Review Article Management of diabetes mellitus type‑2 in the geriatric population: Current perspectives Sukhminder Jit Singh Bajwa, Vishal Sehgal1, Sanjay Kalra2, Manash Pratim Baruah3
Department of Anaesthesiology and Intensive Care Medicine, Gian Sagar Medical College and Hospital, Patiala, Punjab, 2Department of Endocrinology, Bharti Hospital and B.R.I.D.E., Karnal, Haryana, 3Department of Endocrinology, ECXEL Center, Guwahati, Assam, India, 1Department of Internal Medicine, The Common Wealth Medical College, Scranton, PA 18510, USA
ABSTRACT The prevalence of diabetes mellitus (DM) has increased exponentially throughout the world and there is rapid increase in elderly diabetics. DM is associated with increased mortality and considerable morbidity including stroke, heart disease, and diminished quality of life in the elderly. However, the unique features of geriatric diabetes have not been given due a prominence in medical literature. Hypoglycemia remains the biggest complicating factor and needs to be avoided in the elderly. Most people in the geriatric age group have some degree of renal insufficiency and medications need to be adjusted wisely with changing renal profile. Because safer and more effective pharmacological therapy is available, an individual approach to DM in the elderly is essential.
Address for correspondence: Dr. Sukhminder Jit Singh Bajwa, E-mail: sukhminder_ [email protected] Received : 10‑05‑13 Review completed : 06‑06‑13 Accepted : 29‑09‑13
KEY WORDS: Chronic kidney disease, diabetes mellitus, geriatric, new onset diabetes after transplant
T
he epidemic of diabetes mellitus (DM) has engulfed the entire globe and the prevalence is increasing exponentially across the nations. Factors such as increase in life expectancy, increased health awareness and literacy rate, obesity, and sedentary lifestyle has resulted in more and more of DM prevalence in the elderly.[1,2] About 80% of the elderly Access this article online Quick Response Code:
in the United States are either prediabetic or diabetic. As it is in the treatment of any disease, the benefit to risk ratio is to be assessed when treating this particular patient population. This particular article is aimed at making the reader understand the changing body physiology with aging and how it affects the treatment of diabetes in the elderly. For our discussion, elderly is defined as people with chronological age more than or equal to 65 years.
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Changing Body Physiology with Aging
DOI:
Pathophysiological changes of aging causes increase prevalence of diabetes and carbohydrate intolerance in the elderly due to associated decrease in insulin secretion in response to glucose
10.4103/0975-7406.130956
How to cite this article: Bajwa SJ, Sehgal V, Kalra S, Baruah MP. Management of diabetes mellitus type-2 in the geriatric population: Current perspectives. J Pharm Bioall Sci 2014;6:151-7.
Journal of Pharmacy and Bioallied Sciences July-September 2014 Vol 6 Issue 3
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load as well as increased insulin resistance in peripheral tissues.[3] Further, insulin sensitivity also decreases with increasing age and obesity.[4] Body attains the peak body mass around the age of 30. Thereafter there is slow progressive decline of Glomerular filtration rate (GFR) even if there is no superimposed pathology. With aging, most of the population tends to have diabetes and hypertension, which further exacerbates the picture.[5] It changes the pharmacokinetics and pharmacodynamics of the drugs. Dietary constraints also impact the physiology of the body in the elderly. Reduced ability to afford, access, procure, eat, chew, absorb, and digest food may affect glycemic control.[6]
Common Geriatric Syndromes and Diabetes Cognitive impairment Elderly patients with diabetes and cognitive dysfunction may have difficulty performing self‑management and follow complicated treatment regimens.[7] They are less functional compared with nondiabetic elderly.[8,9] Cognitive function should be assessed in elderly diabetic patients when there are frequent episodes of hypoglycemia or deterioration of glycemic control without obvious explanation.[7] Hypoglycemia unawareness becomes a major complicating factor in management of elderly diabetics.[10]
Depression Depression is common in this high risk population and shares a bidirectional link with diabetes. Uncontrolled depression may affect the overall management of diabetes.[11]
Polypharmacy Management of hyperglycemia and its associated risk factors often increases the number of medications even more in the elderly with diabetes. Oral hypoglycemic drug combinations have been found to be effective and safe.[12] But this may not be necessarily true in the elderly where polypharmacy is rampant. This increases the chances of drug–drug interaction.[13] Apart from these, elderly persons with diabetes may consume complementary or alternative medicines (CAM) without informing the physician. This too may increase the risk of hypoglycemia.[13,14]
Falls Benefits of improved glycemic control to reduce diabetes‑related complications must be balanced with the possible risk of falls precipitated by hypoglycemia.
Urinary incontinence Risk factors for this common complication include urinary tract infection, autonomic neuropathy, and polyuria due to hyperglycemia.
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Chronic pain syndrome It affects the elderly diabetics to a varying degree resulting in mild‑to‑severe degree of pain. At times, pain can be refractory to treatment also.
Diagnosis of Diabetes The diagnostic criterion for diabetes and prediabetes in the elderly is the same as in general population.[15] Almost three‑quarters of elderly have prediabetes. In contrast, 33% of elderly have diabetes. Prediabetes is particularly important as it is potentially the stage where diabetes may be arrested or reversed with appropriate life style changes.[16] Insulin resistance has already set in when patient becomes prediabetic.
Pitfalls of HbA1c monitoring in the elderly HbA1c is more specific but less sensitive than fasting plasma glucose as a diagnostic tool for diabetes.[17,18] It should be interpreted cautiously in the elderly keeping in view the co‑morbidities in changing body physiology. Because of these changes it can be a misleading diagnostic tool. In rapid cell turnover states like hemolytic anemia HbA1c could be falsely low. During treatment with iron, B12 or erythropoietin as in chronic kidney disease (CKD) there may be rapid red blood cell turnover and falsely low HbA1c.[19,20] In contrast, in low cell turnover states especially iron, B12 or folate deficiency or in the very elderly when marrow turnover is low, HbA1c may be falsely high. In CKD HbA1c may be falsely high or low. When there is high carbamylated hemoglobin it may be falsely high, and if erythropoietin is being used it may be falsely low [Table 1].
Management of glycemia Frailty, cognitive decline and polypharmacy are complicating factors that complicate the glycemic control in the elderly.[21] Addition of hypoglycemic medications, whether oral or injectable, adds to the burden of polypharmacy. The key treatment goal remains avoidance of hypoglycemia while optimizing glycemic control.[22] Newer agents may help the clinician in achieving glycemic control while avoiding hypoglycemia. The clinician needs to be familiar with the pharmacokinetics and pharmacodynamics of these medications to safely use them for optimizing glycemic control. Elderly diabetics typically have multiple comorbidities, which may make it challenging for the clinician to optimize glycemic control. This is especially true for people having renal insufficiency, which is fairly common in the elderly.[23] Medications with shorter Table 1: Pitfalls in monitoring of HbA1C Pitfalls of HBA1C Falsely high HbA1C
Falsely low HbA1C
Low red cell turnover states Iron, Vit B12, folate deficiency
High red cell turnover states Iron, Vit B12, folate, erythropoietin therapy CKD (high carbamylated haemoglobin) CKD (Exogenous erythropoietin) CKD: Chronic kidney disease, HbA1C: Glycated haemoglobin Journal of Pharmacy and Bioallied Sciences July-September 2014 Vol 6 Issue 3
Bajwa, et al.: Management of diabetes in elderly
half‑life and inactive metabolites may in general be more suitable for the elderly. Treatment needs to be individualized keeping in view the comorbidities and functionality of the patient. Here under is a brief description of the hypoglycemic agents [Table 2] with particular reference to geriatric age group. The efficacy, safety, and tolerability of these drugs have been adjudged on the basis of various clinical trials and analyzes, as reviewed in earlier international guidelines.[24]
Sulfonylureas Sulfonylureas and insulin are the major cause of severe hypoglycemia in the elderly.[25] The goal of treatment in the elderly remains glycemic control with priority on preventing hypoglycemia.[22] Preference is given to short‑acting sulfonylurea glipizide. [26] This is consistent with American Diabetes Association recommendations, which recommend the use of second‑generation sulfonylureas, but not glyburide.[27]
Biguanides Metformin is the prototype of this class and only drug in its class which is clinically used. It is contraindicated in patients with serum creatinine >1.5 in men and >1.4 in women. It also has a relative contraindication in people with heart failure. Its major advantages include minimal or no hypoglycemia and a cardio‑protective effect, as proven in the landmark UKPDS study.[28] Metformin associated lactic acidosis (MALA) is another complication of metformin. Though rare, it can be fatal. A high index of suspicion is required to diagnose MALA, which occurs more frequently in elderly patients with renal impairment.
