It has been estimated that in US, 7.8 % (accounting to 22.6million) of the population is suffering from diabetes. Out of which only 17.9million people are diagnosed and 5.7 million have not been diagnosed (Gossain & Aldasouqi, 2010) .In UK, the prevalence for diabetes is 9.1% and the cases who have been diagnosed are 1.7% and only 18.5% have been undiagnosed (Gossain & Aldasouqi, 2010). The problems associated with the undiagnosed patients are they develop micro vascular complications like (nephropathy, neuropathy and retinopathy) macro vascular complications like (myocardial infarction, stroke vascular disease) (Gossain & Aldasouqi, 2010).In a study which was carried out by populations from United Kingdom,Germany,United States,Japan,Italy,Netherlands,Swedan and Western Australia showed that mortality associated with diagnosed older adults for type2 diabetes is lower than the general older diabetic population of age >60 years(Barnett et al, 2006). These studies included few databases like Medline, CINAHL, EMBASE, National Research Register and Cochrane from 1975 to 2004 consisting of review articles were compared and the results were observed(Barnett et al, 2006).The major obstacle for diagnosing type2 diabetes is lack of suitable biomarker which distinguish between diabetic and non- diabetic patients, recent approach towards it is HbA1c test which acts a biomarker for diagnosis of Type2 diabetes but there are few limitations when compared with other diagnostic tests like FPG and OGTT(Nicholson & Hall, 2011).
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Screening for diabetes
By screening at earlier stage it helps to delay pre diabetes to diabetes and we should know how to screen for diabetes (Gossain & Aldasouqi, 2010). The complications suggested by American Diabetes Association (ADA) by screening adults which are obese are physical inactivity, hypertension, Triglyceride level>250mg/dl and HDL- (Dankner et al, 2009)cholesterol level <35 mg/dl, high risk of ethnic populations, women with polycystic ovarian syndrome and clinical implications associated with the insulin resistance and cardiovascular disease (Gossain & Aldasouqi, 2010).In the absence of the above conditions then diabetes have to be diagnosed only after 45 years of age. As mentioned by screening at earlier stage may reduce complications which are associated by type2 diabetes which was observed by a clinical study conducted to evaluate the rate of undetected type2 diabetes in older adults who were screened 25 years ago, also to analyze the characteristics of type2 diabetes patients(Dankner et al, 2009). This study consisted of a group of 623 older adults of 25 year cohort with 53.5% of males aged between 58-93 years were subjected to anthropometric measurements, laboratory experiments of 12-h fasting venous blood and 2-h oral glucose tolerance tests. The results showed that higher percentage of males was estimated to have type2 diabetes with triglyceridesâ‰¥1.7mmol/l, blood pressure â‰¥130mmHg, large waist circumference and the prevalence for the diagnosis of individuals with undetected type2 diabetes was 13.2% and previously diagnosed diabetes was 18.9%(Dankner et al, 2009). When the compared with the known diabetic patients, undetected were slightly younger, with less number of complications and have rated their health profile more favorable(Dankner et al, 2009).
Table: Criteria for the diagnosis of diabetes
IFG or IGT
2-h postload glucose(PG)Â±<140mg/dl
FPGâ‰¥100 and <126mg/dl (IFG)
2-h postload glucose (PG)Â±â‰¥140 and <200mg/dl (IGT)
2-h postload glucose (PG)Â±<140mg/dl
Symptoms of diabetes and casual plasma glucose concentration â‰¥ 200 mg/dl
The preferable screening tests for diabetes are fasting plasma glucose (FPG) and 75-g oral glucose tolerance test (OGTT) also called as 2-h glucose test because they are easy to perform, acceptable to patients, more convenient and less expensive(Association, 2004). The table below represents the values for screening tests
Fasting Blood Glucose
From 70 to 99mg/dL (3.9 to 5.5 mmol/L)
Normal fasting glucose
From 100 to 125mg/dL (5.6 to 6 9mmol/L)
Impaired fasting glucose (pre-diabetes)
126mg/dL (7.0 mmol/L) and above more than one testing event
Oral Glucose Tolerance Test (OGTT)
Less than 140mg/dL (7.8 mmol/L)
Normal glucose tolerance
From 140 to 200mg/dL(7.8 to 11.1 mmol/L)
Impaired glucose tolerance (pre-diabetes)
Over 200mg/dL (11.1 mmol/L) on more than one testing event
Always on Time
Marked to Standard
Levels are applicable except during pregnancy sample drawn 2 hours after a 75-gram glucose drink
The ADA recommends that currently available screening methods as FPG and OGTT (Gossain & Aldasouqi, 2010)
Requires plasma glucose and overnight fast
Requires plasma glucose and overnight fast
Sensitivity of FPG is low and fails to detect 30-50% of individual
It is inconvenient , costly, labor intensive, time consuming and has low reproducibility which brings uncertainty and confusion to the diagnosis
(Gossain & Aldasouqi, 2010)
Though FPG and OGTT are widely used for screening HbA1C should be considered for monitoring the glycaemic control of Diabetes.
Type2 Dibates must be evaluated for those patients with BMIâ‰¥25 Kg/m2;at age starting from 45 years and should be screened evry 3 years to avoid the risk factors or for earlier detection of the pre-diabetes and treat the diabetes with appropriate treatments available.
The Fasting plasma gluocse(FPG) is the recommeneded screening test for type2 diabetes since it is easier to perform, acceptable by patients, patients and inexpensive. The oral glucose tolerance test (OGTT) is preferred for diagnosiss only if the FPG tet is normal.
Screening should be performed only if it is standardized and is demanded by the clinical situations of the patients and the screening tests should meet the patients criteria.
Screening outside the health care community is not recommmended because it is not beneficial at the same time the results may cause harm with variations.
Screening tools or tests
Urine Glucose: This test predicts the positive values ranging from 11% to 37% and the sensitivity is quite low (16%to64%) and cannot measure glucose above the renal threshold(Echouffo-Tcheugui et al, 2011). It is not completely quantitative method affecting the urine concentration and the fluid intake so this test is not recommended for screening diabetes also the reason being it cannot detect large proportions of the individuals(Echouffo-Tcheugui et al, 2011). The advantages of this test are it is inexpensive, does not require blood sample, quick processing time and can be testing during fasting, random or postprandial state(Echouffo-Tcheugui et al, 2011).
