|Year : 2014 | Volume
| Issue : 4 | Page : 111-120
Tight glycemic control and cardiovascular effects in type 2 diabetic patients
Latha Subramanya Moodahadu1, Ruchi Dhall2, Abdul Hamid Zarġar3, Sudhakar Banġera4, Lalitha Ramani5, Ramesh Katipally1
1 Dr. Reddy's Laboratories Ltd., Hyderabad Telangana, India
2 Consultant Physician, Ahmedabad, Gujarat, India
3 Member Institute Body, AIIMS and Endocrinologist, Advanced Center for Diabetes and Endocrine Care, Srinagar, Jammu and Kashmir, India
4 Program Director, Clinical Development Service Agency, Gurgaon, India
5 General Practitioner and Family Physician, Hyderabad, Telangana, India
|Date of Web Publication||9-Feb-2015|
Dr. Latha Subramanya Moodahadu
G 5, Mount Meru Apartment, Road 5, Avenue 7, Banjara Hills, Hyderabad 500 034, Andhra Pradesh
Source of Support: None, Conflict of Interest: Dr Latha, Manager,
Global Medical Affairs, Dr Reddy's Laboratories Ltd., Hyderabad.
Ramesh Katipally, Group Product Manager, Dr Reddy's
| Abstract|| |
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.
Keywords: Diabetes mellitus, gliptins, non pharmacological measures, oral hypoglycemic agents, tight glycemic control
|How to cite this article:|
Moodahadu LS, Dhall R, Zarġar AH, Banġera S, Ramani L, Katipally R. Tight glycemic control and cardiovascular effects in type 2 diabetic patients. Heart Views 2014;15:111-20
|How to cite this URL:|
Moodahadu LS, Dhall R, Zarġar AH, Banġera S, Ramani L, Katipally R. Tight glycemic control and cardiovascular effects in type 2 diabetic patients. Heart Views [serial online] 2014 [cited 2019 Apr 25];15:111-20. Available from: http://www.heartviews.org/text.asp?2014/15/4/111/151084
| 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.  It has been estimated that 65% of diabetic patients die of cardiovascular diseases. 
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). ,,
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.  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.
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. 
Two studies, ADVANCE  and ACCORD,  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.
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.  Sitagliptin, saxagliptin, allogliptin and linagliptin have been approved for clinical use. These gliptins are usually combined with either metformin or sulfonylureas. 
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.  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.  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. 
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. 
Tight glycemic control was found to be beneficial in terms of better therapeutic outcome in trauma patients  and in those who were admitted to ICU for non-cardiac surgery.  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.  TGC appeared to reduce the fibrinolytic impairment and associated morbidity in patients with severe sepsis/septic shock. 
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. , 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%).  Bashir MI et al., 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.  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. 
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. 
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. 
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., and Piccini et al., 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.  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. 
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.  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. 
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.  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. 
Evidences indicate that increase in HbA1c levels can result in greater incidence of stroke and death due to heart failure in DM patients.  In diabetic patients, with acute ischemic stroke, uncontrolled hyperglycemia results in poor prognosis and clinical outcome. 
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 ,,, liver , and eye. , 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. 
| 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.  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. 
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. 
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. 
| 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. 
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. 
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. 
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.  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. 
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.  A meta-analysis by Kovalaske et al., also supports these findings. 
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.  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. 
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. 
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. 
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. ,,
| 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, , 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,  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.  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  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.  Interestingly, Dore DD, et al., have found no evidence of pancreatitis with the use of GLP-1. , Moreover, its use in renal and hepatic insufficiency is not established. 
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.  However, few have a different thought on this arguing that elderly patients will have more benefit compared to younger patients.  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.  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. ,,,
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. 
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.  Moreover, pharmacoeconomic studies indicate that by maintaining TGC in diabetic patients is highly cost effective in terms of reduced mortality, mortality, hospital cost,  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.
| References|| |
Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93.
Gotto AM Jr. Cardiologist′s role in improving glucose control and global cardiovascular risk in patients with type 2 diabetes mellitus. Am J Cardiol 2007;99:3B-5B.
Juurlink DN, Gomes T, Lipscombe LL, Austin PC, Hux JE, Mamdani MM. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: Population based cohort study. BMJ 2009;339:b2942.
Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, Ali F, Sholley C, Worrall C, et al
. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010;304:411-8.
Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al
., PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet 2005;366:1279-89.
American Diabetes Association. Standards of Medical Care in Diabetes-2013. Diabetes Care 2013;36 Suppl 1:S11-66.
Schramm TK, Gislason GH, Vaag A, Rasmussen JN, Folke F, Hansen ML, et al
. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: A nationwide study. Eur Heart J 2011;32:1900-8.