Thiazolidinedione They are well tolerated in older adults, and do not cause hypoglycemia. However, thiazolidinediones should not be used in patients with class III or IV heart failure due to concerns regarding fluid retention. Atypical hip fractures have also limited their utility particularly in the elderly.[29] Table 2: Status of oral hypoglycemics in geriatric diabetes Class Sulfonylureas
Molecule
Glibenclamide Glipizide Gliclazide Glimepiride Meglitinides Repaglinide Biguanides Metformin Thiazolidinediones Pioglitazone Alpha‑glucosidase inhibitors Acarbose Voglibose Dopamine modulators Bromocriptine DPP‑4 inhibitors Sitagliptin Vildagliptin Saxagliptin Linagliptin
Efficacy Safety/Tolerability +++ + +++ +++ +++ +++ +++ + + + ++ ++ ++ ++
0 +++ ++ ++ +++ ++ ++ ++ ++ ++ +++ +++ +++ +++
DPP: Dipeptidyp peptidase Journal of Pharmacy and Bioallied Sciences July-September 2014 Vol 6 Issue 3
Meglitinides Repaglinide, a rapid acting insulin secretagogue, is principally metabolized by the liver. Dose adjustments with this agent do not appear to be necessary in patients with renal insufficiency.[30] It is a safe drug to use in elderly as the risk of hypoglycemia is lower.[31]
Alpha‑glucosidase inhibitors This class of drugs, including acarbose, vaglibose, and meglitol, inhibit the gastrointestinal alpha‑glycosidase that digests starch and other complex carbohydrates thereby slowing the absorption of glucose.[32] Chances of hypoglycemia are minimal. The main side effect that limits their use is flatulence.
Bromocriptine Timed release bromocriptine is approved for use in type 2 diabetes. It acts by resetting the hyper‑dopaminergic tone of the hypothalamus, which is disturbed in diabetes. The action occurs through dopaminergic receptors. Its proven cardiovascular safety makes it an attractive drug in selected geriatric patients. Limited efficacy and transient gastrointestinal side effects are some of the limiting factors.
DPP‑IV inhibitors These are attractive agents to use in the elderly. In fact, the gliptins have been shown to have a much more beneficial effect in the elderly, perhaps because levels of DPP4 (dipeptidyp peptidase-IV) increase with advancing age. They are associated with low risk of hypoglycemia, weight neutrality, and a low risk of drug–drug interactions.[33,34] Patients with renal insufficiency need dose readjustment of sitagliptin, saxagliptin, and vildagliptin, but not of linaglitpin. Hepatic insufficiency is a contraindication for vildagliptin, but not for the other drugs in this class. The DPP4 inhibitors are considered cardiosafe, and have been used in acute coronary syndrome settings as well.
GLP‑1 therapies Liraglutide and exenatide, administered as once daily and twice daily subcutaneous injections, are available for use. There is no risk of hypoglycemia with the use of GLP‑1 (glucagon-like peptide-1). analogs alone.[35] They are sometimes associated with significant reduction in weight. There have been case reports of acute pancreatitis and deterioration in renal function in patients taking GLP‑1 therapies.[36] When used with basal insulin, they mitigate weight gain that is associated with insulin use and improves baseline and postprandial hyperglycemia.[37] These drugs may be used in normal weight or over weight elderly, but should be avoided in frail patients. Once weekly exenatide long acting release (LAR) injection is also available now.
Pramlintide It is administered as mealtime subcutaneous injection with insulin. It is available for the treatment of both type 1 and 153
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insulin‑treated type 2 diabetes. It requires multiple subcutaneous injections and, therefore, its role in the management of diabetes in the elderly is limited.[36]
Insulin Insulin is underutilized in the elderly. It has become easier to use once daily long‑acting insulin. Hyperglycemia may cause symptoms of fatigue, which elderly may attribute to old age. Insulin metabolism is altered in patients with chronic renal failure, so that less insulin is needed when GFR is below 50 ml/min. Dose adjustment is also needed in cases of recurrent hypoglycemia.[38] Insulin is the most cost‑effective treatment for diabetes, in both old as well as young. The safety and convenience of insulin therapy has improved with the availability of modern insulin analogs: Rapid acting aspart, lispro, and glulisine, premixed aspart and lispro, as well as basal detemir and glargine. Insulin can be considered a first‑tier therapy for diabetes associated with severe symptomatic hyperglycemia.[39] Insulin has no upper dose limit and, unlike other antidiabetic agents, it has no contraindications to its use.[40] Comorbidity caused by multiple pathology, as well as ill‑health associated with specific conditions such as impaired cognitive function, depression, inflammatory arthropathy, and cardiac or renal failure, may make insulin titration in the elderly a challenge. Age‑related changes result in functional disability, affecting the patient’s ability to administer insulin, monitor blood glucose, and manage hypoglycemia.[41] Use of accurate, convenient injection devices makes insulin use much simpler. Also, appropriate choice of simple, easy to use insulin regimes, makes the therapy more acceptable. The South Asian Consensus guidelines recognize that the initiation of insulin therapy is a challenging task, especially in older adults who often have multiple comorbidities and physical limitations. It, however, strongly believes that physicians should not avoid usage of insulin, using age as a bar.[24] Essentially, the need to start insulin in older patients is not different from younger patients. Technical superiority of a product (analog vs. conventional), or an injection device (pen vs. syringes), should play a role in planning and executing insulin therapy in the elderly to make it more comfortable and acceptable as well. All patients must be sensitized to the importance of self and structured monitoring of blood glucose at home. In frail and very old patients, it is essential to ensure the presence of responsible attendants/family members during selecting the right dose of insulin, injecting that dose, and monitoring by a glucometer.[42] Premixed insulin Conventionally, premixed insulins are used twice daily, with breakfast and supper. Premixed insulin preparations are more convenient and less prone to errors in dosing. Premix insulin is the preferred insulin in the social situation prevailing in the South Asian countries because of the following reasons: Simple start, option to intensify with same insulin, coverage of both FPG and PPG, and eventually effective HbA1c control.[43] Premixed analogs can be injected immediately
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before or after meals, offering added advantages of flexibility, ability to decide dosage after assessing caloric intake, and avoidance of hypoglycemia. Premixed aspart can also be given once daily (Once Mix) for initiation, with beneficial results.[44] A pilot multicenter study from India examining the role of Designer Insulin Regimen in Clinical Practice has depicted that both premix insulin analogs (two injections per day) and basal bolus analog regimen (four injections per day) can be used in an equally effective way for initiating insulin therapy in T2DM. However, premix insulin analog fared better than the basal bolus regimen in lowering HbA1c (1.58 vs. 1.16%; P 150 mg/dl and PPPG is >200 mg/dl and/or HbA1c is >8.5%. Long‑acting analogs are preferred over NPH basal insulin. Metformin and morning sulfonylureas should be continued along with basal insulin therapy. The panel prefers a conservative initial starting dose of 0.1 U/kg/day. After initiation, the dose should be titrated once or twice every week on the basis of glucose monitoring results, targeting FBG. High HbA1c may be due to postprandial hyperglycemia.
