Although various DPP-4 inhibitors have different pharmacokineic and pharmodynamic profiles, they are remarkably similar with regards anti-hyperglycemic properties with a very safe adverse effect profile (weight neutral without causing hypoglycemia).

A list of available and expected gliptins are as follows:

  • Sitagliptin (Merck Sharp and Dohme Corp, approved as Januvia by US FDA in year 2006)
  • Vidagliptin (Novartis, approved as Galvus by EU in year 2007)
  • Saxagliptin (Bristol-Myers Squibb, approved as Onglyza by US FDA in 2010)
  • Linagliptin (Boerhinger Ingelheim, approved as Tradjenta by US FDA in year 2011)
  • Alogliptin (developed by Takeda Pharmaceutical Company Limited, approved for use in Japan)
  • Dutogliptin (being developed by Phenomix Corporation)
  • Gemiglaptin (being developed by LG Life Sciences)
  • (Sitagliptin, Vidagliptin, Saxagliptin-are-approved-for-use-in-India)

The DPP-4 inhibitors based on their structure can be divided into those that mimic the DPP-4 molecule (peptidomimetics, vildagliptin and saxagliptin) and those that do not (non-peptidomimetics, sitagliptin, alogliptin, linagliptin) as shown in [Table 1] and [Table 2]. They are competitive reversible inhibitors of the DPP-4 substrate acting extra-cellularly. The molecules have varying affinities toward the DPP-4 substrate [Table 3]. In general, the peptidomimetics have lesser selectivity toward DPP-4 compared to DPP8/9. Lesser the relative selectivity toward DPP-4 and greater the relative inhibition of DPP8/9 greater is the possibility of side effects (allergic skin manifestations etc). [14],[15],[16],[17],[18],[28],[29],[30],[31],[32],[33],[34],[40],[41],[42],[43]
Table 1: Pharmacokinetic profile of DPP-4 inhibitors/gliptins[14-18,28-34,40-43]

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Table 2: Pharmacokinetic profile continued[14-18,28-34,40-43]

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Table 3: DPP-4 inhibitor in vitro selectivity, (fold selectivity for DPP-4 vs. other enzymes)[14-18,28-34,40-43]

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The mechanism of DPP-4 inhibition differs from peptidomimetics (vildagliptin, saxagliptin) compared to non-peptidomimetics (sitagliptin, alogliptin, linagliptin). Non-peptidomimetics form non-covalent extra-cellular interactions with residues in the catalytic site of the DPP-4 substrate, thereby resulting in potent, immediate inhibition. In contrast, inhibition of the DPP-4 substrate by peptidomimetics occurs in a manner that involves formation of a reversible covalent enzyme-inhibitor complex. This complex binds and dissociates from the catalytic site of the DPP-4 substrate very slowly resulting in persistent DPP-4 inhibition even after the drug has inactivated. This means that the catalytic activity remains inhibited even after the free drug has been cleared from the circulation and may help to explain why vildagliptin and saxagliptin inhibit DPP-4 activity for longer than their relatively short half-lives would suggest. DPP-4 inhibition by the specific DPP-4 inhibitors occurs extracellularly. Because the inactivation is extra-cellular the functioning of major intracellular proteins is preserved, accounting for the lack of immune dysfunction that could have otherwise resulted, should they have been affected. [14],[15],[16],[17],[18],[28],[29],[30],[31],[32],[33],[34],[40],[41],[42],[43]

The pharmocokinetic profile of the drugs are mentioned in [Table 1] and [Table 2]. DPP-4 inhibitor in vitro selectivity, (fold selectivity for DPP-4 vs. other enzymes) has been mentioned in [Table 3].

   Efficacy Data Common to Gliptins Top

As "monotherapy"

Fasting glycemia reduction - approximately 18 mg/dl (10 - 35 mg/dl)

Post-prandial glycemia reduction - approximately 25 mg/dl (20 - 60 mg/dl)

HbA1c reduction - approximately 0.75% (0.4 - 1.2%)

When compared to metformin, SU (glimerperide, glipizisde), thiazolidinediones (rosiglitazone, pioglitazone), and alfa-glucosidase inhibitors (voglibose), the use of gliptin has shown to be equally efficacious and non-inferior. When compared to SU the incidence of hypoglycemia was near negligible with the added advantage of being weight neutral. [44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58]

A meta-analysis comparing the efficacy of sitagliptin versus vildagliptin showed that the overall HbA1c reduction was ~0.74% and 0.73%, respectively. The glycemic outcomes were better if the initial HbA1c was higher >9% versus <8%. [40]

A recent meta-analysis suggested that using a gliptin (vildagliptin, sitagliptin, saxagliptin or alogliptin) in patients with T2DM was associated with a greater proportion of patients achieving their HbA1c goal of <7%, without any weight gain or hypoglycemia. [41]

As "add on therapy to metformin"

Data suggests that when a gliptin is added onto patients inadequately controlled with metformin there results a substantial improvement in HbA1c (range 0.50 - 0.75%) with as many twice as number of patients achieving an HbA1c of <7% compared to metformin alone. Furthermore, for the first time data has suggested that in patients with HbA1c between 7% and 8% while on metformin therapy, rather than optimizing the dose of metformin from 1 to 2 gm/day or greater, as most existing guidelines suggest, by adding a gliptin to an already existing dose of metformin the degree of HbA1c reduction is greater (additional HbA1c - 0.7% benefit) than that achieved by up-titrating the dose of metformin (additional HbA1c - 0.3% benefit), with far greater number of patients achieving HbA1c target of <7%..