Heller S, ADVANCE Collaborative Group. A summary of the ADVANCE trial. Diabetes Care 2009;32:357-S61.
The Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, et al
. Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med 2008; 358:2545-59.
Elhadd TA, Ghosh S, Collier A, Ahmed AE. Advances in pharmacotherapy of Type 2 diabetes (Part-3: The gliptins). Sudan Med J 2010;46:65-72.
Scheen AJ, Paquot N. Gliptin versus a sulphonylurea as add-on to metformin. Lancet 2012;380:450-2.
Berhan A, Berhan Y. Efficacy of alogliptin in type 2 diabetes treatment: A meta-analysis of randomized double-blind controlled studies. BMC Endocr Disord 2013;13:9.
Clement M, Bhattacharya O, Conway JR. Is tight glycemic control in type 2 diabetes really worthwhile? Yes. Can Fam Physician 2009;55:580-8.
Scalea TM, Bochicchio GV, Bochicchio KM, Johnson SB, Joshi M, Pyle A. Tight glycemic control in critically injured trauma patients. Ann Surg 2007;246:605-10.
Krinsley JS. Glycemic control, diabetic status, and mortality in a heterogeneous population of critically ill patients before and during the era of intensive glycemic management: Six and one-half years experience at a university-affiliated community hospital. Semin Thorac Cardiovasc Surg 2006;18:317-25.
Schellhase KG, Koepsell TD, Weiss NS. Glycemic control and the risk of multiple microvascular diabetic complications. Fam Med 2005;37:125-30.
Savioli M, Cugno M, Polli F, Taccone P, Bellani G, Spanu P, et al
. Tight glycemic control may favor fibrinolysis in patients with sepsis. Crit Care Med 2009;37:424-31.
Fatim J, Karoli R, Chandra A, Naqvi N. Attitudinal determinants of fasting in type 2 diabetes mellitus patients during Ramadan. J Assoc Physicians India 2011;59:630-4.
Hui E, Devendra D. Diabetes and fasting during Ramadan. Diabetes Metab Res Rev 2010;26:606-10.
Zargar AH, Siraj M, Jawa AA, Hasan M, Mahtab H. Maintenance of glycaemic control with the evening administration of a long acting sulphonylurea in male type 2 diabetic patients undertaking the Ramadan fast. Int J Clin Pract 2010;64:1090-4.
Bashir MI, Pathan MF, Raza SA, Ahmad J, Khan AK, Ishtiaq O, et al
. Role of oral hypoglycemic agents in the management of type 2 diabetes mellitus during Ramadan. Indian J Endocrinol Metab 2012;16:503-7.
Ahmed MH, Abdu TA. Diabetes and Ramadan: An update on use of glycemic therapies during fasting. Ann Saudi Med 2011;31:402-6.
Velayudhan M. Managing diabetes during the Muslim fasting month of Ramadan. Med J Malaysia 2012;67:353-5.
Cherian B, Meka N, Katragadda S, Arora R. Therapeutic implications of diabetes in cardiovascular disease. Am J Ther 2009;16:e51-9.
Bi Y, Zhu D, Cheng J, Zhu Y, Xu N, Cui S, et al
. The status of glycemic control: A cross-sectional study of outpatients with type 2 diabetes mellitus across primary, secondary, and tertiary hospitals in the Jiangsu province of China. Clin Ther 2010;32:973-83.
Tarantini L, Di Lenarda A, Velussi M, Faggiano P, Comaschi M, Faglia E, et al
. Diabetes mellitus, left ventricular dysfunction and congestive heart failure. Ital Heart J Suppl 2004;5:605-15.
Piccini JP, Klein L, Gheorghiade M, Bonow RO. New insights into diastolic heart failure: Role of diabetes mellitus. Am J Med 2004;116 Suppl 5A: 64-75S.
Marfella R, Sasso FC, Cacciapuoti F, Portoghese M, Rizzo MR, Siniscalchi M, et al
. Tight glycemic control may increase regenerative potential of myocardium during acute infarction. J Clin Endocrinol Metab 2012;97:933-42.
Marfella R, Di Filippo C, Portoghese M, Ferraraccio F, Rizzo MR, Siniscalchi M, et al
. Tight glycemic control reduces heart inflammation and remodeling during acute myocardial infarction in hyperglycemic patients. J Am Coll Cardiol 2009;53:1425-36.
Tandon N, Ali MK, Narayan KM. Pharmacologic prevention of microvascular and macrovascular complications in diabetes mellitus: Implications of the results of recent clinical trials in type 2 diabetes. Am J Cardiovasc Drugs 2012;12:7-22.
Weiss IA, Valiquette G, Schwarcz M. Impact of glycemic treatment choices on cardiovascular complications in type 2 diabetes. Cardiol Rev 2009;17:165-75.