Inpatient
Blood glucose monitoring Traditional meters and strips as well as continuous glucose monitoring, which measure the glucose levels in the interstitial tissue, have been fairly successful in optimizing glycemic control and reducing hypoglycemia.[48] Different types of sensors are in the process of being developed. They have the potential to be useful in the geriatric age group where underlying dementia and functional impairment might impede successful glycemic control. HbA1c, in conjunction with fasting plasma glucose, is an important tool in the management of DM both for diagnostic purposes and assessing the response to therapy.[49] Its absolute values may have some differences in racial and ethnic groups.[50]
Management of Diabetes in Different Clinical Settings Principles of management Management of DM is highly challenging in the elderly for the reasons well explained earlier. The main goals during management include • Optimizing functional and daily routine activities. • Avoidance of both hyperglycemia and hypoglycemia. • Minimizing and preventing microvascular and macrovascular complications.
Outpatient To minimize risk for hypoglycemia, the target goals of HbA1c have been defined as less than 8% in elderly as compared with 7% in the general population.[51] This is to minimize hypoglycemia, which is shown to increase morbidity and mortality especially in the elderly. Educating about hypoglycemia awareness and glycemic control is an important concept.[52,53] Diabetes self‑management is one of the key to successful management of diabetes.[54] Focus should always be to prevent hypoglycemia in the elderly. Care coordination is one of the key approaches in successfully treating diabetic patients.[55‑57] It goes a long way in reducing the disease burden and cost to the society.[58] It is especially true when patient is discharged from the hospital or admitted Journal of Pharmacy and Bioallied Sciences July-September 2014 Vol 6 Issue 3
Hospitalizations are a big stressor more so for the elderly. Clinician might encounter stress hyperglycemia especially in perioperative settings. Stress hyperglycemia has the similar complications like infection and poor wound healing. This is due to release of counter regulatory hormones and cytokines.[59] It also gives the clinician an opportunity to diagnose prediabetes. A standard approach of long acting insulin with mealtime and correctional insulin remains the standard even in the treatment of stress hyperglycemia.
Critical care settings Initial studies had focused on the benefits of intensive glycemic control with I/V insulin in the postoperative settings, but subsequent studies in medical intensive care unit (ICU) showed increased mortality.[10,60] The recommended standard is to keep the glucose level less than 180 mg%.[61] Hyperglycemia in critical care settings may be encountered secondary to enteral and parenteral nutrition and variability of food intake in critical care settings. Some medications may contribute to the same.[62] In contrast, hypoglycemia related to severe sepsis in the demented geriatric patients has been shown to have grave prognosis too.[63]
Perioperative management of diabetic patients and hyperglycemia There have been variable results from the recent studies in contrast to the initial studies, which reported benefits of ‘tight glycemic control with insulin’ during the perioperative period.[64] The variation of results between efficacy and safety of conventional insulin regimen and intensive control with insulin in these studies can be attributed to numerous factors such as the variable impact of hyperglycemia on surgical outcome, different targets set for the blood glucose levels, ethnic and demographic variations, nature, duration and severity of surgical insults, preoperative morbidities and hemodynamic instability and so on.[65‑68] Tight glycemic control has been advocated by various international advisory committees in spite of various conflicting reports in literature so as to improve the surgical outcome.[69,70] Insulin may not have direct effect on decreasing surgical morbidity and mortality but potentially have various indirect roles due to its anabolic actions in normalizing the lipids and cholesterol levels, significantly effecting protein metabolism, modulation of nitric oxide activity and antiinflammatory effects.[71,72] Further, surgical outcome is determined by the type of surgery, the duration of surgical procedure, severity of surgery (major or minor), presence of preoperative comorbidities, which are invariably present in elderly population, chronological age of 155
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DM and the extent to which glycemic control is exercised. Glucose, insulin and potassium (GIK) and variable rate insulin infusion regimen are the two most commonly used insulin regimens in perioperative settings in Indian health centers. Infusion pumps are costly gadgets with limited feasibility for use in low resource settings. As such there is always a need to improvise alternate methods without losing the advantages associated with these costly gadgets. A simple yet effective method that can be used in peripheral health centers and remote locations consists of micro‑drip sets attached to 500 ml of 5% dextrose solution. Insulin and potassium can be administered with the help of such methods thus achieving therapeutic goals. Diabeto‑anesthesia is an unexplored sub‑specialty, which needs to be developed for a better surgical outcome in the near future.[73] Adequate control of hyperglycemic status during perioperative period is associated with a good surgical outcome as has been established by various studies involving cardiac surgery, cardio‑thoracic surgery, neuro‑surgery besides general surgical procedures.[74]
10. 11. 12. 13.
14. 15. 16. 17. 18.
19.
Conclusion The data regarding glycemic control in the elderly is minimal. It is challenging for the physician to have an optimum glycemic control. Treatment needs to be individualized in this age group keeping in mind the benefit to risk ratio.[75,76] There is plethora of new diabetic medications in the market and physician needs to choose wisely.
Acknowledgement
20. 21. 22. 23.
The authors acknowledge the following endocrinologists for preparing, drafting, and editing of the present manuscript: Dr. Ganapathy Bantwal, MD, DM (Endocrinology); Dr. Rakesh Sahay, MD, DM (Endocrinology); Dr. Mathew John, MD, DM (Endocrinology); Dr. Ambika Gopalakrishnan Unnikrishnan, MD, DM (Endocrinology).
24.
References
26.
1. 2. 3. 4. 5. 6. 7. 8. 9.
Zarowitz BJ. Management of diabetes mellitus in older persons. Geriatr Nurs 2006;27:77‑82. Liao EP. Patterns of medication initiation in newly diagnosed diabetes mellitus: Quality and cost implications. Am J Med 2012;125:S1‑2. Meneilly GS, Elliott T, Tessier D, Hards L, Tildesley H. NIDDM in the elderly. Diabetes Care 1996;19:1320‑5. Rizvi AA. Management of diabetes in older adults. Am J Med Sci 2007;333:35‑47. Moritz DJ, Ostfeld AM, Blazer D 2nd, Curb D, Taylor JO, Wallace RB. The health burden of diabetes for the elderly in four communities. Public Health Rep 1994;109:782‑90. Kalra S, Kalra B, Saluja S. Dietary management in geriatric patients of diabetes mellitus: Special considerations. Internet J Geriatr Gerontol 2009;5. Abbatecola AM, Paolisso G, Corsonello A, Bustacchini S, Lattanzio F. Antidiabetic oral treatment in older people: Does frailty matter? Drugs Aging 2009;26 Suppl 1:53‑62. Blaum CS, Ofstedal MB, Langa KM, Wray LA. Functional status and health outcomes in older americans with diabetes mellitus. J Am Geriatr Soc 2003;51:745‑53. Saczynski JS, Jónsdóttir MK, Garcia ME, Jonsson PV, Peila R, Eiriksdottir G, et al. Cognitive impairment: An increasingly important
156
25.
27. 28.
29.
30. 31. 32. 33.