Random blood glucose: This test for screening diabetes is limited because of its low performance, when compared with oral glucose tolerance test (OGTT) it showed only sensitivity of 41% and specificity of 93% with a cut-off â‰¥ 6.9mmol/L.A recent study also against OGTT, with a cut-off of â‰¥ 7.2mmol/L showed only sensitivity of 63% and specificity of 87%(Echouffo-Tcheugui et al, 2011).This test also had limitations which included the measurement could be affected by several factors like phlebotomy and lifestyle changes, requirement of prompt processing of < 2 hours and processing errors(Echouffo-Tcheugui et al, 2011). Although this test has many limitations, it could be used as it is inexpensive, easy to measure and no fasting required.
Fasting plasma glucose: This test is used for screening for hyperglycemia and many studies have been conducted against OGTT. A study of young African American patients with dysglycemia showed that fasting plasma glucose is not sensitive for diagnosis of impaired glucose tolerance (IGT). Another study by Korean population found that threshold of fasting plasma glucose â‰¥ 7mmol/L detected only 55.7% of patients with specificity of 100%.(Echouffo-Tcheugui et al, 2011)The optimal cut off for fasting plasma glucose isâ‰¥ 6.1mmol/L with sensitivity of 85.2% and the specificity decreased to 88.5%(Echouffo-Tcheugui et al, 2011).If this test was used it had few limitations like patients are set for this test only if after overnight fast of atleast 8 hours, processing errors and the measurement can be affected by phlebotomy and lifestyle changes. The advantages of using this test are inexpensive, simple to measure the glucose levels and can be easily correlated with the presence of complications(Echouffo-Tcheugui et al, 2011).
HbA1c- Diagnostic tool for T2D
The diagnosis of t2d generally takes place either by fasting glucose or 2-h glucose following a 75-g oral glucose tolerance test (Balkau et al, 2003). The third one is HbA1c which is not proposed as there are problems related to the standardization of the assay(Association, 2004). The frequently used method for diagnosis of t2d is fasting plasma glucose test (Balkau et al, 2003).The criteria for diagnosis of t2d is based on the absence or presence of retinopathy since it is a particular complication in t2d patients and is shown in table below
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Table: Criteria for Good diagnostic test
By identifying the disease without high specificity (mostly screening negative without disease) or high sensitivity (mostly screening positive with the disease)
Having low analytical variability
Having biological or individual variability ( one test is adequate to identify the patients with t2d )
From the figure below we can illustrate that that none of the three tests show as an ideal one for diagnostic test and figures a b and c represents as below explained in the figure and showing the evidence for the choice of diagnostic test and its threshold (Balkau et al, 2003).
(Balkau et al, 2003)
Figure: (A) Theoretical distribution of perfect diagnostic tool fasting plasma glucose which leads to an unequivocal diagnosis into diabetic and no diabetic classes (B) A fasting plasma glucose distribution with subjects having high values; a skewed distribution (C) Mathematically modeling fasting glucose distribution from (B), 2 groups can be distinguished (Balkau et al, 2003).
From Hoorn Study, the 6 year incidence of type2 diabetes has been studied in relation to the fasting and 2-h hyperglycemia as impaired fasting glucose(IFG) and impaired glucose tolerance(IGT) in table: . There were two groups consisting of isolated fasting glucose (IFG and NGT (normal glucose tolerance)) or isolated 2-h hyperglycemia (NFG and IGT) had similar odd ratios predicting for later diabetes in comparison with the normal fasting and 2-h glucose and have shown both had a 40fold higher risk.
Table: Relative risk of the incidence of type2 diabetes according to fasting and 2-h plasma glucose groups (6 years of follow-up in the Hoorn Study)
Fasting /2-h glucose (mmol/l)
Incident Diabetes mellitus/total number subjects
IFG and NGT
NFG and IGT
IFG and IGT
(Balkau et al, 2003)
As a part of the criteria for the diagnostic test, analytical variability has shown improvement in the three glycaemic measures but human error can take place during the drawing of blood in the treatment. For biological or individual variation, 2-h glucose has high variability than fasting glucose.
The evidence that favors the use of HbA1c test for diagnosing diabetes is based on the data showing the prevalence of the micro vascular complications like retinopathy increases in the non- diabetic patients which is directly proportional to the A1c concentration(Gomez-Perez et al, 2010). The advantages of HbA1c test in comparison with the FPG and 2HPG according to the International Expert Committee report are HbA1c test is in the process of standardizing across the world by the method applied to National Glycohemoglobin Standardization Program (NGSP) or by Diabetes Control and Complications Trial assay(Gomez-Perez et al, 2010). It was then reported that two out of eight manufacturers withdrew from the study since the results were not promising with point of care(POC) methods, only 2 have met the <0.85 % error criterion of the NGSP. This study shows that HbA1c test when estimated with POC analyzers were not worthy for diagnosing diabetes(Gomez-Perez et al, 2010). The other advantages are no fasting is required, can be tested anytime of the day with venous blood sample, lower intraindividual variability (<2%) less than fasting plasma glucose and is not affected by any changes in lifestyle(Echouffo-Tcheugui et al, 2011).A study was carried out by Japanese populations, a 5year evaluation of the HbA1c test which may be more practical than fasting plasma glucose was observed and resulted that HbA1c could be more practical since it resulted in the values which were similar to that of the FPG test and were also compared with the OGTT and 2-h glucose test, which showed similar activity even with the HbA1c test (Nakagami et al, 2010).The limitations for this test are variable values are obtained with the method causing errors like nonglycemia with anemia and hemoglobinopathies,insensitive, for detecting impaired glucose tolerance, expensive method than glucose testing where the net cost of HbA1c is 13.6 times higher than that of the fasting plasma glucose measurement which increases the economic burden on the health system and the limited availability of this test across the world because it includes HPLC method where the reference material differs in the quality and the availability of resources (Echouffo-Tcheugui et al, 2011).The other limitations of HbA1c test include problems associated with the selection of the HbA1c threshold methodologies and the ethnic issues because in few studies conducted the threshold of HbA1câ‰¥6.5% according to International Expert Committee and NHANES III survey but in other studies by Bennett and coworkers showed between 6.0 and 6.2%(Gomez-Perez et al, 2010). In this way, the threshold of A1ctest showed variations in test results and the diagnostic criteria which proved that using HbA1c is not suitable. This test also showed increased value in A1c with respect to aging studied by NHANES study 2001-2004(Gomez-Perez et al, 2010).HbA1c levels were affected by the chronic kidney disease where the increase blood urea nitrogen caused the formation carbamylated hemoglobin which cannot be distinguished from the glycated hemoglobin. It was reported that HbA1c should not be used in few hemoglobin traits like HbS, HbC, HbE and HbF causing abnormal hemoglobin and is also affected by the anemia and iron deficiency(Gomez-Perez et al, 2010). The other factors which modify HbA1c levels are HIV infection causes lower values of HbA1c and which increases the HbA1c levels are by the hyperbilirubinemia, chronic alcoholism, hypertriglceridemia, chronic ingestion of opioid drugs and salicylates(Gomez-Perez et al, 2010). Use of antioxidants may alter the HbA1c levels.