The use of a gliptin compared to an SU as second line therapy added onto patients inadequately controlled on metformin therapy, provided non-inferiority data for use of gliptin suggesting that it might replace the use of traditionally used SU in the future. [5],[50],[52],[56],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67]

As "add on therapy to sulfonyureas"

Since the use of gliptin has shown to improve beta-cell health and promote insulin secretion in a glucose-dependent fashion, the concomitant use of SU can potentially be complicated by hypoglycemia. It is therefore suggested that the minimum possible dose of SU be started along with use of gliptin. If the patient is already on an SU and addition of gliptin is considered, the dose of SU should be halved and then up-titrated as required. Gliptins have been shown to non-inferior in efficacy to SU (glipizide, glimeperide, gliclazide) with the added advantage of being weight neutral and being virtually free of hypoglycemia. Whether compared head to head with an SU (HbA1c reduction of approximately 0.8% in both groups) or added to an SU (further HbA1c reduction of approximately a gliptin was found to be effective (HbA1c reduction 0.5-0.8%) with significantly greater number of patients achieving the HbA1c of <7%. [1],[63],[68],[69],[70],[71],[72],[73]

As add "on therapy to thiazolidinedione"

The addition of a gliptin to TZD therapy in patients inadequately controlled have been associated with average HbA1c reduction of approximately 0.7-1%. On the other hand, the use of gliptin along with TZD in drug-naïve T2DM patients has been shown to reduce HbA1c by up to 2% after 24 weeks, compared with 1.1% with pioglitazone monotherapy. Besides the reduction in HbA1c there have been other beneficial effects seen with this combination such as improvement in inflammatory markers, beta-cell health (homeostasis model assessment-beta-cell, HOMA-beta and pro-insulin/insulin ratio) and markers of insulin resistance (homeostasis model of insulin resistance, homeostasis model assessment-IR). This combination has however been plagued by an average weight gain of 2.5 - 5 kg and peripheral edema. The weight gain can however be dealt with a comprehensive lifestyle-weight-management program. [61],[64],[70],[73],[74],[75],[75],[76],[77],[78],[79],[80]

As "add on therapy to insulin"

The addition of gliptin to insulin (long-acting, intermediate-acting insulin or premixed) has been associated with an additional HbA1c reduction of approximately 0.6%. A greater proportion of patients were seen to achieve HbA1c level < 7. Fasting plasma glucose improved by approximately 15.0 mg/dl (0.8 mmol/l) and 2-h post-meal glucose improved by approximately 36.1 mg/dl (2.0 mmol/l). The presumed improvement in glycemia is because of improvement in beta-cell health and suppression of glucagon predominantly. [81],[82],[83],[84]


This is the first gliptin to be US FDA approved (October 2006). The recommended dose is 100 mg once a day. Its absorption is unaffected by food. For patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min) the recommended dose is 50 mg/day and for severe renal impairment (creatinine clearance is <30 mL/min) the recommended dose is 25 mg/day. In a meta-analysis [40] it was shown to be more effective at reducing fasting blood sugar compared to vildagliptin, but overall efficacy was similar. For patients with hepatic impairment no change in dose is recommended for Childs grade A or B, however for Child grade C sitagliptin use in not recommended. The Asian study (China India Korea study) suggested that sitagliptin was more effective in the Indian population with greater HbA1c reductions of approximately 1.3% compared to placebo. Recent data is emerging that in addition to improving beta-cell health, DPP-4 inhibitors also help improve insulin resistance and plasma levels of triglyceride-rich lipoproteins of both intestinal and hepatic origin (cardiovascular benefit). [14],[15],[16],[18],[28],[29],[32]


This is the second gliptin to be approved for commercial use although still not US FDA approved. The recommended dose is 50 mg twice a day. Its absorption is unaffected by food. It is extensively metabolized by the liver and has >90% bioavailability following a single oral dose. No dosage adjustment is required for liver disease although a greater amount of inactive metabolites (30% greater) are retained in patients with severe liver disease (Childs grade C). In patients with renal impairment no dose adjustment is required for mild renal insufficiency however for moderate renal insufficiency half the recommended dose of 50 mg is suggested. [14],[15],[16],[18],[28],[29],[32],[47]


This is the third gliptin to be approved for commercial use, and US FDA approved. The recommended dose is 5 mg once a day. Its absorption is unaffected by food. Saxagliptin is metabolized mainly by cytochrome P450 (CYP) 3A4 to a major active monohydroxylated metabolite, 5-hydroxy saxagliptin which is half as potent as saxagliptin. Approximately 75% of the total dose of saxagliptin is renally excreted (comprising 24% saxagliptin, 36% 5-hydroxy saxagliptin and minor metabolites of saxagliptin), while 22% of a saxagliptin dose was eliminated in the feces, mainly as metabolites. One-half the usual dose of saxagliptin 5 mg (i.e. 2.5 mg orally once daily) is recommended for patients with moderate (CLCR 30-50 mL/min) or severe (CLCR<30 mL/min not on dialysis) renal impairment or ESRD, but no dose adjustment is recommended for those with mild renal impairment or any degree of hepatic impairment. [14],[15],[16],[18],[28],[29],[32],[51],[52]


Linagliptin is a new agent in the DPP-4 inhibitor class that is currently undergoing regulatory review in Japan, the EU, and the USA. It is recommended in the dose of 5 mg once a day. It has a favorable pharmacokinetic profile has a potential advantage over currently approved gliptins in that it primarily undergoes non-renal elimination. Linagliptin is predominantly excreted via the enterohepatic system, with 84.7% of the drug eliminated in the feces and only 5% eliminated via the urine. It therefore appears to be safe in patients with renal failure. [15],[16],[18],[28],[29],[32],[54]