Lazar HL, Chipkin SR, Fitzgerald CA, Bao Y, Cabral H, Apstein CS. Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation 2004;109:1497-502.
Brown JR, Furnary AP, Mackenzie TA, Duquette D, Helm RE, Paliotta M, et al
., Northern New England Cardiovascular Disease Study Group. Does tight glucose control prevent myocardial injury and inflammation? J Extra Corpor Technol 2011;43:144-52.
Drechsler C, Krane V, Ritz E, März W, Wanner C. Glycemic control and cardiovascular events in diabetic hemodialysis patients. Circulation 2009;120:2421-8.
Kruyt ND, Biessels GJ, Devries JH, Roos YB. Hyperglycemia in acute ischemic stroke: Pathophysiology and clinical management. Nat Rev Neurol 2010;6:145-55.
Sawicki PT, Bender R, Berger M, Mühlhauser I. Non-linear effects of blood pressure and glycosylated haemoglobin on progression of diabetic nephropathy. J Intern Med 2000;247:131-8.
Fioretto P, Bruseghin M, Berto I, Gallina P, Manzato E, Mussap M. Renal protection in diabetes: role of glycemic control. J Am Soc Nephrol 2006;17:S86-9.
Park L, Wexler D. Update in diabetes and cardiovascular disease: Synthesizing the evidence from recent trials of glycemic control to prevent cardiovascular disease. Curr Opin Lipidol 2010;21:8-14.
Thomaseth K, Pacini G, Morelli P, Tonolo G, Nosadini R. Importance of glycemic control on the course of glomerular filtration rate in type 2 diabetes with hypertension and microalbuminuria under tight blood pressure control. Nutr Metab Cardiovasc Dis 2008;18:632-8.
Hamaguchi E, Takamura T, Sakurai M, Mizukoshi E, Zen Y, Takeshita Y, et al.
Histological course of nonalcoholic fatty liver disease in Japanese patients: Tight glycemic control, rather than weight reduction, ameliorates liver fibrosis. Diabetes Care 2010;33:284-6.
Mesotten D, Wauters J, Van den Berghe G, Wouters P, Milants I, Wilmer A. The effect of strict blood glucose control on biliary sludge and cholestasis in critically ill patients. J Clin Endocrinol Metab 2009;94:2345-52.
Raman R, Gupta A, Kulothungan V, Sharma T. Prevalence and risk factors of diabetic retinopathy in subjects with suboptimal glycemic, blood pressure and lipid control. Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic Study (SN-DREAMS, Report 33). Curr Eye Res 2012;37:513-23.
The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes 1995;44:968-83.
Shorr RI, de Rekeneire N, Resnick HE, Yaffe K, Somes GW, Kanaya AM, et al.
Glycemia and cognitive function in older adults using glucose-lowering drugs. J Nutr Health Aging 2006;10:297-301.
Steil GM, Langer M, Jaeger K, Alexander J, Gaies M, Agus MS. Value of continuous glucose monitoring for minimizing severe hypoglycemia during tight glycemic control. Pediatr Crit Care Med 2011;12:643-8.
Puar TH, Khoo JJ, Cho LW, Xu Y, Chen YT, Chuo AM, et al.
Association between glycemic control and hip fracture. J Am Geriatr Soc 2012;60:1493-7.
Redelmeier DA, Kenshole AB, Ray JG. Motor vehicle crashes in diabetic patients with tight glycemic control: A population-based case control analysis. PLoS Med 2009;6:e1000192.
Egi M, Finfer S, Bellomo R. Glycemic control in the ICU. Chest 2011;140:212-20.
Reeds D. Near-normal glycemia for critically ill patients receiving nutrition support: Fact or folly. Curr Opin Gastroenterol 2010;26:152-5.
Siegelaar SE, Devries JH, Hoekstra JB. Patients with diabetes in the intensive care unit; not served by treatment, yet protected? Crit Care 2010;14:126.
Bhamidipati CM, LaPar DJ, Stukenborg GJ, Morrison CC, Kern JA, Kron IL, et al
. Superiority of moderate control of hyperglycemia to tight control in patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2011;141:543-51.
Leibowitz G, Raizman E, Brezis M, Glaser B, Raz I, Shapira O. Effects of moderate intensity glycemic control after cardiac surgery. Ann Thorac Surg 2010;90:1825-32.
Dokun AO. Lessons learned from glycemia control studies. Curr Diab Rep 2010;10:133-8.
Kovalaske MA, Gandhi GY. Glycemic control in the medical intensive care unit. J Diabetes Sci Technol 2009;3:1330-41.
Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: A meta-analysis. JAMA 2008;300:933-44.