complication of type 2 diabetes: The age, gene/environment susceptibility‑Reykjavik study. Am J Epidemiol 2008;168:1132‑9. Kalra S, Bajwa SS, Baruah M, Sehgal V. Hypoglycaemia in anesthesiology practice: Diagnostic, preventive, and management strategies. Saudi J Anaesth 2013;7:447-52. Black SA, Markides KS. Depressive symptoms and mortality in older Mexican Americans. Ann Epidemiol 1999;9:45‑52. Koliaki C, Doupis J. Linagliptin/Metformin fixed‑dose combination treatment: A dual attack to type 2 diabetes pathophysiology. Adv Ther 2012;29:993‑1004. Sehgal V, Bajwa SS, Sehgal R, Bajaj A, Khaira U, Kresse V. Polypharmacy and potentially inappropriate medication use as the precipitating factor in readmissions to the hospital. J Fam Med Prim Care 2013;2:194‑9. Bajwa SS, Panda A. Alternative medicine and anesthesia: Implications and considerations in daily practice. Ayu 2012;33:475‑80. Basevi V, Di Mario S, Morciano C, Nonino F, Magrini N. American Diabetes Association. Standards of medical care in diabetes-2011. Diabetes Care 2011;34 Suppl 1:S11-61. Schwarz PE. Prediabetes: High risk factor for diabetes mellitus type 2?‑Successful prevention with early interventions for lifestyle modification. Dtsch Med Wochenschr 2012;137:1788. Herman WH, Fajans SS. Hemoglobin A1c for the diagnosis of diabetes: Practical considerations. Pol Arch Med Wewn 2010;120:37‑40. Shibata K, Suzuki S, Sato J, Ohsawa I, Goto S, Iritani I, et al. Diagnostic accuracy of glycohemoglobin A1c (HbA1c) for postprandial hyperglycemia was equivalent to that of fasting blood glucose. J Clin Epidemiol 2005;58:1052‑7. Brown JN, Kemp DW, Brice KR. Class effect of erythropoietin therapy on hemoglobin A (1c) in a patient with diabetes mellitus and chronic kidney disease not undergoing hemodialysis. Pharmacotherapy 2009;29:468‑72. Ng JM, Cooke M, Bhandari S, Atkin SL, Kilpatrick ES. The effect of iron and erythropoietin treatment on the A1C of patients with diabetes and chronic kidney disease. Diabetes Care 2010;33:2310‑3. Abbatecola AM, Paolisso G. Diabetes care targets in older persons. Diabetes Res Clin Pract 2009;86 Suppl 1:S35‑40. Inkster B, Zammitt NN, Frier BM. Drug‑induced hypoglycaemia in type 2 diabetes. Expert Opin Drug Saf 2012;11:597‑614. Suh DC, Kim CM, Choi IS, Plauschinat CA. Comorbid conditions and glycemic control in elderly patients with type 2 diabetes mellitus, 1988 to 1994 to 1999 to 2004. J Am Geriatr Soc 2008;56:484‑92. Baruah MP, Kalra S, Unnikrishnan AG, Raza SA, Somasundaram N, John M, et al. Management of hyperglycemia in geriatric patients with diabetes mellitus: South Asian consensus guidelines. Indian J Endocrinol Metab 2011;15:75‑90. Brunton SA. Hypoglycemic potential of current and emerging pharmacotherapies in type 2 diabetes mellitus. Postgrad Med 2012;124:74‑83. Bao YQ, Zhou J, Zhou M, Cheng YJ, Lu W, Pan XP, et al. Glipizide controlled‑release tablets, with or without acarbose, improve glycaemic variability in newly diagnosed Type 2 diabetes. Clin Exp Pharmacol Physiol 2010;37:564‑8. Skoff RA, Waterbury NV, Shaw RF, Egge JA, Cantrell M. Glycemic control and hypoglycemia in Veterans Health Administration patients converted from glyburide to glipizide. J Manag Care Pharm 2011;17:664‑71. Evans JM, Ogston SA, Emslie‑Smith A, Morris AD. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: A comparison of patients treated with sulfonylureas and metformin. Diabetologia 2006;49:930‑6. Colhoun HM, Livingstone SJ, Looker HC, Morris AD, Wild SH, Lindsay RS, et al. Scottish Diabetes Research Network Epidemiology Group. Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose‑lowering drugs. Diabetologia 2012;55:2929‑37. Scott LJ. Repaglinide: A review of its use in type 2 diabetes mellitus. Drugs 2012;72:249‑72. Landgraf R. Meglitinide analogues in the treatment of type 2 diabetes mellitus. Drugs Aging 2000;17:411‑25. Kumar S, Narwal S, Kumar V, Prakash O. Alpha‑glucosidase inhibitors from plants: A natural approach to treat diabetes. Pharmacogn Rev 2011;5:19‑29. 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
Journal of Pharmacy and Bioallied Sciences July-September 2014 Vol 6 Issue 3
Bajwa, et al.: Management of diabetes in elderly
34.
35.
36. 37.
38. 39.
40. 41. 42. 43.
44. 45.
46. 47.
48. 49.
50. 51.
52. 53.
diabetes mellitus during Ramadan. Indian J Endocrinol Metab 2012;16:503‑7. Yoshida T, Akahoshi F, Sakashita H, Kitajima H, Nakamura M, S o n d a S, e t a l . D i s c o v e r y a n d p r e c l i n i c a l p r o f i l e o f teneligliptin (3‑[(2S,4S)‑4‑[4‑(3‑methyl‑1‑phenyl‑1H‑pyrazol‑5‑yl) piperazin‑1‑yl] pyrrolidin‑2‑y lcarbonyl] thiazolidine): A highly potent, selective, long‑lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Bioorg Med Chem 2012;20:5705‑19. Thearle M, Brillantes AM. Unique characteristics of the geriatric diabetic population and the role for therapeutic strategies that enhance glucagon‑like peptide‑1 activity. Curr Opin Clin Nutr Metab Care 2005;8:9‑16. VanDeKoppel S, Choe HM, Sweet BV. Managed care perspective on three new agents for type 2 diabetes. J Manag Care Pharm 2008;14:363‑80. Berlie H, Hurren KM, Pinelli NR. Glucagon‑like peptide‑1 receptor agonists as add‑on therapy to basal insulin in patients with type 2 diabetes: A systematic review. Diabetes Metab Syndr Obes 2012;5:165‑74. Neumiller JJ, Setter SM. Pharmacologic management of the older patient with type 2 diabetes mellitus. Am J Geriatr Pharmacother 2009;7:324‑42. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193‑203. Nathan DM. Clinical practice. Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med 2002;347:1342‑9. Hendra TJ. Starting insulin therapy in elderly patients. J R Soc Med 2002;95:453‑5. Bajwa SJ, Kalra S, Baruah M, Bajwa SK. Insulin injection guidelines for peri‑operative and critically ill patients. J Sci Soc 2013;40:68‑75. Kalra S, Balhara YP, Baruah MP, Chadha M, Chandalia HB, Chowdhury S, et al. Forum for injection techniques, India: The first Indian recommendations for best practice in insulin injection technique. Indian J Endocrinol Metab 2012;16:876‑85. Bajwa SJ, Kalra S, Baruah MP, Bajwa SK. An acute need for awareness of insulin injection guidelines in operative and intensive care units. Anesth Essays Res 2013;7:1‑3. Strojek K, Bebakar WM, Khutsoane DT, Pesic M, Mahelova S, Thomsen HF, et al. Once‑daily initiation with biphasic insulin aspart 30 versus insulin glargine in patients with type 2 diabetes inadequately controlled with oral drugs: An open‑label, multinational RCT. Curr Med Res Opin 2009;25:2887‑94. Joshi SR, Kalra S, Badgandi M, Rao YS, Chawla M. Designer insulins regimens in clinical practice‑pilot multicenter Indian study. J Assoc Physicians India 2005;53:775‑9. Unnikrishnan AG, Tibaldi J, Hadley‑Brown M, Krentz AJ, Ligthelm R, Damci T, et al. Practical guidance on intensification of insulin therapy with BIAsp 30: A consensus statement. Int J Clin Pract 2009;63:1571‑7. Wong J, Yue D. Starting insulin treatment in type 2 diabetes. Aust Preser 2004;27:93‑6. Floyd B, Chandra P, Hall S, Phillips C, Alema‑Mensah E, Strayhorn G, et al. Comparative analysis of the efficacy of continuous glucose monitoring and self‑monitoring of blood glucose in type 1 diabetes mellitus. J Diabetes Sci Technol 2012;6:1094‑102. Nomura K, Inoue K, Akimoto K. A two‑step screening, measurement of HbA1c in association with FPG, may be useful in predicting diabetes. PLoS One 2012;7:e36309. Herman WH, Ma Y, Uwaifo G, Haffner S, Kahn SE, Horton ES, et al. Diabetes Prevention Program Research Group. Differences in A1C by race and ethnicity among patients with impaired glucose tolerance in the Diabetes Prevention Program. Diabetes Care 2007;30:2453‑7. Alam T, Weintraub N, Weinreb J. What is the proper use of hemoglobin A1c monitoring in the elderly? J Am Med Dir Assoc 2006;7 Suppl 3:S60‑4, 59. Tessier D, Avila‑Funes JA, Aguilar‑Navarro S. Specific needs in the care of elderly with diabetes mellitus. Rev Invest Clin 2010;62:323‑6.