Linagliptin has been shown to hasten wound healing in preclinical studies with evidence of improvement in wound re-epithelialization. [56]


Alogliptin is a dipeptidyl peptidase-4 inhibitor that is approved in Japan for the treatment of adult patients with T2DM. It is recommended in the dose of 25 mg once a day. It is unaffected by food. Its predominant route of excretion is the kidneys. Caution must be used in patients with renal impairment with need for appropriate dose adjustments. As most of it is eliminated through the kidney, it is unlikely that hepatic impairment will affect its dosage. [14],[15],[16],[18],[28],[29],[32]

Adverse effects

Dipeptidyl peptidase 4 inhibitors were generally well tolerated in most studies. Adverse reactions have been associated with non-selective inhibition of other members of the DPP-4 gene family (DPP-8/9). Since DPP-4/CD26 is a marker of activated T-cell, initial concerns were related to immune dysfunction associated with DPP-4/CD26 inactivation. DPP-4 inactivation by a gliptin occurs extra-cellularly in comparison to DPP-8/9 which is intracellular. As long as other members of the DPP-4 gene family remain un-affected immune dysfunction is not seen. [14],[15],[16],[18],[28],[29],[32],[57]

Their strength lies in the fact that they are weight neutral and do not cause any significant hypoglycemia. A meta-analysis [40] suggested an increased risk of nasopharyngitis (6.4% for DPP4 inhibitor {sitagliptin>vildagliptin} vs. 6.1% for comparator) headache (5.1% for DPP4 inhibitor (vildagliptin>sitagliptin} vs 3.9% for comparator), urinary tract infection (3.2% for DPP4 inhibitor {sitagliptin = vildagliptin} vs 2.4% for comparator). Although rare an increased incidence of extremity pain was seen with DPP-4 inhibitors. No increased incidences in gastro-intestinal side-effects were observed. Saxagliptin use has been linked with a reduction in lymphocyte count. [14],[15],[16],[18],[28],[29],[32],[57]

No significant drug-drug interaction has been reported with DPP-4 inhibitors, except for saxagliptin where caution needs to be exercised when used along with drugs metabolized by hepatic CYP3A4/5 system (atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). They are otherwise safe to use with commonly used anti-hyperglycemics (TZD, SU), anti-hypertensives, anti-hyperlipidemics, antibiotics, digoxin, warfarin, etc. [14],[15],[16],[18],[28],[29],[32],[57]

The US FDA issued a warning in 2007 of risk of pancreatitis with use of drugs acting on the incretin system, following reports of pancreatitis with use of GLP-1 analogues (http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm079781.htm). Post-marketing surveillance has identified isolated rare cases of pancreatitis with use of DPP-4 inhibitors. No direct cause and effect relationship has been found though between the two. It must be emphasized that diabetes and hypertriglyceridemia are itself independent risk factors for development of pancreatitis and an analysis of a US healthcare database showed that rates of pancreatitis with exenatide or sitagliptin were no different from metformin or glyburide. [85]

In preclinical studies an increased risk of medullary carcinoma of the thyroid was seen however as human thyroid has a low expression of GLP-1 receptors unlike the mice it is not surprising that it appears to be safe in human

beings. [86],[87]

Although clinical studies with DPP-4 inhibitors havn't shown any adverse skin reaction, post-marketing survellance programs have suggested isolated rare cases of serious hypersensitivity skin reactions including Stevens-Johnson syndrome. [88]

Although not approved for use in cardiovascular patients there is some suggestion that DPP-4 inhibitors like GLP-1 analogues have a cardiovascular friendly profile Preclinical studies have suggested endothelial benefit, anti-atherosclerotic effects [89] and blood pressure lowering effects. [90] Several large cardiovascular outcome trials are currently underway which will specifically address the impact of the incretin-based therapies on macrovascular risk.

For patients with hepatic insufficiency except for vildagliptin no dose adjustment is necessary for gliptins. Vildagliptin is not recommended for patients with alanine aminotransferase or aspartate aminotransferase more than three times the upper limit of normal. [32],[91],[92]

For patients with renal insufficiency, sitagliptin, vildagliptin, and saxagliptin can be used in patients with mild renal insufficiency without dose adjustment; however only sitagliptin and saxagliptin can be used in patients with moderate or severe renal insufficiency. In the European Union, however sitagliptin and saxagliptin is not currently recommended for use in patients with more moderate or severe renal impairment. Linagliptin appears to be safe in renal insufficiency. [32],[47],[61],[92],[93],[94]

   Current Position of Gliptins in Diabetes Management Guidelines Top

The American Diabetes Association (ADA), American Association of Clinical Endocrinologists (AACE), European Society, and NICE (UK) guidelines suggest that gliptins should be considered over other anti-diabetic therapies especially if the patient is experiencing an increased incidence of hypoglycemias and/or weight gain. It is clear that even major guidelines appreciate their usefulness with the only apprehension being that they haven't withstood the test of time and therefore classified under less well-validated therapies. As data emerges suggesting sustained anit-hyperglycenic benefits they should replace current practices that include popular use of SU +/- insulin as second and third line agents to metformin. [95],[96],[97]

Current indications for use of gliptins are:

  1. First line in T2DM with HbA1c <7%
  2. Second line as add-on therapy in T2DM patients already on 1 out of the following {metfromin, SU, TZD, alfa-glucosidase inhibitor, miglitinide})for uncontrolled T2DM with HbA1c >7%
  3. Third line as add-on therapy in T2DM patients already on combination therapy (2 out of the following {metfromin, SU, TZD, alfa-glucosidase inhibitor, miglitinide)