There have been many debates regarding the use of HbA1c as diagnosis for diabetes, many studies proved against its use since its sensitivity (39%) is very low for clinical practice and are expensive and the arguments in favor of the HbA1c suggest that it is a bio marker for glycaemic control and as a prognostic factor for further complications(Gomez-Perez et al, 2010). According to my opinion, I would suggest that HbA1c can be used in near future and further studies have to be conducted to obtain the details and increase its sensitivity and making it a cost effective method. For now I would be for the fasting plasma glucose test as the best option for the diagnosis of the type2 diabetes.
The 50-g oral glucose challenge test:
This test was performed between various groups of individuals of undiagnosed diabetes, undiagnosed diabetes or dysglycemia and dysglycemia and observed their detection characteristic curves values as 0.90, 0.82 and 0.79, but this study was subjected to selection of ethnic groups of blacks and white races(Echouffo-Tcheugui et al, 2011). This study lacked in validation of variable populations and the sensitivity of test. The advantages of using this test are fasting are not required and the measurement is not affected by anytime of the day(Echouffo-Tcheugui et al, 2011). The limitations of this test are inconvenience caused to administer the test, variability in the test results by testing and retesting(Echouffo-Tcheugui et al, 2011).
Capillary blood testing: finger prick point-of-care testing: The use of capillary blood testing in screening of diabetes is unclear and there have been few studies conducted. An Australian study have detected that capillary blood testing indicated lower values of blood glucose than fasting plasma glucose(Echouffo-Tcheugui et al, 2011) .The values when tested with capillary blood testing were observed as 0.76 and 0.71 for dysglycemia and diabetes whereas for fasting plasma blood glucose as 0.87 and 0.81.The study with capillary blood testing was performed among Asian Indians which showed good sensitivity of (66.5%-70.5%) and specificity of (65.5%-69.5%) for impaired glucose tolerance (IGT),impaired fasting glucose (IFG) and Type2Diabetes(Echouffo-Tcheugui et al, 2011). This test is simple without phlebotomy and inexpensive. It is not recommended as it is not standardized and precision may not be high(Echouffo-Tcheugui et al, 2011).
Treatments for typ2 diabetes
Type2 diabetes worsens humans life causing micro and macro vascular complications has led to many deaths also declining the life expectancy by 10 years(Nicholson & Hall, 2011). The action against this chronic disease have been the major goal either by delaying the complications or preventing this disorder which is a challenging approach already achieved by few treatments and few more in the near future expecting increase in the life expectancy and reducing the number of deaths worldwide. When it comes to treatment for type2 diabetes, there have been novel treatment options which include drug therapy by understanding the pathophysiology of the Diabetes Mellitus, surgical strategies and insulin therapy.
Type2 diabetes is characterized by hyperglycemia, insulin resistance, and decline in the pancreatic Î²- cell function periodically. These abnormalities can be controlled or prevented by lifestyle management, new pharmaceutical approaches from the knowledge acquired from pathophysiology of type2 diabetes(Nicholson & Hall, 2011). Drug therapy involves currently available anti diabetic classes of agents which are shown in Table
Table: Currently available drugs for treatment of type2 diabetes
New agents - primary treatment
Glucagon like peptide-1 (GLP-1) receptor agonists
Dipeptidyl peptidase- IV (DPP-4) inhibitors
Insulin analogues, basal and short acting
Current proved agents- primary treatment
New agents- secondary treatment
Î±- Glucosidase inhibitors
synthetic amylin analogues
(Nicholson & Hall, 2011)
Incretins are the peptides derived from gut which are released with respect to the intake of meals. The function of incretins is to increase amount the insulin produced by pancreas before the blood glucose level increases after the intake of food(Nicholson & Hall, 2011). Two classes of incretins namely, Glucagon like peptide-1 (GLP-1) receptor agonists produced by the neuroendocrine L cells of the colon and ileum and glucose-dependent insulinotropic peptide (GIP) secreted by K cells of jejunum and duodenum(Karaca et al, 2009). The function of these both classes is to lower the blood glucose level by releasing them immediately after the food intake. Only GLP-1 enhancers or mimetics can be used in the treatment of type2 diabetes because Î²-cells are resistant to GIP due to the down regulation of the pancreatic receptors under diabetic terms(Karaca et al, 2009).GLP-1 is responsible for reducing the apoptosis of Î²- cell through Gs protein- coupled receptor and improving the proliferating Î²- cell production, the process of lowering blood glucose level takes place once the food reaches the intestine and GLP-1 is released by the gut automatically in a way stimulating the pancreas to release the insulin and inhibiting the secretion of glucagon, which removes the glucose from the blood and takes it into cell that can be used as energy(Karaca et al, 2009).GLP-1, acts only when there is high blood glucose level and lowers it without leading to hypoglycemia. Another interesting function, it slowdowns the food intake into the stomach in order to maintain the stable blood glucose level after the meal and signals to the brain indicating the stomach is full in that way reducing the appetite(Nicholson & Hall, 2011).