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54. Khalam A, Dilip C, Shinu C. Drug use evaluation of diabetes mellitus in hospitalized patients of a tertiary care referral hospital. J Basic Clin Physiol Pharmacol 2012;23:173‑7. 55. Association Diabetes Association. Standards of medical care in diabetes‑‑2012. Diabetes Care 2012;35 Suppl 1:S11‑63. 56. Sinclair AJ. Diabetes in the elderly: A perspective from the United Kingdom. Clin Geriatr Med 1999;15:225‑37. 57. Marquess JG. The elderly and diabetes: An age trend and an epidemic converging. Consult Pharm 2008;23 (Suppl B):5‑11. 58. Khan R, Foster GR, Chowdhury TA. Managing diabetes in patients with chronic liver disease. Postgrad Med 2012;124:130‑7. 59. Bhattacharyya SK, Else BA. Medical costs of managed care in patients with type 2 diabetes mellitus. Clin Ther 1999;21:2131‑42. 60. McCowen KC, Malhotra A, Bistrian BR. Stress‑induced hyperglycemia. Crit Care Clin 2001;17:107‑24. 61. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359‑67. 62. Lazar HL. How important is glycemic control during coronary artery bypass? Adv Surg 2012;46:219‑35. 63. Pichardo‑Lowden A, Gabbay RA. Management of hyperglycemia during the perioperative period. Curr Diab Rep 2012;12:108‑18. 64. Arinzon Z, Fidelman Z, Berner YN, Adunsky A. Infection‑related hypoglycemia in institutionalized demented patients: A comparative study of diabetic and nondiabetic patients. Arch Gerontol Geriatr 2007;45:191‑200. 65. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449‑61. 66. Brunkhorst FM, Engel C, Bloos F, Meier‑Hellmann A, Ragaller M, Weiler N, et al. German Competence Network Sepsis [SepNet]. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125‑39. 67. Bajwa SJ. Intensive care management of critically sick diabetic patients. Indian J Endocrinol Metab 2011;15:349‑50. 68. Bajwa SS, Kalra S. Glycaemic control in ICU. In: Bajaj S, et al. editors. Vol 1. Endocrine Society of India Manual of Clinical Endocrinology; 2012. p. 115‑23. 69. Kosiborod M, Inzucchi SE, Krumholz HM, Xiao L, Jones PG, Fiske S, et al. Glucometrics in patients hospitalized with acute myocardial infarction: Defining the optimal outcomes‑based measure of risk. Circulation 2008;117:1018‑27. 70. Deedwania P, Kosiborod M, Barrett E, Ceriello A, Isley W, Mazzone T, et al. American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism. Hyperglycemia and acute coronary syndrome: A scientific statement from the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 2008;117:1610‑9. 71. Pinto DS, Skolnick AH, Kirtane AJ, Murphy SA, Barron HV, Giugliano RP, et al. TIMI Study Group. U‑shaped relationship of blood glucose with adverse outcomes among patients with ST‑segment elevation myocardial infarction. J Am Coll Cardiol 2005;46:178‑80. 72. Svensson AM, McGuire DK, Abrahamsson P, Dellborg M. Association between hyper‑ and hypoglycaemia and 2 year all‑cause mortality risk in diabetic patients with acute coronary events. Eur Heart J 2005;26:1255‑61. 73. Malmberg K, Rydén L, Wedel H, Birkeland K, Bootsma A, Dickstein K, et al. DIGAMI 2 Investigators. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): Effects on mortality and morbidity. Eur Heart J 2005;26:650‑61. 74. Bajwa SS, Kalra S. Diabeto‑anaesthesia: A subspecialty needing endocrine introspection. Indian J Anaesth 2012;56:513‑7. 75. Reider J, Lin H, DiNardo M. Efficacy of a guideline for treatment of corticosteroid related hyperglycemia in the hospital. Diabetes 2008;57:A574. 76. Paiva I, Baptista C, Ribeiro C, Leitao P, Carvalheiro M. Diabetes in the elderly: Our reality. Acta Med Port 2006;19:79‑84.
Source of Support: Nil, Conflict of Interest: None declared.
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Department of Anaesthesiology and Intensive Care Medicine, Gian Sagar Medical College and Hospital, Patiala, Punjab, 2Department of Endocrinology, Bharti Hospital and B.R.I.D.E., Karnal, Haryana, 3Department of Endocrinology, ECXEL Center, Guwahati, Assam, India, 1Department of Internal Medicine, The Common Wealth Medical College, Scranton, PA 18510, USA
ABSTRACT The prevalence of diabetes mellitus (DM) has increased exponentially throughout the world and there is rapid increase in elderly diabetics. DM is associated with increased mortality and considerable morbidity including stroke, heart disease, and diminished quality of life in the elderly. However, the unique features of geriatric diabetes have not been given due a prominence in medical literature. Hypoglycemia remains the biggest complicating factor and needs to be avoided in the elderly. Most people in the geriatric age group have some degree of renal insufficiency and medications need to be adjusted wisely with changing renal profile. Because safer and more effective pharmacological therapy is available, an individual approach to DM in the elderly is essential.
Address for correspondence: Dr. Sukhminder Jit Singh Bajwa, E-mail: sukhminder_ [email protected] Received : 10‑05‑13 Review completed : 06‑06‑13 Accepted : 29‑09‑13
KEY WORDS: Chronic kidney disease, diabetes mellitus, geriatric, new onset diabetes after transplant
T
he epidemic of diabetes mellitus (DM) has engulfed the entire globe and the prevalence is increasing exponentially across the nations. Factors such as increase in life expectancy, increased health awareness and literacy rate, obesity, and sedentary lifestyle has resulted in more and more of DM prevalence in the elderly.[1,2] About 80% of the elderly Access this article online Quick Response Code:
in the United States are either prediabetic or diabetic. As it is in the treatment of any disease, the benefit to risk ratio is to be assessed when treating this particular patient population. This particular article is aimed at making the reader understand the changing body physiology with aging and how it affects the treatment of diabetes in the elderly. For our discussion, elderly is defined as people with chronological age more than or equal to 65 years.
Website: www.jpbsonline.org
Changing Body Physiology with Aging
DOI:
Pathophysiological changes of aging causes increase prevalence of diabetes and carbohydrate intolerance in the elderly due to associated decrease in insulin secretion in response to glucose
10.4103/0975-7406.130956
How to cite this article: Bajwa SJ, Sehgal V, Kalra S, Baruah MP. Management of diabetes mellitus type-2 in the geriatric population: Current perspectives. J Pharm Bioall Sci 2014;6:151-7.
Journal of Pharmacy and Bioallied Sciences July-September 2014 Vol 6 Issue 3
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load as well as increased insulin resistance in peripheral tissues.[3] Further, insulin sensitivity also decreases with increasing age and obesity.[4] Body attains the peak body mass around the age of 30. Thereafter there is slow progressive decline of Glomerular filtration rate (GFR) even if there is no superimposed pathology. With aging, most of the population tends to have diabetes and hypertension, which further exacerbates the picture.[5] It changes the pharmacokinetics and pharmacodynamics of the drugs. Dietary constraints also impact the physiology of the body in the elderly. Reduced ability to afford, access, procure, eat, chew, absorb, and digest food may affect glycemic control.[6]
Common Geriatric Syndromes and Diabetes Cognitive impairment Elderly patients with diabetes and cognitive dysfunction may have difficulty performing self‑management and follow complicated treatment regimens.[7] They are less functional compared with nondiabetic elderly.[8,9] Cognitive function should be assessed in elderly diabetic patients when there are frequent episodes of hypoglycemia or deterioration of glycemic control without obvious explanation.[7] Hypoglycemia unawareness becomes a major complicating factor in management of elderly diabetics.[10]
Depression Depression is common in this high risk population and shares a bidirectional link with diabetes. Uncontrolled depression may affect the overall management of diabetes.[11]
Polypharmacy Management of hyperglycemia and its associated risk factors often increases the number of medications even more in the elderly with diabetes. Oral hypoglycemic drug combinations have been found to be effective and safe.[12] But this may not be necessarily true in the elderly where polypharmacy is rampant. This increases the chances of drug–drug interaction.[13] Apart from these, elderly persons with diabetes may consume complementary or alternative medicines (CAM) without informing the physician. This too may increase the risk of hypoglycemia.[13,14]
Falls Benefits of improved glycemic control to reduce diabetes‑related complications must be balanced with the possible risk of falls precipitated by hypoglycemia.