Contraindications or indication for stopping gliptin therapy includes previous or current adverse reaction to gliptins (hypersensitivity) or failure to achieve an HbA1c reduction of greater than 0.5% over a 6 month period. [95],[96],[97]

   Conclusions Top

Gliptins have revolutionized the concept of diabetes management and have provided a breath of fresh air to healthcare professionals dealing with diabetes. They provide an effective and safe alternative to the management of diabetes. Shown to reduced HbA1c from 0.5 to up to 2% effectively and safely (weight neutral without any if at all hypoglycemia) this new class of drugs is here to stay. Even major diabetes management guidelines have acknowledged them for their safe adverse effect profile and urge healthcare professionals to use gliptins should they be struggling with regards weight or hypoglycemias with their patients. Recently, plagued with issues such as pancreatitis and cancer, these drugs need to stand the test of time and should they emerge victorious they will represent the only class of drugs that help improve beta-cell health, addressing the original triumvirate pathogenetic theory proposed for T2DM.

   References Top

1.Weir GC, Bonner-Weir S. Five stages of evolving [beta]-cell dysfunction during progression to diabetes. Diabetes 2004;53 Suppl 3:S16-21.  Back to cited text no. 1
2.Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773-95.  Back to cited text no. 2
3.Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: Progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999;281:2005-12.  Back to cited text no. 3
4.Bell DS. A Comparison of agents used to manage type 2 diabetes mellitus: Need for reappraisal of traditional approaches. Treat Endocrinol 2004;3:67-76.  Back to cited text no. 4
5.Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, et al. Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2006;29:1963-72.  Back to cited text no. 5
6.DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 1995;333:541-9.  Back to cited text no. 6
7.UKPDS 28: A randomized trial of efficacy of early addition of metformin in sulfonylurea-treated type 2 diabetes. U.K. Prospective Diabetes Diabetes Study Group. Diabetes Care 1998;21:87-92  Back to cited text no. 7
8.Koro CE, Bowlin SJ, Bourgeois N, Fedder DO. Glycemic control from 1988 to 2000 among U.S. adults diagnosed with type 2 diabetes: A preliminary report. Diabetes Care 2004;27:17-20.  Back to cited text no. 8
9.DeFronzo RA. Lilly Lecture 1987. The triumvirate: beta cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988;37:667-87.  Back to cited text no. 9
10.DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in non-insulin dependent diabetes mellitus. J. Clin Invest 1985;76:149-55.  Back to cited text no. 10
11.DeFronzo RA, Ferrannini E. Regulation of hepatic glucose metabolism in humans. Diabetes Metab Rev 1987;3:415-9.  Back to cited text no. 11
12.Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 1995;44:863-70.  Back to cited text no. 12
13.Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;1:785-9.  Back to cited text no. 13
14.Drucker DJ. The biology of incretin hormones. Cell Metab 2006;3:153-65.  Back to cited text no. 14
15.Drucker DJ, Nauck MA. The incretin system: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696-705.  Back to cited text no. 15
16.Meier JJ, Nauck MA. Incretins and the development of type 2 diabetes. Curr Diab Rep 2006;6:194-201.  Back to cited text no. 16
17.Moore B. On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane. Biochem J 1906;1:28-38.  Back to cited text no. 17
18.Holst JJ. The physiology and pharmacology of incretins in type 2 diabetes mellitus. Diabetes Obes Metab 2008;10 Suppl 3:14-21.  Back to cited text no. 18
19.Pitman MR, Menz RI, Abbott CA. Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DP8). Biol Chem 2010;391:959-72.  Back to cited text no. 19
20.Baron AD, Schaeffer L, Shragg P, Kolterman OG. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 1987;36:274-83.  Back to cited text no. 20
21.Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005;54:3427-34.  Back to cited text no. 21
22.Mentis N, Vardarli I, Köthe LD, Holst JJ, Deacon CF, Theodorakis M, et al. GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes. Diabetes 2011;60:1270-6.  Back to cited text no. 22
23.Hare KJ, Vilsbøll T, Asmar M, Deacon CF, Knop FK, Holst JJ. The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action. Diabetes 2010;59:1765-70.   Back to cited text no. 23
24.Sawada F, Inoguchi T, Tsubouchi H, Sasaki S, Fujii M, Maeda Y, et al. Differential effect of sulfonylureas on production of reactive oxygen species and apoptosis in cultured pancreatic beta-cell line, MIN6. Metabolism 2008;57:1038-45.  Back to cited text no. 24
25.UK Prospective Diabetes Study 16: Overview of 6 years' therapy of type II diabetes: a progressive disease. UK Prospective Diabetes Study Group. Diabetes 1995;44:1249-58.  Back to cited text no. 25
26.Finegood DT, McArthur MD, Kojwang D, Thomas MJ, Topp BG, Leonard T, et al. Beta-cell mass dynamics in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death. Diabetes 2001;50:1021-9.  Back to cited text no. 26
27.Porter LE, Freed MI, Jones NP. Rosiglitazone improves [beta]-cell function as measured by proinsulin/insulin ratio in patients with type 2 diabetes [abstract]. Diabetes 2000;49 Suppl. 1:A122.  Back to cited text no. 27
28.Deacon CF. DPPIV and diabetes. Clin Chem Lab Med 2008;46:A18.  Back to cited text no. 28
29.Martin JH, Deacon CF, Gorrell MD, Prins JB. Incretin-based therapies - review of the physiology, pharmacology and emerging clinical experience. Intern Med J 2011;41:299-307.  Back to cited text no. 29
30.Lindgren O, Mari A, Deacon CF, Carr RD, Winzell MS, Vikman J, et al. Differential islet and incretin hormone responses in morning versus afternoon after standardized meal in healthy men. J Clin Endocrinol Metab 2009;94:2887-92.  Back to cited text no. 30
31.Rasmussen HB, Branner S, Wiberg FC, Wagtmann N. Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat Struct Biol 2003;10:19-25.  Back to cited text no. 31
32.Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: A comparative review. Diabetes Obes Metab 2011;13:7-18.  Back to cited text no. 32