GLP-1 mode of action
GLP-1 binds to the specific G-protein coupled receptor on the Î²- cell membrane which leads to the pathway of insulin secretion by increasing the intracellular cyclic AMP and other intracellular messengers (Levy, 2006).GLP-1 is far from the site of the insulin secretion, so by triggering the ATP-dependent potassium channel (KATP channel) which is close to the insulin secretion machinery, through the metabolism of glucose and other nutrient secretagogues are stimulated by the mitochondria to increase ATP/ADP ratio as shown in the Figure(Levy, 2006). This closes the KATP channel and depolarizes the cell by increased concentration of intracellular potassium. Voltage- dependent channels of calcium are then opened to increase the intracellular calcium concentration leading to the process of stimulating the fusion of releasable insulin granules with the membrane for the secretion of insulin(Levy, 2006).GLP-1 binds to its receptors which increases the intracellular concentration of cyclic AMP and other messengers for the insulin secretion and stimulating insulin production and also for the development of Î²-cells. This receptor agonist stimulates the transcription and translation of the proinsulin gene by refilling intracellular insulin(Levy, 2006).
Commercially available GLP-1 agonists in UK are Exenatide and Liraglutide. Exenatide, is a naturally occurring peptide isolated form salivary secretions of lizard Heloderma Suspectum, administered twice daily as injections providing tolerable daily replacement of GLP-1(Nicholson & Hall, 2011).It is being used in treatment of Type2 diabetes in coincident with Metformin and Sulphonylurea treatment with reduction of 1-2% in HbA1c and weight loss of 2-5Kg(Mikhail, 2006).Although, there are many uses in contrast the side effects include diarrhea and nausea which was seen in 40-50% of patients when studied in correlation with placebo during the first 8 weeks of the therapy(Mikhail, 2006). According to recent studies, the dosage for Exenatide of 5Âµg weekly once improved the glycaemic control with similar weight loss and without increase episode of hypoglycemia(Mikhail, 2006).
Liraglutide is another incretin exhibiting prolonged activity than Exenatide with a half life of 11 to 13 hours and recommended dose of 0.6mg subcutaneously once in a day for week and can be increased thereafter for about 1.2 or 1.8mg daily. It is involved in reducing blood pressure, obesity related risk factors and HbA1c levels. According to animal studies, high doses may lead to thyroid medullary cancer but no clear supporting evidence is available(Nicholson & Hall, 2011). There have been studies conducted by the Liraglutide Effects and Action in Diabetes (LEAD) trials to study the safety and efficacy of Liraglutide consisting of 6 LEAD trials, where the Liraglutide was compared with rosiglitazone, insulin glargline, Sitagliptin, glimerpiride and exenatide(Hanna et al, 2012). These trials lasted for 26 weeks resulted in Liraglutide with the decreased level of A1C by an average of 0.84% to 1.5% from a baseline A1C of 8.3% to 8.6%(Hanna et al, 2012). The Lead-6 study was conducted to compare the liraglutide of 1.8mg once daily was compared with 10mg of exenatide from which few results were observed stating that A1C reduction was more significant for liraglutide with respect to the baseline than exenatide of 1.2% Vs 0.79%, p<0.0001 and also liraglutide showed more reduction in postprandial glucose than exenatide of 1.16 Vs 0.6 mmol<0.0001(Hanna et al, 2012).Exenatide showed significant reduction in postprandial glucose level than liraglutide after breakfast and dinner with p<0.0001 and p<0.0005(Hanna et al, 2012).These values reflect the benefits of using exenatide and liraglutide with respect to their mode of action in the required type2 diabetic patients.
The therapeutic efficacy of GLP-1 based therapies can be improved by the development of the GLP-1 enhancers that are resistant to degradation of DPP-IV peptide or by developing DPP-4 inhibitors(Karaca et al, 2009).According to the recent advances in GLP-1 receptor agonists there have been few drugs which are in various stages of developments. Alibiglutide, a long acting GLP-1 receptor agonist which is developed by genetic fusion of a DPP-IV resistant GLP-1 to human albumin with a half life of 6 to 8 years(Davidson, 2009). Taspoglutide (R1583) is a human GLP-1 receptor agonist analogue was under randomized clinical trials with respect to a placebo. In a clinical trial conducted, AVE0010 is an exendin related GLP-1, which has shown four times greater affinity than native GLP-1 towards the treatment of Type2 Diabetes(Davidson, 2009). In summary, Incretin therapy is an effective treatment for type2 diabetes from the currently available treatments in consideration with hypoglycemia events.
Table: GLP-1 peptide for type2 diabetes
Amylin / Eli Lilly
AC-2993 LAR (long-acting release)
Modified long-acting Exendin-4(1-39)
No structural information available
Amylin/ Eli Lilly/Alkermes
GLP-1 along with
- Lys26 contains a hexadecanoyl fatty acid chain on its Îµ- amino acid
-Lys34 is replace with Arg34
GLP-1 along with
- Lys37 contains chemical reactive killer on its Îµ- amino acid
- Gly37 replaced with Lys37
- Ala8 replace with D- Ala8
Recombinant GLP-1 albumin protein
GLP-1 along with
- Lys34 contains an octanoyl fatty acid chain on its Îµ- amino acid
- Lys26 replaced with Arg26
- His7replaced with des-His7
- N-terminally extended with His
- C-terminally extended with 6 Lys residues
No structural information available
No structural information available
Transition Therapeutics/Novo Nordisk
GLP-1 fused to the protein Transferrin (T.f)
(Green et al, 2005)
Table: Dipeptidyl peptidase-IV (DPP-IV) inhibitors launched since 2005 and the pipeline of new agents currently in phase III development.
