Tight glycemic control and cardiovascular effects in type 2 diabetic patients.

Diabetes Mellitus (DM) with poor glycemic control is one of the leading causes for cardiovascular mortality in diabetic patients. Tight glycemic control with glycosylated haemoglobin of <7 gms% is recommended as a routine and < 6.5 gms% is recommended for young and newly diagnosed diabetics. Treatment goal aims at achieving near normal blood glucose level, and directed at management of other co morbid conditions such as obesity, hypertension and dyslipidemia. Oral hypoglycemic agents are the preferred drugs, alone or in combination. Preference for glitazones is declining due to the increasing evidences of associated adverse events. Gliptins appear as promising agents with lesser tendency to cause hypoglycemia, but their long term safety and efficacy is yet to be established. We emphasize the role of preventive measures in prediabetics and in established DM, treatment should be individualized and customized to minimize hypoglycemic effects and to retain quality of life.

INTRODUCTION

Increasing incidence and onset at a younger age has changed the treatment strategy of diabetes mellitus (DM) towards prevention, delaying onset and minimizing disease complications. Best proven treatment strategy is to prevent the onset of disease by life style modification. Prevention of long term complications of DM is one of the greatest challenges encountered in clinical practice.

Once DM develops, treatment goal is aimed at maintaining optimal blood sugar levels in plasma to minimize the risk of development of cardiovascular, renal and other complications. Cardiovascular complications can be minimized, if tight glycemic control (TGC) is ensured from the time of diagnosis of DM. In addition, some hypoglycemic agents, when used in the treatment, can themselves cause cardiovascular events, thus adding to the complication. Despite intensive treatment strategy, 15% of cardiovascular events defy prevention.[1] It has been estimated that 65% of diabetic patients die of cardiovascular diseases.[2]

The use of glitazones though found to be of equivalent efficacy as of sulfonylureas has led to a controversy regarding their usage. Glitazones are associated with worsening of lipid profile, fluid retention and weight gain. Moreover, if used for over a decade, glitazones may significantly increase the cardiovascular risk in diabetic patients, who are as such at high risk for coronary artery diseases (CAD).[345]

An alternative and safer strategy to minimize cardiovascular complications is the need of the hour. Maintaining the blood glucose levels to the near normal range has been found to be a suitable alternative treatment strategy. Here, we discuss the concept of TGC and its effects on the cardiovascular system, starting with the available treatment modalities in diabetic patients.

SEARCH STRATEGY

References for this review were identified through searches of PubMed for articles published from January, 1995, to April, 2013, by use of the terms “tight glycemic control”, in combination with the term “diabetes”. Relevant articles published during this period were identified through searches in the authors' personal files, in Google Scholar, and Springer Online Archives Collection. Articles resulting from these searches and relevant references cited in those articles were reviewed. Articles published in English, Italian (abstract) and Portuguese (abstract) were included.

AVAILABLE TREATMENT

All patients with type 1 DM and many patients with type 2, especially in the advanced stages receive insulin therapy, to achieve normal or near normal glycemia.

For a newly diagnosed case, oral hypoglycemic agent (OHA) is the preferred choice of drug. Metformin is the first drug of choice.[6] Tolbutamide and chlorpropamide are prescribed among the first generation sulfonylureas (SUs); tolbutamide is considered for the initial treatment of type 2 DM, whereas use of chlorpropamide is reserved due to its long duration of action and increased episodes of hypoglycemia. Of the second generation SUs, glyburide though coupled with easy dosing schedule, its side effects notably hypoglycemia has to be kept in mind. Extra attention should be paid while prescribing this to the elderly or patients with renal complications.

Use of SUs is associated with mortality (due to cardiovascular and other cause), glimepiride and glipizide resulting in higher mortality rate as compared to gliclazide. Classification of OHA is given in Figure 1. Figure 2 outlines the management of diabetes mellitus.