Urinary incontinence Risk factors for this common complication include urinary tract infection, autonomic neuropathy, and polyuria due to hyperglycemia.
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Chronic pain syndrome It affects the elderly diabetics to a varying degree resulting in mild‑to‑severe degree of pain. At times, pain can be refractory to treatment also.
Diagnosis of Diabetes The diagnostic criterion for diabetes and prediabetes in the elderly is the same as in general population.[15] Almost three‑quarters of elderly have prediabetes. In contrast, 33% of elderly have diabetes. Prediabetes is particularly important as it is potentially the stage where diabetes may be arrested or reversed with appropriate life style changes.[16] Insulin resistance has already set in when patient becomes prediabetic.
Pitfalls of HbA1c monitoring in the elderly HbA1c is more specific but less sensitive than fasting plasma glucose as a diagnostic tool for diabetes.[17,18] It should be interpreted cautiously in the elderly keeping in view the co‑morbidities in changing body physiology. Because of these changes it can be a misleading diagnostic tool. In rapid cell turnover states like hemolytic anemia HbA1c could be falsely low. During treatment with iron, B12 or erythropoietin as in chronic kidney disease (CKD) there may be rapid red blood cell turnover and falsely low HbA1c.[19,20] In contrast, in low cell turnover states especially iron, B12 or folate deficiency or in the very elderly when marrow turnover is low, HbA1c may be falsely high. In CKD HbA1c may be falsely high or low. When there is high carbamylated hemoglobin it may be falsely high, and if erythropoietin is being used it may be falsely low [Table 1].
Management of glycemia Frailty, cognitive decline and polypharmacy are complicating factors that complicate the glycemic control in the elderly.[21] Addition of hypoglycemic medications, whether oral or injectable, adds to the burden of polypharmacy. The key treatment goal remains avoidance of hypoglycemia while optimizing glycemic control.[22] Newer agents may help the clinician in achieving glycemic control while avoiding hypoglycemia. The clinician needs to be familiar with the pharmacokinetics and pharmacodynamics of these medications to safely use them for optimizing glycemic control. Elderly diabetics typically have multiple comorbidities, which may make it challenging for the clinician to optimize glycemic control. This is especially true for people having renal insufficiency, which is fairly common in the elderly.[23] Medications with shorter Table 1: Pitfalls in monitoring of HbA1C Pitfalls of HBA1C Falsely high HbA1C
Falsely low HbA1C
Low red cell turnover states Iron, Vit B12, folate deficiency
High red cell turnover states Iron, Vit B12, folate, erythropoietin therapy CKD (high carbamylated haemoglobin) CKD (Exogenous erythropoietin) CKD: Chronic kidney disease, HbA1C: Glycated haemoglobin Journal of Pharmacy and Bioallied Sciences July-September 2014 Vol 6 Issue 3
Bajwa, et al.: Management of diabetes in elderly
half‑life and inactive metabolites may in general be more suitable for the elderly. Treatment needs to be individualized keeping in view the comorbidities and functionality of the patient. Here under is a brief description of the hypoglycemic agents [Table 2] with particular reference to geriatric age group. The efficacy, safety, and tolerability of these drugs have been adjudged on the basis of various clinical trials and analyzes, as reviewed in earlier international guidelines.[24]
Sulfonylureas Sulfonylureas and insulin are the major cause of severe hypoglycemia in the elderly.[25] The goal of treatment in the elderly remains glycemic control with priority on preventing hypoglycemia.[22] Preference is given to short‑acting sulfonylurea glipizide. [26] This is consistent with American Diabetes Association recommendations, which recommend the use of second‑generation sulfonylureas, but not glyburide.[27]
Biguanides Metformin is the prototype of this class and only drug in its class which is clinically used. It is contraindicated in patients with serum creatinine >1.5 in men and >1.4 in women. It also has a relative contraindication in people with heart failure. Its major advantages include minimal or no hypoglycemia and a cardio‑protective effect, as proven in the landmark UKPDS study.[28] Metformin associated lactic acidosis (MALA) is another complication of metformin. Though rare, it can be fatal. A high index of suspicion is required to diagnose MALA, which occurs more frequently in elderly patients with renal impairment.
Thiazolidinedione They are well tolerated in older adults, and do not cause hypoglycemia. However, thiazolidinediones should not be used in patients with class III or IV heart failure due to concerns regarding fluid retention. Atypical hip fractures have also limited their utility particularly in the elderly.[29] Table 2: Status of oral hypoglycemics in geriatric diabetes Class Sulfonylureas
Molecule
Glibenclamide Glipizide Gliclazide Glimepiride Meglitinides Repaglinide Biguanides Metformin Thiazolidinediones Pioglitazone Alpha‑glucosidase inhibitors Acarbose Voglibose Dopamine modulators Bromocriptine DPP‑4 inhibitors Sitagliptin Vildagliptin Saxagliptin Linagliptin
Efficacy Safety/Tolerability +++ + +++ +++ +++ +++ +++ + + + ++ ++ ++ ++
0 +++ ++ ++ +++ ++ ++ ++ ++ ++ +++ +++ +++ +++
DPP: Dipeptidyp peptidase Journal of Pharmacy and Bioallied Sciences July-September 2014 Vol 6 Issue 3
Meglitinides Repaglinide, a rapid acting insulin secretagogue, is principally metabolized by the liver. Dose adjustments with this agent do not appear to be necessary in patients with renal insufficiency.[30] It is a safe drug to use in elderly as the risk of hypoglycemia is lower.[31]
Alpha‑glucosidase inhibitors This class of drugs, including acarbose, vaglibose, and meglitol, inhibit the gastrointestinal alpha‑glycosidase that digests starch and other complex carbohydrates thereby slowing the absorption of glucose.[32] Chances of hypoglycemia are minimal. The main side effect that limits their use is flatulence.
Bromocriptine Timed release bromocriptine is approved for use in type 2 diabetes. It acts by resetting the hyper‑dopaminergic tone of the hypothalamus, which is disturbed in diabetes. The action occurs through dopaminergic receptors. Its proven cardiovascular safety makes it an attractive drug in selected geriatric patients. Limited efficacy and transient gastrointestinal side effects are some of the limiting factors.
DPP‑IV inhibitors These are attractive agents to use in the elderly. In fact, the gliptins have been shown to have a much more beneficial effect in the elderly, perhaps because levels of DPP4 (dipeptidyp peptidase-IV) increase with advancing age. They are associated with low risk of hypoglycemia, weight neutrality, and a low risk of drug–drug interactions.[33,34] Patients with renal insufficiency need dose readjustment of sitagliptin, saxagliptin, and vildagliptin, but not of linaglitpin. Hepatic insufficiency is a contraindication for vildagliptin, but not for the other drugs in this class. The DPP4 inhibitors are considered cardiosafe, and have been used in acute coronary syndrome settings as well.
GLP‑1 therapies Liraglutide and exenatide, administered as once daily and twice daily subcutaneous injections, are available for use. There is no risk of hypoglycemia with the use of GLP‑1 (glucagon-like peptide-1). analogs alone.[35] They are sometimes associated with significant reduction in weight. There have been case reports of acute pancreatitis and deterioration in renal function in patients taking GLP‑1 therapies.[36] When used with basal insulin, they mitigate weight gain that is associated with insulin use and improves baseline and postprandial hyperglycemia.[37] These drugs may be used in normal weight or over weight elderly, but should be avoided in frail patients. Once weekly exenatide long acting release (LAR) injection is also available now.