Sitagliptin + Metformin
Vildagliptin +Metformin + Alogliptin benzoate
Launched 2007 Preregistration
Merck & Co
Merck & Co
Bristol- Myers Squibb
(Karaca et al, 2009)
The effect of incretins is short lived because of Dipeptidyl peptidase-IV (DPP-4) enzyme is responsible for cleaving the incretins at two NH2- terminal of the amino acid in less than 2 minutes, where the second amino acid being alanine or proline which leads to the inactivation of GLP-1 and resulting in the high blood glucose level(Nicholson & Hall, 2011). Therefore, DPP-4 inhibitors also have been developed to prolong the activity of GLP-1 and maintain the stability of blood glucose level. Sitagliptin, Saxagliptin and Vildagliptin combined with Metformin are currently available DPP-4 inhibitors in UK having longer action and can be administered orally with one time daily dosage unlike GLP-1 agonists. These drugs can control the HbA1c concentration by 1%, improve Î²-cell function, Monotherapy or combination with other drugs are safe and effective to use but cannot reduce appetite or weight(Jain & Saraf, 2010). Inhibition of DPP-4 activity may cause adverse events like immunological reactions, neurogenic inflammation and increased blood pressure in contrast; the advantage of DPP-4 also cleaves chemokines, neuropeptide Y, substance P and gastrointestinal releasing peptide(Nicholson & Hall, 2011).It has been reported that sitagliptin reduces HbA1c levels by 0.7% , linagliptin by 0.49% and saxagliptin by 0.43% to 0.54% (Germino, 2011).These three DPP-IV inhibitors have reduced the risk of hypoglycemia but as mentioned above when used as Monotherapy or in combination with metformin proved them to be more effective. The evidence has been suggested from few clinical trials conducted individually with the placebo group. A clinical study of 24-week,randomized ,double blind study with 741 patients suffering with Type2 diabetes were treated with sitagliptin resulting in the prevalence of hypoglycemia of 0.8% which was similar to that of placebo group (Germino, 2011). Another study was conducted to evaluate the efficacy of 100mg of sitagliptin against placebo in 12 older patients of mean age 73.2 years resulted in insignificant difference in the glucose levels but the mean (SD) insulin AUC at 30 and 180 minutes were (962 Vs 692 pmol/min/L, p=0.003) and insulin concentrations recorded at 120 to 180 minutes were (1235 Vs 788 pmol/L, p= 0.002) (Germino, 2011).DPP-IV inhibitors are generally recommended when the patients don't reach the targets for the treatments in combination with the lifestyle intervention and with GLP- 1 receptors (Hanna et al, 2012)
Sitagliptin is an orally available potent reversible DPP-IV inhibitor approved by the U.S Food and Drug Administration (FDA) in October 2006 as Monotherapy for the treatment of type2 diabetes(Tahrani et al, 2010). This agent improves glycaemic control in both Monotherapy and combination therapies. In a clinical study conducted for sitagliptin monotherapy consisting of 743 patients for a duration of 12 weeks,randomized,double-blind and placebo controlled has reduced HbA1c from (-0.38% to -0.77%) and FPG (8.64mg/dL to 26.1mg/dL) with respect to placebo(Wu et al, 2009). In combination therapy of sitagliptin clinical trial was studied by Raz and associates to evaluate the effects of sitagliptin when added to the metformin in patients with HbA1c values from 8-11% having slightly severe condition(Davidson, 2009). These trials were randomized with (n= 190) patients where metformin was administered as monotherapy initially and continued for about 30 weeks with 100mg (n=96) of sitagliptin or placebo (n=94) once daily(Davidson, 2009). The results established at week18, all 3 methods; HbA1c, FPG and 2-h PPG reduced values from baseline by 1.0%,32.4mg/dL and 64.8mg/dL when compared to placebo(Wu et al, 2009). Sitagliptin has also ameliorated Î²-cell function by evaluation of proinsulin/insulin ratio and maintained the homeostasis of Î²-cell function. The adverse effects caused by this drug are nasopharyngitis, nausea, headache, respiratory tract infection, leg swelling with TZDs, hypoglycemia when in combination with Sulphonylurea and renal impairment when reduced dose is proposed. According to recent reports there have post marketing adverse reactions of angioedema, anaphylaxis, rashes and Stevens-Johnson syndrome(Tahrani et al, 2010).
Figure: structure of sitagliptin
Vildagliptin is another orally available DPP-IV inhibitor which is responsible for reducing HbA1c by 0.44 to1.4% as monotherapy and in combination therapy with metformin, glimerpiride, pioglitazone or insulin may cause few side effects compared to placebo(Piya et al, 2010). Vildagliptin is synthesized in liver to inactivate the metabolites leading to rare hepatitis which has been studied in few reports(Piya et al, 2010). A clinical study demonstrates Vildagliptin drug as monotherapy conducted by Ahren and colleagues of a double blind study consisting of (n=18 and 100mg of Vildagliptin) versus placebo (n=19) for a duration of 4 weeks(Wu et al, 2009). The findings from this study state that DPP-IV inhibitors improved the metabolic control by reducing the glucagon concentrations. Another study, a 12 week, double-blind consisting of 279 patients with base range of HbA1c levels 6.8-10% of total hemoglobin and FPG level from 6.1-15mmol/L were randomized to obtain different doses of Vildagliptin (25-100 mg daily).HbA1c levels reduced by 0.43% (P=0.003) and 0.4% (P=0.004) with doses of 50mg and 100mg once daily when compared to the placebo. Vildagliptin decreased the degradation of GLP-1 and improved Î²-cell function at higher doses of 100mg twice daily(Wu et al, 2009). According to Matikainen et al, Vildagliptin improved postprandial plasma triglyceride after having a heavy meal when given at dosed of 50mg for about 4weeks of duration(Wu et al, 2009). 50mg daily dosage of Vildagliptin reduced HbA1c, FPG and postprandial glucose (PPG) with respect to placebo(Lee et al, 2011; Wu et al, 2009).There were few evidences which stated that Vildagliptin in combination therapy with metaformin reduced the HbA1c values by 0.7% in comparison with placebo in a group of (n=51) for about 12 weeks. The placebo with metformin group consisted of (n=56) and the HbA1c mean baseline level was 7.8% and mean fasting plasma glucose was 9.8mmol/L(Wu et al, 2009). At the 40th-week of the extended trial it was observed that HbA1c level reduced by additional 0.066%(Wu et al, 2009).These results indicates that Vildagliptin can be effectively use in the treatment of type2 diabetes to maintain the stability of glycaemic control. The side effects caused due to Vildagliptin is hepatitis which was observed in few reports and no major adverse reactions were seen in the immune functionalities.(Tahrani et al, 2010)
Figure: Structure of Vildagliptin
(Wu et al, 2009).