Figure 1

Insulin secretogogues and oral hypoglycemic agents

Figure 2

Treatment of DM

It has been advocated that the newer generation of SUs such as glimepiride, glipizide, gliclazide, is associated with less CAD risk than the older generation SUs. Of these newer agents, only gliclazide has shown lesser incidence of development of CAD.[7]

Two studies, ADVANCE[8] and ACCORD,[9] have attempted to achieve near normal glycemic control with different treatment strategies in a similar group of patients [Figure 3]. Both studies showed the treatment strategies were effective in reducing HbA1c, with a target of near normal glycosylated hemoglobin (HbA1c) level achieved in 58% in ADVANCE study and 54% in ACCORD study. Treatment strategy followed in ADVANCE study was considerably safer in terms of all cause mortality including cardiovascular ones. Severe hypoglycemia and weight gain were seen in 0.7% and 0.2%, respectively in ADVANCE study group as against 3.1% and 3.5% in ACCORD group, indicating that these two adverse events (AEs) were less with gliclazide therapy.

Figure 3

Treatment strategies of ADVANCE and ACCORD studies

With increasing evidence of adverse effects of antidiabetic agents such as glitazones, clinicians are focusing on glucagon like peptides (GLP) and gliptins for the management of type 2 DM. Gliptins are newer agents that inhibit dipeptidyl peptidase-4 (DPP-4). DPP-4 is an enzyme which inactivates GLP1, and glucose dependent insulinotropic peptide (GIP), which in turn increases incretin level as well as its activity, thus promoting insulin release and additionally suppressing glucagon.[10] Sitagliptin, saxagliptin, allogliptin and linagliptin have been approved for clinical use. These gliptins are usually combined with either metformin or sulfonylureas.[11]

Allogliptin is approved by the US FDA for use in type 2 DM and available as mono drug and in combination with metformin HCl and pioglitazone. Its efficacy has been studied in 14 clinical trials involving 8500 type 2 DM patients. In 26 weeks, it produced a HbA1c reduction of 0.4–0.6% compared to placebo.[12] Berhan A et al. have analysed allogliptin's efficacy in reducing HbA1c in type 2 DM patients, in a meta-analysis, and found it to be effective.[13] Vidagliptin is not approved for clinical use in the United States.

GLYCEMIC CONTROL

Treatment goals in diabetic patients include achieving a near normal glycemic levels, which is considered as TGC, to minimize microvascular complications that are associated with DM. American diabetes Association recommends maintaining HbA1c levels < 7% in the majority of patients, which is achievable by maintaining fasting blood glucose between 70–130 mg/dL, postprandial levels < 180mg/dL and mean blood glucose levels between 150–160 mg/dL.

In newly diagnosed DM patients, young adults with long life expectancy, those without disease complications, and those with more stringent control of HbA1c levels of 6.0–6.5% can be maintained if achieved without any adverse events such as hypoglycemia. Elderly patients, those prone to hypoglycemic episodes, those with shorter life expectancy, those with disease complications and those with serious systemic diseases, and in whom achieving TGC is difficult are candidates ideally requiring to maintain HbA1c between 7.5%–8%. Recent position statement shifts the theme of treatment to individualization of treatment.[6]

Tight glycemic control

Maintaining the blood sugar levels at optimal range is the key challenge in the treatment of DM as hyperglycemia over a period is associated with development of disease complication. Hence, treatment strategies have been directed towards achieving TGC early in the disease with OHAs and insulin. Physicians aim to achieve a target HbA1c at 6.5–7.0% to reduce microvascular and other complications based on the results of UKPDS 1998, ADVANCE and VADT study. Clement et al. strongly support TGC in diabetic patients for better clinical outcome and survival rates.[14]

Tight glycemic control was found to be beneficial in terms of better therapeutic outcome in trauma patients[15] and in those who were admitted to ICU for non-cardiac surgery.[16] In type 2 DM patients with one end organ complication, TGC reduces the risk of development of complication in another (second) organ indicating that maintaining near normal glycemia even in later stage of disease also offers benefits in these patients.[17] TGC appeared to reduce the fibrinolytic impairment and associated morbidity in patients with severe sepsis/septic shock.[18]