33.Yu DM, Yao TW, Chowdhury S, Nadvi NA, Osborne B, Church WB, et al. The dipeptidyl peptidase IV family in cancer and cell biology. FEBS J 2010;277:1126-44.  Back to cited text no. 33
34.Lankas GR, Leiting B, Roy RS, Eiermann GJ, Beconi MG, Biftu T, et al. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: Potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes 2005;54:2988-94.  Back to cited text no. 34
35.Maedler K, Carr RD, Bosco D, Zuellig RA, Berney T, Donath MY. Sulfonylurea induced beta-cell apoptosis in cultured human islets, J Clin Endocrinol Metab 2005;90:501-6.  Back to cited text no. 35
36.Larsen PJ, Tang-Christensen M, Jessop DS. Central administration of glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat. Endocrinology 1997;138:4445-55.  Back to cited text no. 36
37.Jin SL, Han VK, Simmons JG, Towle AC, Lauder JM, Lund PK. Distribution of glucagonlike peptide I (GLP-I), glucagon, and glicentin in the rat brain: An immunocytochemical study. J Comp Neurol 1988;271:519-32.  Back to cited text no. 37
38.Egan JM, Margolskee RF. Taste cells of the gut and gastrointestinal chemosensation. Mol Interv 2008;8:78-81.  Back to cited text no. 38
39.Marchetti P, Del Guerra S, Marselli L, Lupi R, Masini M, Pollera M, et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab 2004;89:5535-41.  Back to cited text no. 39
40.Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: Systematic review and meta-analysis. JAMA 2007;298:194-206.  Back to cited text no. 40
41.Esposito K, Cozzolino D, Bellastella G, Maiorino MI, Chiodini P, Ceriello A, et al. Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. Diabetes Obes Metab 2011;13:594-603.  Back to cited text no. 41
42.Scheen AJ. Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab 2010;12:648-58.  Back to cited text no. 42
43.Kim D, Wang L, Beconi M, Eiermann GJ, Fisher MH, He H, et al. (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl) butan-2-amine: A potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 2005;48:141-51.  Back to cited text no. 43
44.Mohan V, Yang W, Son HY, Xu L, Noble L, Langdon RB, et al. Efficacy and safety of sitagliptin in the treatment of patients with type 2 diabetes in China, India, and Korea. Diabetes Res Clin Pract 2009;83:106-16.  Back to cited text no. 44
45.Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006;49:2564-71.  Back to cited text no. 45
46.Barzilai N, Guo H, Mahoney EM, Caporossi S, Golm GT, Langdon RB, et al. Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial. Curr Med Res Opin 2011;27:1049-58.  Back to cited text no. 46
47.Keating GM. Vildagliptin: A review of its use in type 2 diabetes mellitus. Drugs 2010;70:2089-112.  Back to cited text no. 47
48.Balas B, Baig MR, Watson C, Dunning BE, Ligueros-Saylan M, Wang Y, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab 2007;92:1249-55.   Back to cited text no. 48
49.Pi-Sunyer FX, Schweizer A, Mills D, Dejager S. Efficacy and tolerability of vildagliptin monotherapy in drug-naïve patients with type 2 diabetes. Diabetes Res Clin Pract 2007;76:132-8.  Back to cited text no. 49
50.Göke B, Hershon K, Kerr D, Calle Pascual A, Schweizer A, Foley J, et al. Efficacy and safety of vildagliptin monotherapy during 2-year treatment of drug-naïve patients with type 2 diabetes: comparison with metformin. Horm Metab Res 2008;40:892-5.  Back to cited text no. 50
51.Rosenstock J. Clinical overview of saxagliptin for Type 2 diabetes management. Expert Rev Endocrinol Metab 2010;5:809-23.  Back to cited text no. 51
52.Dhillon S, Weber J. Saxagliptin. Drugs 2009;69:2103-14.  Back to cited text no. 52
53.Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R, et al. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin 2009;25:2401-11.  Back to cited text no. 53
54.Scott LJ. Linagliptin: In type 2 diabetes mellitus. Drugs 2011;71:611-24.  Back to cited text no. 54
55.Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of ?-cell function in patients with inadequately controlled type 2 diabetes: A randomized controlled trial. Diabetes Obes Metab 2011;13:258-67.  Back to cited text no. 55
56.Linke A, Frank S, Mark M, Klein T. The DPP-4 inhibitor linagliptin (BI 1356) improves wound healing in ob/ob mice. Diabetes 2009;58(Suppl 1):A161.  Back to cited text no. 56
57.Scott LJ. Alogliptin: A review of its use in the management of type 2 diabetes mellitus. Drugs 2010;70:2051-72.  Back to cited text no. 57
58.Pratley RE. Alogliptin: A new, highly selective dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. Expert Opin Pharmacother 2009;10:503-12.  Back to cited text no. 58
59.Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE, Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care 2007;30:1979-87.  Back to cited text no. 59
60.Brazg R, Xu L, Dalla Man C, Cobelli C, Thomas K, Stein PP, et al. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycemic control and [beta]-cell function in patients with type 2 diabetes. Diabetes Obes Metab 2007;9:186-93.  Back to cited text no. 60
61.Rosenstock J, Baron MA, Schweizer A. Vildagliptin is as effective as rosiglitazone in lowering HbA1c but without weight gain in drug-naive patients with type 2 diabetes (T2DM) [abstract no. 557-P]. Diabetes 2006;55 Suppl. 1:133.  Back to cited text no. 61
62.Filozof C, Schwartz S, Foley JE. Effect of vildagliptin as add-on therapy to a low-dose metformin. World J Diabetes 2010;1:19-26.  Back to cited text no. 62
63.Matthews DR, Dejager S, Ahren B, Fonseca V, Ferrannini E, Couturier A, et al. Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: Results from a 2-year study. Diabetes Obes Metab 2010;12:780-9.  Back to cited text no. 63
64.Banerji MA, Purkayastha D, Francis BH. Safety and tolerability of vildagliptin vs. thiazolidinedione as add-on to metformin in type 2 diabetic patients with and without mild renal impairment: A retrospective analysis of the GALIANT study. Diabetes Res Clin Pract 2010;90:182-90.  Back to cited text no. 64
65.Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev 2010;26:540-9.  Back to cited text no. 65
66.DeFronzo RA, Hissa MN, Garber AJ, Luiz Gross J, Yuyan Duan R, Ravichandran S, et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care 2009;32:1649-55.  Back to cited text no. 66