Saxagliptin is an orally administered drug with once daily having high specificity for DPP-IV receptors and higher potency than Vildagliptin and sitagliptin(Piya et al, 2010). It was approved by the FDA in July 2009 and by the EMEA in October 2009.This drug can be used in combination therapy with insulin, metformin, sulphonylurea and TZDs rather than the monotherapy because trials have resulted the reductions in HbA1c levels as combination therapy with metformin is 7.6% whereas monotherapy has resulted low reduction of HbA1c from6.5 to 7.5% (Kania et al, 2011).Evidences show that efficacy and tolerability of saxagliptin when used in combination with metformin for about 24 weeks which was a randomized, double blind study with baseline HbA1c levels of (-0.72% to -0.90%) resulted in maximum number of patients with HbA1c reductions of (<7.0%). Also this trial continued with the combination therapies of Saxagliptin +sulphonylurea and saxagliptin + thiazolidinedione resulted in the reduction of HbA1c from (-0.54% to -0.64% and -0.64% to -0.94%) (Kania et al, 2011).Studies have reported that saxagliptin with dosage levels of 2.5mg to 10mg have shown results of reduced HbA1c levels of 0.5 to 0.8% without weight gain with tolerable side effects and low episodes of hypoglycemia(Tahrani et al, 2010).The side effects include urinary tract infection, headache and upper respiratory tract infection and are not recommended to the patients with severe hepatic or renal impairment and should be taken care that this drug does not affect the CYP3A4/5 enzyme since this enzyme is responsible metabolic activity of the DPP-IV inhibitor, which can be affected by ketoconazole and diltiazem leading to the striking of plasma concentration of saxagliptin (Piya et al, 2010).
Table: Differences between DPPIV and GLP-1 receptor agonists
GLP-1 receptor agonists
Route of administration
Once daily (Liraglutide)
Twice Daily (Exenatide
Once or twice daily
Increased insulin secretion
Decreased glucagon secretion
Decrease in systolic blood pressure
Nausea and vomiting
*Baseline A1c of 8%-8.5%
(Hanna et al, 2012).
Thiazolidinediones (TZDs) are considered as insulin sensitizers because they increase the efficiency of the glucose transporters(Nicholson & Hall, 2011). They act at adipocyte and the muscle by reducing the HbA1c concentration from 1-2% during fast and postprandial excursions. TZDs mode of action is mediated via peroxisome proliferator activated gamma nuclear receptors (PPAR-Î³) throughout the body, exerting insulin sensitization in fat and muscles resulting in the altered gene transcription in the adipocytes (DeFronzo & Abdul-Ghani, 2011) . This altered gene transcription modifies the fatty acid metabolism where there is reduction in the circulating free fatty acids about 20-40% which enhances signaling of insulin-receptor in skeletal muscle resulting in the improved insulin sensitivity all over the body(Gross & Staels, 2007).
Figure :Thiazolidinediones reduce blood glucose level by stimulating nuclear peroxisome proliferator activated receptor Î³ (PPAR-Î³) along with retinoid X receptor (RXR) promotes transcription of insulin sensitive genes(Bailey, 2000). This effect occurs in adipocytes which strongly express PPAR Î³(Bailey, 2000). Stimulation of PPA Î³ causes improved expression of glucose transporter GLUT4 fatty acid protein (FATP), an enzyme involved in lipogenesis(Bailey, 2000). Finally, decreases free fatty acids and improves glucose utilization via glucose-fatty acid cycle(Bailey, 2000).
TZDs include troglitazone; rosiglitazone and pioglitazone improve glycaemic control and insulin sensitivity. Troglitazone enhances oral glucose tolerance in obese and lean IGT individuals and in IGT women with gestational diabetes mellitus (Wolffenbuttel & Graal, 1996). Diabetes Prevention Program was conducted in which there was a decrease of 23% of IGT conversion into diabetes when troglitazone even after discontinuing the drug for 10 months due to hepatotoxicity (DeFronzo & Abdul-Ghani, 2011). According to the evidence from studies, rosiglitazone, pioglitazone and troglitazone improved the Î²-cell function related to the reversal lipotoxicity because troglitazone enhances the insulin sensitivity and preserves Î²-cell function and prevents the progression of IGT to Type2 diabetes (DeFronzo & Abdul-Ghani, 2011).The benefits of using TZDs for treating type2diabetess reduces the exposure of Î²-cell to lipotoxicity which leads to Î²-cell death, acts a anti-inflammatory agent and improves peripheral and coronary vascular endothelial function (Stumvoll et al).The side effects caused for this drug used in treatment of type2 diabetes are myocardial infarction, which was observed in 42 trials of rosiglitazone Vs placebo resulting in cardiovascular effects of 43% increased odds ratio of myocardial infarction and 64% increased odd ratio of cardiovascular deaths. Another important study, PROactive study (Prospective Pioglitazone Clinical Trial in Macrovascular Events) concluded that by taking pioglitazone for treating type2 diabetes reduced the risk of myocardial infarction and reduced mortality due to cardiovascular complications(Nicholson & Hall, 2011). In an observational study it was observed that by using pioglitazone there was a decrease of 22% of myocardial infarction when compared with rosiglitazone and a 15% decrease in coronary revascularization(Nicholson & Hall, 2011).FDA has restricted the use of rosiglitazone because it showed elevated risk of cardiovascular events (Germino, 2011).
Type 2 diabetes is associated with insulin resistance and Î²- cell failure leading to the decrease in the insulin secretion and increasing the blood glucose levels(Raccah, 2006). This increase in blood glucose levels may lead to hyperglycemia(Raccah, 2006). There have been many problems associated with hyperglycemia with microvascular complications like retinopathy, nephropathy, myocardial infarction, macrovascular mortality and neuropathy(Raccah, 2006). Prolonged hyperglycemia induces glucotoxicity resulting in insulin resistance and impaired Î²-cell function which in turn lead to hyperglycemia(Raccah, 2006). This cycle has been broken down by insulin regimens. It has been estimated that by the time type2 diabetes is diagnosed only 50% of Î²-cell function is left. According to few studies, it was observed that newly diagnosed patients when treated with insulin therapy for about 10 years mean HbA1c levels achieved were of 7.0% compared with 7.9% in conventional therapy and also there was a reduction of 16% in macrovascular complications (P=0.052) and 25% reduction in microvascular complications (P<0.001).. Fasting Blood Glucose (FBG) and Postprandial Blood Glucose (PPG) contribute toward the glycaemic control.FBG levels should be normalized in patients with poor glycaemic control for which new therapies generally include basal, prandial and premixed insulins. New basal insulin analogues are beneficial for maintaining FBG.The role of insulin therapy is to mimic the physiologic insulin secretion which can be performed by short acting insulins used for bolus therapy to maintain postprandial glycaemic levels and long acting insulins used for basal therapy(Fonseca, 2006). Insulin detemir and glargline have shown advantages over the traditional insulins like Neutral Protamine Hagedorn insulin and premixed insulin with less weight gain and reduced risk of hyperglycemia. If a patient's condition worsens then prandial insulin is added to basal insulin analogue resulting in basal-bolus regimen. This approach was established but unfortunately many obstacles exist like believing insulin regimens are complex, fear of injections and weight gain. Basal insulin state is generally at low constant rate promoting lipolysis and hepatic glucose production between meals and overnight contributing 50% of daily insulin input. The normal blood glucose levels are in range between 4 to 9 mmol/L (72-162 mg/dL) avoiding hypoglycemia and hyperglycemia events.