Tight glycemic control during religious fast

Fasting has become an integral part of many religions throughout the world, especially in the Asian continent. Among all, those who follow Islam observe a month fast (without food and water in any form), throughout the day from sunrise to sunset, during the month of Ramadan. This requires different therapeutic approach and adjustment in the management of many chronic diseases, especially of DM. Maintaining a glycemic control and dosing of hypoglycemic agents in diabetic patients observing religious fast is a difficult practical situation encountered by physicians. In spite of regular monitoring of blood glucose levels, hypoglycemic episodes do occur, sometimes requiring medical intervention.[1920] Zargar et al. have observed that the glycemic control was maintained with the evening administration of a long acting SU in male patients (n = 136) with type 2 diabetes during fast. There was a reduction of –0.8% in mean HbA1c at the end of study (6.8%), compared to baseline (7.6%).[21] Bashir MI et al.,[22] also support the use of the newer generation long acting SUs in these patients. Role of gliptins alone on patients who are fasting is not clearly established; Ahmed MH et al., have studied the effect of vidagliptin with metformin on these patients and found that former was as effective as gliclazide but safer in terms of relatively lesser chance of hypoglycemic episodes.[23] Dose adjustments and dose schedules have to be reconsidered for these patients. Velayudhan M suggests a reduction in total dose of insulin and OHAs, administering only 70% of the previous dose. Frequency of drug administration should be rescheduled to only twice a day, with a larger proportion of the dose to be given after the evening meal and a smaller proportion before pre dawn meal. The importance of awareness through patient education, changes in patient's attitude among patients is also emphasized along with frequent blood glucose monitoring.[24]

Factors influencing glycemic control

Several factors influence the level of glycemic control. Life style modification, weight reduction, diet control, physical exercises and patient education are few among them. These, along with hypoglycemic agents have shown to have an impact on the proatherogenic effects of DM. With weight reduction and increasing the physical activity during pre-diabetic stage, onset of frank DM can be delayed and even prevented. Life style modifications and use of hypoglycemic agents are extremely crucial in increasing the insulin sensitivity to achieve TGC, which in turn aid in cutting the cardiovascular risk factors in these patients.[25]

Bi Y et al., studied the influence of various factors in Chinese population. Of 2966 patients, TGC with HbA1c < 6.5% was seen in 40.2% (1193/2966) patients. Tight control was seen in young patients, those with shorter duration of DM, low body mass index than those with inadequate control. Those with better education, higher income monitored and reassessed their diabetic status frequently. These were the patients who attended DM education sessions and more oriented towards receiving treatment with OHAs and were more likely to consult physicians in tertiary care hospital. Tight control was observed in those who received treatment from tertiary care hospital compared to those treated in primary and secondary care hospitals.[26]

Tight glycemic control and cardiovascular effects

Persistent hyperglycemia is a potential threat to the heart and hence diabetics are more prone to develop cardiovascular complications such as left ventricular systolic and diastolic dysfunction than non-diabetics. Tarantini L et al.,[27] and Piccini et al.,[28] opine that TGC with pharmacotherapy and management of associated factors may reverse the remodeling process thus may be effective in preventing the occurrence of further cardiac events. Marfella et al., suggest that TGC may also increase regeneration of ischemic myocardium by reducing senescent myocyte precursor cells.[29] In a controlled, comparative study, molecular mechanism responsible for post myocardial infarction (MI), remodeling was analyzed by Marfella et al., in 88 patients who had the first episode of acute MI undergoing coronary artery bypass graft (CABG). TGC reduced oxidative stress and inflammation in these patients, indicating a possible reduction in apoptosis in the peri-infarctal area, and remodeling.[30]

Meta analysis of three large clinical trials (ACCORD, ADVANCE, and VADT) indicated that nonfatal myocardial infarction was reduced by 15–17% in patients whose glycemic levels were under tight control.[31] However, there is an argument that TGC is effective as primary prevention method against cardiovascular disease (CVD) in young, newly diagnosed with DM without evidence of macrovascular complications; the same can be detrimental in older patients in whom it can precipitate hypoglycemia and CVD.[32]

Lazar HL et al., have studied the effect of TGC on perioperative outcome in 141 diabetic-CABG patients. These patients were subjected to either TGC of serum glucose, 125 to 200 mg/dL with a modified glucose-insulin-potassium solution or to standard therapy (serum glucose < 250 mg/dL) with intermittent administration of subcutaneous insulin. TGC resulted in lower serum glucose levels (138 ± 4 versus 260 ± 6 mg/dL; P < 0.0001), lower incidence of complications such as atrial fibrillation (16.6% versus 42%; P = 0.0017). This also resulted in shorter postoperative hospital stay (6.5 ± 0.1 versus 9.2 ± 0.3 days; P = 0.003) compared to those who received standard therapy. Further, improved perioperative outcomes in terms of enhanced survival during the initial two years of postsurgery, decreased incidence of recurrent ischemia (5% versus 19%; P = 0.01) and lesser wound complications were the observed benefits with tight glycemic control.[33] Brown JR et al., have assessed the relationship between TGC and myocardial damage in a similar group of 199 patients. TGC was defined so with 90–100% of glucose measures ≤ 150 mg/dL, and if it was < 90%, it was labeled as loose control. Myocardial damage was assessed by estimating cardiac troponin I. In this study, target control was achieved in 45.6% patients. TGC yielded no significant difference in myocardial damage in terms of troponin I release.[34]