67.Forst T, Uhlig-Laske B, Ring A, Graefe-Mody U, Friedrich C, Herbach K, et al. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes. Diabet Med 2010;27:1409-19.  Back to cited text no. 67
68.Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP; Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: A randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007;9:194-205.  Back to cited text no. 68
69.Arechavaleta R, Seck T, Chen Y, Krobot KJ, O'Neill EA, Duran L, et al. Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: A randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2011;13:160-8.  Back to cited text no. 69
70.Derosa G, Maffioli P, Ferrari I, Mereu R, Ragonesi PD, Querci F, et al. Effects of one year treatment of vildagliptin added to pioglitazone or glimepiride in poorly controlled type 2 diabetic patients. Horm Metab Res 2010;42:663-9.  Back to cited text no. 70
71.Filozof C, Gautier JF. A comparison of efficacy and safety of vildagliptin and gliclazide in combination with metformin in patients with Type 2 diabetes inadequately controlled with metformin alone: A 52-week, randomized study. Diabet Med 2010;27:318-26.  Back to cited text no. 71
72.Chacra AR, Tan GH, Ravichandran S, List J, Chen R; CV181040 Investigators. Safety and efficacy of saxagliptin in combination with submaximal sulphonylurea versus up-titrated sulphonylurea over 76 weeks. Diab Vasc Dis Res 2011;8:150-9.  Back to cited text no. 72
73.Karim A, Laurent A, Munsaka M, Wann E, Fleck P, Mekki Q. Coadministration of pioglitazone or glyburide and alogliptin: Pharmacokinetic drug interaction assessment in healthy participants. J Clin Pharmacol 2009;49:1210-9.  Back to cited text no. 73
74.Bailey CJ, Green BD, Flatt PR. Fixed-dose combination therapy for type 2 diabetes: Sitagliptin plus pioglitazone. Expert Opin Investig Drugs 2010;19:1017-25.  Back to cited text no. 74
75.Kushner RF, Sujak M. Prevention of weight gain in adult patients with type 2 diabetes treated with pioglitazone. Obesity (Silver Spring) 2009;17:1017-22.  Back to cited text no. 75
76.Bolli G, Dotta F, Rochotte E, Cohen SE. Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: A 24-week, randomized, double-blind study. Diabetes Obes Metab 2008;10:82-90.  Back to cited text no. 76
77.Hollander P, Li J, Allen E, Chen R; CV181-013 Investigators. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab 2009;94:4810-9.  Back to cited text no. 77
78.Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: A randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2011;13:653-61.  Back to cited text no. 78
79.Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl dipeptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2006;28:1556-68.  Back to cited text no. 79
80.Mikhail N. Combination therapy with DPP-4 inhibitors and pioglitazone in type 2 diabetes: Theoretical consideration and therapeutic potential. Vasc Health Risk Manag 2008;4:1221-7.  Back to cited text no. 80
81.Hollander P, Raslova K, Skjøth TV, Råstam J, Liutkus JF. Efficacy and safety of insulin detemir once daily in combination with sitagliptin and metformin: The TRANSITION randomized controlled trial. Diabetes Obes Metab 2011;13:268-75.  Back to cited text no. 81
82.Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia 2007;50:1148-55.  Back to cited text no. 82
83.Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab 2009;11:1145-52.  Back to cited text no. 83
84.Vilsbøll T, Rosenstock J, Yki-Järvinen H, Cefalu WT, Chen Y, Luo E, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2010;12:167-77.  Back to cited text no. 84
85.Dore DD, Seeger JD, Arnold Chan K. Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin 2009;25:1019-27.  Back to cited text no. 85
86.Crespel A, De Boisvilliers F, Gros L, Kervran A. Effects of glucagon and glucagon-like peptide-1-(7-36) amide on C cells from rat thyroid and medullary thyroid carcinoma CA-77 cell line. Endocrinology 1996;137:3674-80.  Back to cited text no. 86
87.Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, et al. Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology 2010;151:1473-86.  Back to cited text no. 87
88.Product Information - Januvia sitagliptin. Whitehouse Station N: Merck and Co, Inc; 2007.   Back to cited text no. 88
89.Matsubara J, Sugiyama S, Sugamura K, Nozaki T, Nakamura T, Ohba K, et al. Abstract 14739: Dipeptidyl Peptidase-4 Inhibitor, Des-Fluoro-Sitagliptin (DFS), Improved Endothelial Function and Reduced Atherosclerotic Lesion Formation in Apolipoprotein E-deficient Mice. Circulation 2010;122 (21Meeting Abstracts) (Supplement 1  Back to cited text no. 89
90.Hattori S. Sitagliptin reduces albuminuria in patients with type 2 diabetes. Endocr J 2011;58:69-73.  Back to cited text no. 90
91.He YL, Sabo R, Campestrini J, Wang Y, Ligueros-Saylan M, Lasseter KC, Dilzer SC, Howard D, Dole WP.; The influence of hepatic impairment on the pharmacokinetics of dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin. Eur J Clin Pharmacol.; 2007 Jul;63(7):677-86.  Back to cited text no. 91
92.Boulton DW, Li L, Frevert EU, Tang A, Castaneda L, Vachharajani NN, et al. Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin. Clin Pharmacokinet 2011;50:253-65.  Back to cited text no. 92
93.Chan JC, Scott R, Arjona Ferreira JC, Sheng D, Gonzalez E, Davies MJ, et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab 2008;10:545-55.  Back to cited text no. 93
94.Nowicki M, Rychlik I, Haller H, Warren ML, Suchower L, Gause-Nilsson I, et al. Saxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment. Diabetes Obes Metab 2011;13:523-32.  Back to cited text no. 94
95.Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: An algorithm for glycemic control. Endocr Pract 2009;15:540-59.   Back to cited text no. 95
96.Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement of The American Diabetes Association and the European Association for the study of diabetes. Diabetes Care 2009;32:193-203.  Back to cited text no. 96
97.NICE diabetes treatment algorithm. Available from: http://www.nice.org.uk/guidance/CG66 [Last accessed on 2011 May 20].  Back to cited text no. 97