Neutral Protamine Hagedorn (NPH) insulin has been intermediate acting insulin for 60 years with disadvantage of risk of hypoglycemia and hyperglycemia time of action profile and higher inter and intrapatient variability .Though it has disadvantages still NPH is a benchmark for insulin preparations. Basal insulins are combined with OAD therapy (Oral Anti-Diabetic Drug therapy) if the glycaemic control target is no attained within 1 to 3months(Fonseca, 2006).OAD therapy consists sulphonylurea+ metformin Â± thiazolidinediones, where sulphonylurea and metformin are rapid-acting gents used for achieving glycaemic control targets quickly(Fonseca, 2006). Insulin glargline is a long acting, human insulin analogue with 24 hour duration of action and lower intrapatient variability than NHP (0.64 Vs 1.05 mg/Kg per minute; P<0.05).When insulin glargline is used in combination with NPH there were similar reductions of HbA1c levels observed in 426 patients with type2 diabetes and postdinner glucose concentrations of insulin glargline Vs NPH (9.9 Vs 10.7 mmol/L). The advantage of patients using insulin glargline is it showed less nocturnal hypoglycemia (9.9% Vs 24.0% of all patients, insulin glargline Vs NPH, P<0.001).Increased reductions in the HbA1c levels were observed in 570 obese patients using insulin glargline in comparison with NPH, with decreased HbA1c value of 0.42% for insulin glargline based regimen and that of NPH based regimen is by 0.11% (P<0.024).
The second long acting insulin analogue is insulin detemir having intermediate duration of action and lower inter- intra patient variability than NPH.According to European Committee for Proprietary Medicinal Products reported that insulin detemir should only be used as basal-bolus regimen in type2 diabetes because noninferiority in a study was observed for insulin detemir with NPH insulin when both were administered as a part of basal-bolus regimen. In one study, decline of FPG levels and hypoglycemia was observed in insulin detemir in comparison with NPH. Patients gained less weight while using insulin detemir rather than NPH (1.0 & 1.81 Kg; P=0.017).In a study with 395 patients of type2 diabetes, there was decrease in HbA1c levels (P=0.575) and FPG levels (P=0.855) in insulin detemir plus insulin aspart Vs NPH plus regular human insulin, where insulin detemir plus insulin aspart showed a decline of 38% of nocturnal hypoglycemia and also reduction in weight gain (0.51Kg of insulin detemir plus insulin aspart & 1.13Kg of NPH plus regular human insulin) compared to NPH plus regular human insulin. From the above studies we can conclude that both insulin glargline and insulin detemir can be used to maintain improved glycaemic control than NPH and also with reduced risks of hypoglycemia and weight gain.
Prandial insulin is an alternative approach to basal insulin which is a short acting insulin used to control postprandial hyperglycemic peaks. Rapid acting insulin includes insulin apart, insulin glulisine and insulin lispro have fast onset action than Regular Human Insulin (RHI) with peaks occurring at early stage of their activity. In a study, 37 patients were compared with RHI which was administered 30 minutes before the meal with insulin aspart given immediately before the meal. Maximum serum insulin concentration was 27 minutes shorter than insulin aspart than RHI (P=0.039) though it was administered 30 minutes before the meal. Also postprandial excursions were 20% lower with insulin aspart than RHI (P=0.034). Insulin glulisine showed little improvement in the glycaemic control over RHI in 876 patients with type2 diabetes using NPH insulin as basal insulin. The HbA1c levels have reduced by 0.46% in insulin glulisine and 0.30% in RHI (P<0.003).Postprandial glucose levels were low in insulin glulisine Vs RHI (post breakfast 8.66 Vs 9.02 mmol/L; P<0.05 and post dinner 8.54 Vs 9.05 mmol/L; P<0.05).Inpatients who were not administered with sulphonylurea therapy were administered with insulin lispro before meals, reduces 2-hour post prandial glucose levels compared with sulphonylurea from (18.6 to 14.2 mmol/L; P<0.001) and FPG levels decreased from (10.9 to 8.5 mmol/L; P<0.001).Though insulin lispro was more advantageous than sulphonylurea it had a limitation of patients gaining more weight than sulphonylurea (P<0.001).
Table: pharmacokinetic properties and costs of rapid-acting insulin analogues
Onset of Action, min
Duration of Action, h
Price per 10-ml Vial $*
Price per mL per Pen
Regular human insulin
Insulin lispro (Humalog)
Insulin aspart (Novolog)
Insulin glulisine (Apidra)
Inhaled insulin (Exubera)
(Leal et al, 2007)
Inhaled insulin (Leal et al, 2007).
The first inhaled insulin, insulin human (rDNA origin) is an inhalation dry powder manufacture by Pfizer, New York as Exubera. It is administered by inhaling the dry powder and is passed through lungs, which is then directly delivered into the blood stream. It is generally recommended to be given 10 minutes before the meal. Unlike the other insulins, the dosage of inhaled insulin is in mg and not units (U). This inhaled insulin is not suitable for patients with large constituent of insulin resistance and for the patients who require large doses of prandial insulin in order to maintain the glycaemic levels. Inhaled insulin has adverse reactions when compared with rapid acting insulin since it is not recommended for patients with asthma, chronic obstructive pulmonary disease, and impaired lung function and the main reason being the route of administration. Patients who are smokers or stopped smoking for < lees than 6 months are not recommended for inhaled insulin because it was observed in few studies, that 10 to 20% of patients suffered from cough as soon they inhaled this insulin. Another study, demonstrated that 1 to 3% of patients suffered from chest pain, otitis media and xerostoma. Also, less than 0.5% patients suffered from respiratory effects such as dysapnea and pharyngitis .According to the literature available is unclear about postprandial glucose levels, but 2 studies showed that there was reduction (P<0.001).