Evidences indicate that increase in HbA1c levels can result in greater incidence of stroke and death due to heart failure in DM patients.[35] In diabetic patients, with acute ischemic stroke, uncontrolled hyperglycemia results in poor prognosis and clinical outcome.[36]

Tight control in other clinical conditions

Studies have indicated that maintaining an optimal level of glucose (HbA1c < 7%) can prevent further disease complications in nerves, kidney[37383940] liver[4142] and eye.[4344] Cognitive functions have been affected by DM especially in older patients with long standing DM. Hence, to prevent and minimize these unwanted disease effects, TGC is recommended.[45]

DISADVANTAGES OF TGC

Despite having advantages with achieving TGC, there are some associated disadvantages. Hypoglycemia, cost, difficulty in frequent monitoring of blood glucose levels, more stress to the patient in terms of repeated sampling are some of the disadvantages of TGC, of which most frequent AE hypoglycemia needs to be addressed promptly.[31] These events can be prevented by frequent monitoring of blood glucose levels; in ICU, real-time continuous glucose monitor can be used in critically ill patients.[46]

Puar TH et al., studied the relationship between TGC and greater risk of hip fractures in 932 patients with type 2 diabetes mellitus. Patients on insulin or OHAs, whose HbA1c measured within three months of fracture were included in the study and matched with one identical control. It was noted that those with TGC with HbA1c < 6% and 6.1–7.0%, were at the higher risk of hip fracture than those with HbA1c > 8%. This association cautions the over enthusiastic approach, especially in elderly diabetic patients.[47]

Effect of glycemic levels on driving has not been clearly established in diabetic patients. In a population based study, data of 57 drivers involved in a crash and that of 738 drivers who were not involved in a crash obtained from vehicle licensing authorities were analyzed. Those with lower glycemic levels had a greater risk of a crash; for each 1% reduction in HbA1c, there was an increase of 26% in relative risk of a crash suggesting a possible relationship between TGC and increased risk of vehicle accidents.[48]

TIGHT GLYCEMIC CONTROL VERSUS MODERATE CONTROL

Contradicting results from various studies have led to debate whether to have TGC or moderate control of glycemic status. Results of landmark trials in Leuven, Belgium, indicated maintaining a near normal glycemic levels reduce morbidity and mortality, whereas the international multicenter Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study reported otherwise. Latter trial recommends moderate glycemic control between 144 mg/dL and 180 mg/dL to minimize TGC associated hypoglycemic episodes. In the absence of robust supportive evidence, to show the absolute superiority of TGC and effective monitoring devises which exactly measure glycemic status, it is better to abide by the usual practice of moderate control.[49]

Recent reviews and meta-analysis do not support TGC especially for those who are critically ill. Reeds D reviewed and analyzed four studies that compared the outcome of near normal glycemic control (blood sugar of 80–110 mg/dL) with moderate control (blood sugar 150 mg/dL) in critically ill patients. In post surgical patients, clinical outcomes were better in those with near normal glycemic control than with moderate control. However, these effects were seen limited to post surgical patients only. Adverse events such as hypoglycemia were more frequent with near normal glycemic control. Hence, Reed opines that moderate control is safer and not inferior to near normal glycemic control.[50]

Few studies have supported the near normal or TGC during the perioperative period in diabetic patients undergoing CABG. However, there is a controversy. Siegelaar SE et al., opines that diabetes as a risk factor for mortality for patients in ICU, is a misconception. As contrary to the recent concept of TGC for the benefit of patients to control glycemic status in those who are admitted to ICU, it may not be of much help to emphasize the need for change in the treatment approach in these diabetic patients.[51]