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Feng-li Hao,Xiao-fang Han,Xiao-li Wang,Zhi-ru Zhao,Ai-hong Guo,Xin-jian Lu,Xiong-fei Zhao
Biomedicine & Pharmacotherapy. 2019; 109: 181
[Pubmed] | [DOI]
5 Teneligliptin protects against hypoxia/reoxygenation-induced endothelial cell injury
Zhen Zhang,Xiang Jin,Chunfeng Yang,Yumei Li
Biomedicine & Pharmacotherapy. 2019; 109: 468
[Pubmed] | [DOI]
6 Vascular protection of DPP-4 inhibitors in retinal endothelial cells in in vitro culture
Heng Li,Junjun Zhang,Li Lin,Lishuai Xu
International Immunopharmacology. 2019; 66: 162
[Pubmed] | [DOI]
7 Synthesis and discovery of triazolo-pyridazine-6-yl-substituted piperazines as effective anti-diabetic drugs; evaluated over dipeptidyl peptidase-4 inhibition mechanism and insulinotropic activities
B. Bindu,S. Vijayalakshmi,A. Manikandan
European Journal of Medicinal Chemistry. 2019; : 111912
[Pubmed] | [DOI]
8 The Effect of the Chronic Administration of DPP4-Inhibitors on Systemic Oxidative Stress in Rats with Diabetes Type 2
Stefani Bolevich,Isidora Milosavljevic,Nevena Draginic,Marijana Andjic,Nevena Jeremic,Sergey Bolevich,Peter F Litvitsky,Vladimir Jakovljevic
Serbian Journal of Experimental and Clinical Research. 2019; 20(3): 199
[Pubmed] | [DOI]
9 The DPP-4 inhibitor saxagliptin ameliorates ox-LDL-induced endothelial dysfunction by regulating AP-1 and NF-?B
Suxia Ma,Zhifeng Bai,Huiying Wu,Wei Wang
European Journal of Pharmacology. 2019;
[Pubmed] | [DOI]
10 DPP-4 Inhibitors: Renoprotective Potential and Pharmacokinetics in Type 2 Diabetes Mellitus Patients with Renal Impairment
Momir Mikov,Nebojša Pavlovic,Bojan Stanimirov,Maja Ðanic,Svetlana Golocorbin-Kon,Karmen Stankov,Hani Al-Salami
European Journal of Drug Metabolism and Pharmacokinetics. 2019;
[Pubmed] | [DOI]
11 Long-term use of dipeptyl peptidase-4 inhibitors suppresses systemic oxidative stress in rats with type 2 diabetes
S. S. Bolevich,P. F. Litvitsky,V. Jakovljevic,S. B. Bolevich
Sechenov Medical Journal. 2019; 10(4): 21
[Pubmed] | [DOI]
12 The Impact of a Large Bolus Dose of l-leucine and l-isoleucine on Enteroendocrine and Pancreatic Hormones, and Glycemia in Healthy, Inactive Adults
Daniel E. Newmire,Eric Rivas,Sarah E. Deemer,Darryn S. Willoughby,Victor Ben-Ezra
Nutrients. 2019; 11(11): 2650
[Pubmed] | [DOI]
13 Teneligliptin inhibits lipopolysaccharide-induced cytotoxicity and inflammation in dental pulp cells
Xin Liu,Yan Cao,Yan Zhang,Baozhen Sun,Haiying Liang
International Immunopharmacology. 2019; 73: 57
[Pubmed] | [DOI]
14 Patterns of glycaemic control in patients with type 2 diabetes mellitus initiating second-line therapy after metformin monotherapy: R etrospective data for 10?256 individuals from the U nited K ingdom and G ermany
Kamlesh Khunti,Thomas R. Godec,Jesús Medina,Laura Garcia-Alvarez,Josh Hiller,Marilia B. Gomes,Javier Cid-Ruzafa,Bernard Charbonnel,Peter Fenici,Niklas Hammar,Kiyoshi Hashigami,Mikhail Kosiborod,Antonio Nicolucci,Marina V. Shestakova,Linong Ji,Stuart Pocock
Diabetes, Obesity and Metabolism. 2018; 20(2): 389
[Pubmed] | [DOI]
15 Renoprotective Effects of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin: A Review in Type 2 Diabetes
Cristina Mega,Edite Teixeira-de-Lemos,Rosa Fernandes,Flávio Reis
Journal of Diabetes Research. 2017; 2017: 1
[Pubmed] | [DOI]
16 Cost-effectiveness analysis of different dipeptidyl-peptidase 4 inhibitor drugs for treatment of type 2 diabetes mellitus