Pramlintide It is administered as mealtime subcutaneous injection with insulin. It is available for the treatment of both type 1 and 153
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insulin‑treated type 2 diabetes. It requires multiple subcutaneous injections and, therefore, its role in the management of diabetes in the elderly is limited.[36]
Insulin Insulin is underutilized in the elderly. It has become easier to use once daily long‑acting insulin. Hyperglycemia may cause symptoms of fatigue, which elderly may attribute to old age. Insulin metabolism is altered in patients with chronic renal failure, so that less insulin is needed when GFR is below 50 ml/min. Dose adjustment is also needed in cases of recurrent hypoglycemia.[38] Insulin is the most cost‑effective treatment for diabetes, in both old as well as young. The safety and convenience of insulin therapy has improved with the availability of modern insulin analogs: Rapid acting aspart, lispro, and glulisine, premixed aspart and lispro, as well as basal detemir and glargine. Insulin can be considered a first‑tier therapy for diabetes associated with severe symptomatic hyperglycemia.[39] Insulin has no upper dose limit and, unlike other antidiabetic agents, it has no contraindications to its use.[40] Comorbidity caused by multiple pathology, as well as ill‑health associated with specific conditions such as impaired cognitive function, depression, inflammatory arthropathy, and cardiac or renal failure, may make insulin titration in the elderly a challenge. Age‑related changes result in functional disability, affecting the patient’s ability to administer insulin, monitor blood glucose, and manage hypoglycemia.[41] Use of accurate, convenient injection devices makes insulin use much simpler. Also, appropriate choice of simple, easy to use insulin regimes, makes the therapy more acceptable. The South Asian Consensus guidelines recognize that the initiation of insulin therapy is a challenging task, especially in older adults who often have multiple comorbidities and physical limitations. It, however, strongly believes that physicians should not avoid usage of insulin, using age as a bar.[24] Essentially, the need to start insulin in older patients is not different from younger patients. Technical superiority of a product (analog vs. conventional), or an injection device (pen vs. syringes), should play a role in planning and executing insulin therapy in the elderly to make it more comfortable and acceptable as well. All patients must be sensitized to the importance of self and structured monitoring of blood glucose at home. In frail and very old patients, it is essential to ensure the presence of responsible attendants/family members during selecting the right dose of insulin, injecting that dose, and monitoring by a glucometer.[42] Premixed insulin Conventionally, premixed insulins are used twice daily, with breakfast and supper. Premixed insulin preparations are more convenient and less prone to errors in dosing. Premix insulin is the preferred insulin in the social situation prevailing in the South Asian countries because of the following reasons: Simple start, option to intensify with same insulin, coverage of both FPG and PPG, and eventually effective HbA1c control.[43] Premixed analogs can be injected immediately
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before or after meals, offering added advantages of flexibility, ability to decide dosage after assessing caloric intake, and avoidance of hypoglycemia. Premixed aspart can also be given once daily (Once Mix) for initiation, with beneficial results.[44] A pilot multicenter study from India examining the role of Designer Insulin Regimen in Clinical Practice has depicted that both premix insulin analogs (two injections per day) and basal bolus analog regimen (four injections per day) can be used in an equally effective way for initiating insulin therapy in T2DM. However, premix insulin analog fared better than the basal bolus regimen in lowering HbA1c (1.58 vs. 1.16%; P 150 mg/dl and PPPG is >200 mg/dl and/or HbA1c is >8.5%. Long‑acting analogs are preferred over NPH basal insulin. Metformin and morning sulfonylureas should be continued along with basal insulin therapy. The panel prefers a conservative initial starting dose of 0.1 U/kg/day. After initiation, the dose should be titrated once or twice every week on the basis of glucose monitoring results, targeting FBG. High HbA1c may be due to postprandial hyperglycemia.
Inpatient
Blood glucose monitoring Traditional meters and strips as well as continuous glucose monitoring, which measure the glucose levels in the interstitial tissue, have been fairly successful in optimizing glycemic control and reducing hypoglycemia.[48] Different types of sensors are in the process of being developed. They have the potential to be useful in the geriatric age group where underlying dementia and functional impairment might impede successful glycemic control. HbA1c, in conjunction with fasting plasma glucose, is an important tool in the management of DM both for diagnostic purposes and assessing the response to therapy.[49] Its absolute values may have some differences in racial and ethnic groups.[50]
Management of Diabetes in Different Clinical Settings Principles of management Management of DM is highly challenging in the elderly for the reasons well explained earlier. The main goals during management include • Optimizing functional and daily routine activities. • Avoidance of both hyperglycemia and hypoglycemia. • Minimizing and preventing microvascular and macrovascular complications.
Outpatient To minimize risk for hypoglycemia, the target goals of HbA1c have been defined as less than 8% in elderly as compared with 7% in the general population.[51] This is to minimize hypoglycemia, which is shown to increase morbidity and mortality especially in the elderly. Educating about hypoglycemia awareness and glycemic control is an important concept.[52,53] Diabetes self‑management is one of the key to successful management of diabetes.[54] Focus should always be to prevent hypoglycemia in the elderly. Care coordination is one of the key approaches in successfully treating diabetic patients.[55‑57] It goes a long way in reducing the disease burden and cost to the society.[58] It is especially true when patient is discharged from the hospital or admitted Journal of Pharmacy and Bioallied Sciences July-September 2014 Vol 6 Issue 3
Hospitalizations are a big stressor more so for the elderly. Clinician might encounter stress hyperglycemia especially in perioperative settings. Stress hyperglycemia has the similar complications like infection and poor wound healing. This is due to release of counter regulatory hormones and cytokines.[59] It also gives the clinician an opportunity to diagnose prediabetes. A standard approach of long acting insulin with mealtime and correctional insulin remains the standard even in the treatment of stress hyperglycemia.
Critical care settings Initial studies had focused on the benefits of intensive glycemic control with I/V insulin in the postoperative settings, but subsequent studies in medical intensive care unit (ICU) showed increased mortality.[10,60] The recommended standard is to keep the glucose level less than 180 mg%.[61] Hyperglycemia in critical care settings may be encountered secondary to enteral and parenteral nutrition and variability of food intake in critical care settings. Some medications may contribute to the same.[62] In contrast, hypoglycemia related to severe sepsis in the demented geriatric patients has been shown to have grave prognosis too.[63]
Perioperative management of diabetic patients and hyperglycemia There have been variable results from the recent studies in contrast to the initial studies, which reported benefits of ‘tight glycemic control with insulin’ during the perioperative period.[64] The variation of results between efficacy and safety of conventional insulin regimen and intensive control with insulin in these studies can be attributed to numerous factors such as the variable impact of hyperglycemia on surgical outcome, different targets set for the blood glucose levels, ethnic and demographic variations, nature, duration and severity of surgical insults, preoperative morbidities and hemodynamic instability and so on.[65‑68] Tight glycemic control has been advocated by various international advisory committees in spite of various conflicting reports in literature so as to improve the surgical outcome.[69,70] Insulin may not have direct effect on decreasing surgical morbidity and mortality but potentially have various indirect roles due to its anabolic actions in normalizing the lipids and cholesterol levels, significantly effecting protein metabolism, modulation of nitric oxide activity and antiinflammatory effects.[71,72] Further, surgical outcome is determined by the type of surgery, the duration of surgical procedure, severity of surgery (major or minor), presence of preoperative comorbidities, which are invariably present in elderly population, chronological age of 155
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DM and the extent to which glycemic control is exercised. Glucose, insulin and potassium (GIK) and variable rate insulin infusion regimen are the two most commonly used insulin regimens in perioperative settings in Indian health centers. Infusion pumps are costly gadgets with limited feasibility for use in low resource settings. As such there is always a need to improvise alternate methods without losing the advantages associated with these costly gadgets. A simple yet effective method that can be used in peripheral health centers and remote locations consists of micro‑drip sets attached to 500 ml of 5% dextrose solution. Insulin and potassium can be administered with the help of such methods thus achieving therapeutic goals. Diabeto‑anesthesia is an unexplored sub‑specialty, which needs to be developed for a better surgical outcome in the near future.[73] Adequate control of hyperglycemic status during perioperative period is associated with a good surgical outcome as has been established by various studies involving cardiac surgery, cardio‑thoracic surgery, neuro‑surgery besides general surgical procedures.[74]
10. 11. 12. 13.
14. 15. 16. 17. 18.
19.
Conclusion The data regarding glycemic control in the elderly is minimal. It is challenging for the physician to have an optimum glycemic control. Treatment needs to be individualized in this age group keeping in mind the benefit to risk ratio.[75,76] There is plethora of new diabetic medications in the market and physician needs to choose wisely.