Bhamidipati et al., assessed and compared tight (glucose < 120 mg/dL) and moderate glycemic control in 4658 patients. Diabetic patients or with perioperative hyperglycemia (defined as preoperative HbA1c ≥ 8 or postoperative serum glucose > 126 mg/dL) were included and classified into three groups based on glucose levels. Those with postoperative sugar level of ≤ 126 mg/dL considered as tight, with 127–179 mg/dL as moderated and ≥ 180 mg/dL as liberal. Results were in favour of moderate glycemic control as there were of lesser complications in this group compared to tight control group. Renal failure was significantly higher in tight control group (tight 16.4%, 22/134; moderate 8.3%, 232/2785; P = 0.001) and 5.2% (7/134) patients among this, required emergency surgical intervention (moderate 1.9%, 52/2785, P 0= 0.007). In contrast to the predictions of Society of Thoracic Surgeons, lower mortality was in moderated group (tight 2.9%, 4/134; moderate 2.0%, 56/2785; liberal 3.4%, 59/1739; P = 0.02). Lower rates of risk adjusted incidence of complication and mortality were seen in moderate control group proving the superiority of moderate glycemic control over tight control in this study population.[52] Similar observations were made by Leibowitz et al., who observed the effects of insulin in diabetic patients perioperatively to achieve adequate control of glucose supporting the efficacy, safety and superiority of moderate intensity control.[53]

Dokun states that TGC provides protection against microvascular damage in both types of DM, whereas in type 1 DM patients, only macrovascular protection is observed. In type 2 DM patients, TGC is associated with greater risk of hypoglycemia and can have a detrimental effect, especially in critically ill patients. Hence, moderate control is preferred.[54] A meta-analysis by Kovalaske et al., also supports these findings.[55]

Wiener et al., reviewed the data from 29 randomized clinical trials, evaluated and compared the benefits and risks of TGC vs standard care in 8432 critically ill patients. There was no significant difference in mortality rate, requirement of need for dialysis in different strata of glycemic control states. However, risk of septicemia was significantly reduced in TGC group but was associated with greater risk of hypoglycemia.[56] Chen LK et al., opine that treating elderly diabetic patients is a real time challenge and observed that HbA1c of < 7% showed no protective effect in patients with nursing home-acquired pneumonia.[57]

No benefit with TGC

Since 2001, TGC is the target glycemic control for those who are being treated in ICU. Usually insulin is used to achieve this treatment goal. Marik et al., reviewed seven randomized controlled clinical trials involving 11425 patients. No significant change was observed in 28-day mortality, incidence of infections, or need for dialysis. Authors have not found any supportive evidence for TGC in these patients, instead they have observed higher incidence of hypoglycemia and increased mortality rate in those with inadequate nutrition.[58]

The large diabetic trial conducted so far (UKPDS 1998, ACCORD and ADVANCE), though supported the TGC since diagnosis to reduce morbidity and mortality, 10 year post trial follow-up of UKPDS in 2008 showed that initial difference in the glycemic status and control in terms of overall HbA1c was not seen in the post trial period in those who were treated with intensive therapy. Interestingly, during the post trial period, those who received intensive treatment were at a lesser risk of developing disease complications. Wilson and Perry opine that considering pitfalls of TGC in these patients such as a) frequent episodes of hypoglycemia, b) cost associated with frequent strict monitoring of blood glucose c) management of hypoglycemic episodes, and d) quality of life, it is advisable not to have strict control of glycemic status.[59]

New trend

Intensive insulin therapy is being followed to achieve TGC during the perioperative period, to reduce morbidity and mortality in surgical ICU especially to minimize post surgical complication such as infections, but has a potential to cause hypoglycemia which can result in serious neurological complications. Hanazaki et al. have experimented with an artificial endocrine pancreas in these patients and have found that it is safe and effective in reducing post operative infections with no increase in the incidence of hypoglycemia. They recommend TGC using this closed-loop artificial endocrine pancreas system.[606162]

CHALLENGES

Treatment focus is in identifying a suitable agent (s) for initial therapy either mono or in combination of OHAs in treatment naοve patients and for those who are less responsive to treatment. Target oriented treatment strategy is adopted currently in the management of DM, which include the management of overweight and obesity, hyperglycemia, hypertension, and dyslipidemia. One crucial missing element while considering treatment strategy is the fact hypoglycemic drugs themselves may influence CAD and therefore, should be included in the strategy. Pharmacotherapy along with lifestyle modifications and change in the diet can aid in achieving TGC in these patients,[6364] and this can even prevent or postpone the onset of DM in pre-diabetics.