Premixed insulin is a third alternative for the patients with type2 diabetes, which is not controlled by oral therapy. It was observed that 40% of patients with type2diabetes across the world use premixed insulin. A study was performed to evaluate the efficacy of insulin glargline Vs 70/30 premixed insulin in 371 patients and was observed that there was more reduction in HbA1c levels using 70/30 premixed insulin (-1.64% Vs -1.31%;P<0.001) and also decrease in FBG levels (0.9 mmol/L Vs -17mg/dL). It was studied that nocturnal hypoglycemia was not confirmed by insulin glargline initially, but later in few episodes insulin glargline showed greater hypoglycemia levels than 70/30 premixed insulin (mean 4.07 of 70/30 premixed insulin Vs 9.87 insulin glargline episodes/patient- year; P<0.001). It is suggested that patients with poor glycaemic control is safer to continue with insulin glargline rather than discontinuing and initiating with 70/30 premixed insulin.
Insulin Injection Devices (Magnolti & Rayfield, 2007)
Insulin injection devices are currently used for the treatment of Type2 diabetes to maintain glycaemic control. In the traditional methods, vials and syringes have been used which are replaced by insulin pens. Novo Nordisk, New Jersey is the first company to launch insulin pens in the market in 1985 as an alternate to vials and syringes. Insulin pens contains both short acting and long acting insulins like insulin lispro and NPH which can be either basal or bolus regimen. These insulin pens play a vital role in the current market and in patients with type2 diabetes. The increase in demand for insulin pens than vials and syringes are just because they are disposable as well as refillable pens available and are very convenient for the patients to use. Patients fear for injection has been abolished because insulin pens contain needle guard, where the needle is completely invisible for the patients unlike vials/ syringes and can be easily carried just like a pen in pocket. It also increases the patience confidence towards insulin therapy and improves the glycosylated hemoglobin but data is unavailable for the glycaemic control. An open-label study was conducted with 103 diabetic patients to compare Flex Pen over vials/syringes for delivery of insulin twice daily with Novolog 70/30 insulin. It was observed that, 74% of patient's preferred the use of Flex Pen, 85% of patients were discreet to use Flex pen with respect to social situations and 75% reported that Flex pen was easy to use than vials/syringes. It was also evaluated that there were no significant differences in the fasting plasma glucose between the two groups. In a survey of 242 diabetic patients of which 99 were insulin users and 143 were non insulin users, concluded that majority preferred the use of insulin pens than vials/syringes. The other benefits of insulin pens include no refrigeration is required, larger dose display than vial/syringes and the doses can be easy audile for every click indicating 1U of insulin injected. Insulin pens were more accurate than vials and syringes which was demonstrated by a study which was conducted to compare NovoPen, Humalog pen, insulin pumps, vial and syringes at doses 1 to 2U.Pens and pumps were more accurate (P<0.001 at 1U dose) than 1 to 2U of vials and syringes. The rapid use of insulin pens has also spread in Europe where 1002 patients participated in a study conducted in 22 centers across 7 countries indicated that 80% of diabetic patients on insulin used pens atleast for 1 year and in United States it is 3 times that patients use pens more commonly. In contrast to the benefits of insulin pens there were few disadvantages of insulin pens
Table: Major insulin pens currently available in Unite States
Refillable or not
Premixed (Novolin 70/30*)
NPH (Novolin N*)
Regular (Novolin R*)
Better for visually impaired
Analogues are not available
Available only with insulin lispro (no basal insulin available)
Can be purchased only with prescription
It is digital and the memory last for 16 years
This pen is not covered under insurance
Can be used with basal and bolus insulin (with separate pens for each insulin)
and is digital
Available at physicians with free of charge
Premixed (Novolog Mix 70/30*)
May be best pen for visually impaired and is very to use
Both basal and bolus insulin can be used in one pen
NPH (Novolin N*) Lispro (Humalog*)
Premixed (Humalog Mix 75/25,Humalog Mix 50/50, Humulin 70/30)
Easy to use and the only disposable NPH pen
Can prevent accidental discharge of insulin
It is mainly used for pregnant women and also for patients who use NPH as basal insulin
Easy to use and can uphold up to 80U of insulin per injection
(Magnolti & Rayfield, 2007)
Insulin lispro Vs Regular human insulin
Patients with type2 diabetes are generally recommended to use insulin in combination with rapid acting insulin and intermediate acting insulin administered twice every day (Vignati et al, 1997). Regular human insulin is preferred to be administered 30-45minutes before the meal but in practice if we administer regular human insulin too closer to the human meal may lead to increase in post prandial glucose levels and increase in the hypoglycemia levels (Vignati et al, 1997). According to the new insulin, insulin lispro is a rapid acting insulin analogue that can be injected before a meal because of its shorter duration of action and more rapid absorption when compared with regular human insulin(Vignati et al, 1997). A trial was conducted consisting of 707 randomized patients with 379 patients of insulin-dependent diabetes mellitus and 328 patients of non-insulin-dependent diabetes mellitus(Vignati et al, 1997). It was observed that the effect of twice-daily insulin lispro or regular human insulin in combination with NPH human insulin on premeal, 2-hour post prandial and bed time(Vignati et al, 1997). This study concluded that treatment with insulin lispro observed small incremental in glucose level after morning and evening meals. Also lower post prandial levels compared with regular human insulin(Vignati et al, 1997). Insulin lispro in combination with NPH improved the glycaemic control and reduced the risk of hypoglycemic events. The advantage of using insulin lispro is once given just before the meal had faster absorption within 15 to 30 minutes with a maximum peak activity at 30 to 90 minutes and duration of action between 3.5 to 4 hours(Vignati et al, 1997).
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