Chen LK, Chen YM, Lin MH, Peng LN, Hwang S. Care of elderly patients with diabetes mellitus: A focus on frailty. Ageing Res Rev 2010;9 Suppl 1:S18-22.
Marik PE, Preiser JC. Toward understanding tight glycemic control in the ICU: A systematic review and metaanalysis. Chest 2010;137:544-51.
Wilson G, Perry T. Is tight glycemic control in type 2 diabetes really worthwhile? NO. Can Fam Physician 2009;55:581, 583, 585, 587, 588.
Hanazaki K, Maeda H, Okabayashi T. Tight perioperative glycemic control using an artificial endocrine pancreas. Surg Today 2010;40:1-7.
Hanazaki K, Maeda H, Okabayashi T. Relationship between perioperative glycemic control and postoperative infections. World J Gastroenterol 2009;15:4122-4125.
Rogers S, Ramos M. Tight glycemic control using an artificial pancreas to control perioperative hyperglycemia decreases surgical site infection in pancreatectomized or hepatectomized patients. Ann Surg 2009;250:351-2.
LeRoith D, Rayfield EJ. The benefits of tight glycemic control in type 2 diabetes mellitus. Clin Cornerstone 2007;8 Suppl 7:S19-29.
Silva FM, Steemburgo T, Azevedo MJ, Mello VD. Glycemic index and glycemic load in the prevention and treatment of type 2 diabetes mellitus. Arq Bras Endocrinol Metabol 2009;53:560-71.
Furukawa S, Kumagi T, Miyake T, Ueda T, Niiya T, Nishino K, et al
. Suicide attempt by an overdose of sitagliptin, an oral hypoglycemic agent: A case report and a review of the literature. Endocr J 2012;59:329-33.
Information for Healthcare Professionals-Acute pancreatitis and sitagliptin (marketed as Januvia and Janumet). Drugs. US FDA. Available from http://www.fda.gov/Drugs/....ucm183764.htm
[Last accessed on 2013 Apr 01].
Dore DD, Bloomgren GL, Wenten M, Hoffman C, Clifford CR, Quinn SG, et al
. A cohort study of acute pancreatitis in relation to exenatide use. Diabetes Obes Metab 2011;13:559-66.
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
Tice MA. Diabetes management at the end of life: Transitioning from tight glycemic control to comfort. Home Healthc Nurse 2006;24:290-3.
Chin TL, Sauaia A, Moore EE, Chandler JG, Harr JN, Johnson JL, et al
. Elderly patients may benefit from tight glucose control. Surgery 2012;152:315-21.
Triplitt C. Cardiac risk factors and hypoglycemia in an elderly patient: How good is good enough? Consult Pharm 2010;25 Suppl B: 19-27.
Cheng AY, Leiter LA. Glucose lowering and cardiovascular disease: What do we know and what should we do? Eur J Cardiovasc Prev Rehabil 2010;17:S25-31.
Bianchi C, Penno G, Miccoli R, Del Prato S. Blood glucose control and coronary heart disease. Blood glucose control and coronary heart disease. Herz 2010;35:148-59.
Hilleman DE. Cost considerations with tight glycemic control in the acute care setting. Semin Thorac Cardiovasc Surg 2006;18:359-65.
[Figure 1], [Figure 2], [Figure 3]
|This article has been cited by|
||Anti-diabetic activity of aerial parts of Sarcopoterium spinosum
| ||Uriel Elyasiyan,Adi Nudel,Nir Skalka,Konstantin Rozenberg,Elyashiv Drori,Rachela Oppenheimer,Zohar Kerem,Tovit Rosenzweig |
| ||BMC Complementary and Alternative Medicine. 2017; 17(1) |
|[Pubmed] | [DOI]|
||Impact of glycemic control with sitagliptin on the 2-year progression of arterial stiffness: a sub-analysis of the PROLOGUE study
| ||Hirofumi Tomiyama,Takashi Miwa,Kenshi Kan,Munehide Matsuhisa,Haruo Kamiya,Mamoru Nanasato,Tomoki Kitano,Hiroaki Sano,Jun Ohno,Masato Iida,Masataka Sata,Hirotsugu Yamada,Koji Maemura,Atsushi Tanaka,Toyoaki Murohara,Koichi Node |
| ||Cardiovascular Diabetology. 2016; 15(1) |
|[Pubmed] | [DOI]|
||Closed-loop glycaemic control using an implantable artificial pancreas in diabetic domestic pig (Sus scrofa domesticus)
| ||M.J. Taylor,R. Gregory,P. Tomlins,D. Jacob,J. Hubble,T.S. Sahota |
| ||International Journal of Pharmaceutics. 2016; 500(1-2): 371 |
|[Pubmed] | [DOI]|