In England, with available treatment, TGC with HbA1c < 6.5% is achieved only in 26.2% diabetic patients and HbA1c of > 7.5% was seen in 35% diabetic patients,[65] indicating the practical difficulty in achieving the near normal glycemia even in developed countries.

Oral hypoglycemic agents are used either alone or along with insulin in management of type 2 DM. SUs are associated with hypoglycemia and weight gain; moreover, few SUs may increase the risk of cardiovascular events adding to the existing problem. Moreover, with SUs, near normal glycemic control is extremely difficult to achieve. There is no established evidence to prove that SUs reduce morbidity and mortality over a long period. Complex dosing schedule is another complex issue.

Gliptins have shown promising results in these patients with no weight gain and comparatively lesser side effects. Gliptins are weight neutral unlike other SUs, are associated with fewer incidences of hypoglycemia, provide better glycemic control compared to other agents and with fewer side effects. Studies have shown no adverse events with the use of gliptins in diabetic patients observing fast.[22] Dosing schedule is easy with once a day dosing (except for vidagliptin), which makes it more acceptable to patients and enhances treatment compliance. By increasing the levels of GLP-1, they may affect the growth and proliferation of beta cells, thus may have a potential to arrest the progression to complete beta cell failure. Though its effects on diabetic control appear to be promising, its long term effects especially on the disease complications and mortality, safety are still a concern and are yet to be established. Though promoted as not associated with adverse effects, frequently seen effects are nasopharyngeal effects and headache; serious adverse effects such as hypoglycemia and suicidal tendency[66] has been reported, which is more in usage of SUs. Its role in prediabetics in the prevention of development of DM is also subject to further research. There have been incidences of pancreatitis, increase in infections due to its effect on immunity which are the causes of concern with its use. US FDA has issued an early communication regarding development of pancreatitis and pre cancerous findings for pancreas in patients receiving these agents.[67] Interestingly, Dore DD, et al., have found no evidence of pancreatitis with the use of GLP-1.[6869] Moreover, its use in renal and hepatic insufficiency is not established.[10]

Though TGC is the treatment goal in young patients, achieving and maintaining TGC in elderly diabetics, and those with the other end stage diseases is challenging and still controversial. These patients are more prone to have loss of appetite and TGC may lead to episode (s) of hypoglycemia. Hence, some physicians advise moderate glycemic control to maintain and enhance comfort and quality of life.[70] However, few have a different thought on this arguing that elderly patients will have more benefit compared to younger patients.[71] It is advisable not to reduce HbA1c levels < 7% in this population for the risk of development of hypoglycemia.

With disease progression and development of co-morbidities, glycemic targets should be individualized to avoid/reduce drug induced AEs such as hypoglycemia and weight gain.[13] Along with this, various other influencing factors such as age, duration of DM, initial and current glycemic control, prognosis, disease complications and hypoglycemic episodes should be considered.[32727374]

Another challenge is determining the blood glucose levels. Among the tests, laboratories available, decision about the accuracy of the result is debatable. Glycemic levels measured by the patient using digital equipments fail to provide correct results. Hence, physicians should be aware of the accuracy and reliability of the result while planning treatment regimen to achieve tight glycemic control.[49]

Health policies should implement regulations to reduce the burden cost of developing disease complications. Screening strategy should be adopted to identify the disease in pre diabetic state and aim at postponing or preventing the onset of frank DM. Diabetic patients should be screened for the development and progression of disease complications, especially those with myocardial damage, left ventricular dysfunction.[27] Moreover, pharmacoeconomic studies indicate that by maintaining TGC in diabetic patients is highly cost effective in terms of reduced mortality, mortality, hospital cost,[75] thus have a significant effect on the economic burden on individual as well on the country.

CONCLUSION

Recent observations suggest that selectivity of sulfonylurea determines cardiovascular safety. Among sulfonylurea, newer agent, gliclazide is preferable in terms of efficacy, long term vascular benefits, and minimal risk of hypoglycemia and weight gain. Gliptins though appear to be promising agents, their long term safety and efficacy is yet to be proved by more population based studies. We advocate better patient education, active participation and involvement for better clinical outcome; despite the availability of various treatment protocols, treatment priorities should be individualized so that quality of life is not affected in these patients. As there are many patients in pre diabetic stage, regular screening is required to identify them at initial stages of disease to minimize disease complications.