Maurílio de Souza Cazarim,Estael Luzia Coelho da Cruz-Cazarim,André de Oliveira Baldoni,Thais Bueno Enes dos Santos,Paula Gonçalves de Souza,Ingrid de Almeida Silva,Roberta Niriam Reis Rodrigues,Alda Cristina Franco Correa Maia,Leonardo Régis Leira Pereira,Cristina Sanches
Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2017;
[Pubmed] | [DOI]
17 Linagliptin versus sitagliptin in patients with type 2 diabetes mellitus: a network meta-analysis of randomized clinical trials
Khosro Keshavarz,Farhad Lotfi,Ehsan Sanati,Mahmood Salesi,Amir Hashemi-Meshkini,Mojtaba Jafari,Mohammad M. Mojahedian,Behzad Najafi,Shekoufeh Nikfar
DARU Journal of Pharmaceutical Sciences. 2017; 25(1)
[Pubmed] | [DOI]
18 Computational Analysis of Gynura bicolor Bioactive Compounds as Dipeptidyl Peptidase-IV Inhibitor
Lina Rozano,Muhammad Redha Abdullah Zawawi,Muhamad Aizuddin Ahmad,Indu Bala Jaganath
Advances in Bioinformatics. 2017; 2017: 1
[Pubmed] | [DOI]
19 The importance of Pharmacovigilance for the drug safety: Focus on cardiovascular profile of incretin-based therapy
Liberata Sportiello,Concetta Rafaniello,Cristina Scavone,Cristiana Vitale,Francesco Rossi,Annalisa Capuano
International Journal of Cardiology. 2016; 202: 731
[Pubmed] | [DOI]
20 Monitoring safety and use of old and new treatment options for type 2 diabetic patients: a two-year (2013–2016) analysis
Christian Leporini,Rosanna Piro,Francesco Ursini,Francesca Maida,Caterina Palleria,Franco Arturi,Maria Pavia,Giovambattista De Sarro,Emilio Russo
Expert Opinion on Drug Safety. 2016; 15(sup2): 17
[Pubmed] | [DOI]
21 Comparison of charges and resource use associated with saxagliptin and sitagliptin
Varun Vaidya,Keyuri Adhikari,Jack Sheehan,Iftekhar Kalsekar
Health Economics Review. 2015; 6(1)
[Pubmed] | [DOI]
22 Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins
Sandeep Chakraborty,Adela Rendón-Ramírez,Bjarni Ásgeirsson,Mouparna Dutta,Anindya S. Ghosh,Masataka Oda,Ravindra Venkatramani,Basuthkar J. Rao,Abhaya M. Dandekar,Félix M. Goñi
F1000Research. 2015; 2: 286
[Pubmed] | [DOI]
23 The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins
Sandeep Chakraborty,Adela Rendón-Ramírez,Bjarni Ásgeirsson,Mouparna Dutta,Anindya S. Ghosh,Masataka Oda,Ravindra Venkatramani,Basuthkar J. Rao,Abhaya M. Dandekar,Félix M. Goñi
F1000Research. 2015; 2: 286
[Pubmed] | [DOI]
24 DPP-4 inhibitors: pharmacological differences and their clinical implications
Antonio Ceriello,Liberata Sportiello,Concetta Rafaniello,Francesco Rossi
Expert Opinion on Drug Safety. 2014; 13(S1): 57
[Pubmed] | [DOI]
25 Alogliptin for the treatment of Type 2 diabetes
Yutaka Seino,Daisuke Yabe
Expert Review of Endocrinology & Metabolism. 2014; : 1
[Pubmed] | [DOI]
26 Development of a gas chromatography–mass spectrometry method for the analysis of sitagliptin in human urine
Ebru Uçaktürk
Journal of Pharmaceutical and Biomedical Analysis. 2013; 74: 71
[Pubmed] | [DOI]
27 Linagliptin: farmacology, efficacy and safety in type 2 diabetes treatment
Erika Paniago Guedes,Alexandre Hohl,Thais Gomes de Melo,Felipe Lauand
Diabetology & Metabolic Syndrome. 2013; 5(1)
[Pubmed] | [DOI]
28 Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins
Sandeep Chakraborty,Adela Rendón-Ramírez,Bjarni Ásgeirsson,Mouparna Dutta,Anindya S. Ghosh,Masataka Oda,Ravindra Venkatramani,Basuthkar J. Rao,Abhaya M. Dandekar,Félix M. Goñi
F1000Research. 2013; 2: 286
[Pubmed] | [DOI]


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