Acknowledgement
20. 21. 22. 23.
The authors acknowledge the following endocrinologists for preparing, drafting, and editing of the present manuscript: Dr. Ganapathy Bantwal, MD, DM (Endocrinology); Dr. Rakesh Sahay, MD, DM (Endocrinology); Dr. Mathew John, MD, DM (Endocrinology); Dr. Ambika Gopalakrishnan Unnikrishnan, MD, DM (Endocrinology).
24.
References
26.
1. 2. 3. 4. 5. 6. 7. 8. 9.
Zarowitz BJ. Management of diabetes mellitus in older persons. Geriatr Nurs 2006;27:77‑82. Liao EP. Patterns of medication initiation in newly diagnosed diabetes mellitus: Quality and cost implications. Am J Med 2012;125:S1‑2. Meneilly GS, Elliott T, Tessier D, Hards L, Tildesley H. NIDDM in the elderly. Diabetes Care 1996;19:1320‑5. Rizvi AA. Management of diabetes in older adults. Am J Med Sci 2007;333:35‑47. Moritz DJ, Ostfeld AM, Blazer D 2nd, Curb D, Taylor JO, Wallace RB. The health burden of diabetes for the elderly in four communities. Public Health Rep 1994;109:782‑90. Kalra S, Kalra B, Saluja S. Dietary management in geriatric patients of diabetes mellitus: Special considerations. Internet J Geriatr Gerontol 2009;5. Abbatecola AM, Paolisso G, Corsonello A, Bustacchini S, Lattanzio F. Antidiabetic oral treatment in older people: Does frailty matter? Drugs Aging 2009;26 Suppl 1:53‑62. Blaum CS, Ofstedal MB, Langa KM, Wray LA. Functional status and health outcomes in older americans with diabetes mellitus. J Am Geriatr Soc 2003;51:745‑53. Saczynski JS, Jónsdóttir MK, Garcia ME, Jonsson PV, Peila R, Eiriksdottir G, et al. Cognitive impairment: An increasingly important
156
25.
27. 28.
29.
30. 31. 32. 33.
complication of type 2 diabetes: The age, gene/environment susceptibility‑Reykjavik study. Am J Epidemiol 2008;168:1132‑9. Kalra S, Bajwa SS, Baruah M, Sehgal V. Hypoglycaemia in anesthesiology practice: Diagnostic, preventive, and management strategies. Saudi J Anaesth 2013;7:447-52. Black SA, Markides KS. Depressive symptoms and mortality in older Mexican Americans. Ann Epidemiol 1999;9:45‑52. Koliaki C, Doupis J. Linagliptin/Metformin fixed‑dose combination treatment: A dual attack to type 2 diabetes pathophysiology. Adv Ther 2012;29:993‑1004. Sehgal V, Bajwa SS, Sehgal R, Bajaj A, Khaira U, Kresse V. Polypharmacy and potentially inappropriate medication use as the precipitating factor in readmissions to the hospital. J Fam Med Prim Care 2013;2:194‑9. Bajwa SS, Panda A. Alternative medicine and anesthesia: Implications and considerations in daily practice. Ayu 2012;33:475‑80. Basevi V, Di Mario S, Morciano C, Nonino F, Magrini N. American Diabetes Association. Standards of medical care in diabetes-2011. Diabetes Care 2011;34 Suppl 1:S11-61. Schwarz PE. Prediabetes: High risk factor for diabetes mellitus type 2?‑Successful prevention with early interventions for lifestyle modification. Dtsch Med Wochenschr 2012;137:1788. Herman WH, Fajans SS. Hemoglobin A1c for the diagnosis of diabetes: Practical considerations. Pol Arch Med Wewn 2010;120:37‑40. Shibata K, Suzuki S, Sato J, Ohsawa I, Goto S, Iritani I, et al. Diagnostic accuracy of glycohemoglobin A1c (HbA1c) for postprandial hyperglycemia was equivalent to that of fasting blood glucose. J Clin Epidemiol 2005;58:1052‑7. Brown JN, Kemp DW, Brice KR. Class effect of erythropoietin therapy on hemoglobin A (1c) in a patient with diabetes mellitus and chronic kidney disease not undergoing hemodialysis. Pharmacotherapy 2009;29:468‑72. Ng JM, Cooke M, Bhandari S, Atkin SL, Kilpatrick ES. The effect of iron and erythropoietin treatment on the A1C of patients with diabetes and chronic kidney disease. Diabetes Care 2010;33:2310‑3. Abbatecola AM, Paolisso G. Diabetes care targets in older persons. Diabetes Res Clin Pract 2009;86 Suppl 1:S35‑40. Inkster B, Zammitt NN, Frier BM. Drug‑induced hypoglycaemia in type 2 diabetes. Expert Opin Drug Saf 2012;11:597‑614. Suh DC, Kim CM, Choi IS, Plauschinat CA. Comorbid conditions and glycemic control in elderly patients with type 2 diabetes mellitus, 1988 to 1994 to 1999 to 2004. J Am Geriatr Soc 2008;56:484‑92. Baruah MP, Kalra S, Unnikrishnan AG, Raza SA, Somasundaram N, John M, et al. Management of hyperglycemia in geriatric patients with diabetes mellitus: South Asian consensus guidelines. Indian J Endocrinol Metab 2011;15:75‑90. Brunton SA. Hypoglycemic potential of current and emerging pharmacotherapies in type 2 diabetes mellitus. Postgrad Med 2012;124:74‑83. Bao YQ, Zhou J, Zhou M, Cheng YJ, Lu W, Pan XP, et al. Glipizide controlled‑release tablets, with or without acarbose, improve glycaemic variability in newly diagnosed Type 2 diabetes. Clin Exp Pharmacol Physiol 2010;37:564‑8. Skoff RA, Waterbury NV, Shaw RF, Egge JA, Cantrell M. Glycemic control and hypoglycemia in Veterans Health Administration patients converted from glyburide to glipizide. J Manag Care Pharm 2011;17:664‑71. Evans JM, Ogston SA, Emslie‑Smith A, Morris AD. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: A comparison of patients treated with sulfonylureas and metformin. Diabetologia 2006;49:930‑6. Colhoun HM, Livingstone SJ, Looker HC, Morris AD, Wild SH, Lindsay RS, et al. Scottish Diabetes Research Network Epidemiology Group. Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose‑lowering drugs. Diabetologia 2012;55:2929‑37. Scott LJ. Repaglinide: A review of its use in type 2 diabetes mellitus. Drugs 2012;72:249‑72. Landgraf R. Meglitinide analogues in the treatment of type 2 diabetes mellitus. Drugs Aging 2000;17:411‑25. Kumar S, Narwal S, Kumar V, Prakash O. Alpha‑glucosidase inhibitors from plants: A natural approach to treat diabetes. Pharmacogn Rev 2011;5:19‑29. 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
Journal of Pharmacy and Bioallied Sciences July-September 2014 Vol 6 Issue 3
Bajwa, et al.: Management of diabetes in elderly
34.
35.
36. 37.
38. 39.
40. 41. 42. 43.
44. 45.
46. 47.
48. 49.
50. 51.
52. 53.
diabetes mellitus during Ramadan. Indian J Endocrinol Metab 2012;16:503‑7. Yoshida T, Akahoshi F, Sakashita H, Kitajima H, Nakamura M, S o n d a S, e t a l . D i s c o v e r y a n d p r e c l i n i c a l p r o f i l e o f teneligliptin (3‑[(2S,4S)‑4‑[4‑(3‑methyl‑1‑phenyl‑1H‑pyrazol‑5‑yl) piperazin‑1‑yl] pyrrolidin‑2‑y lcarbonyl] thiazolidine): A highly potent, selective, long‑lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Bioorg Med Chem 2012;20:5705‑19. Thearle M, Brillantes AM. Unique characteristics of the geriatric diabetic population and the role for therapeutic strategies that enhance glucagon‑like peptide‑1 activity. Curr Opin Clin Nutr Metab Care 2005;8:9‑16. VanDeKoppel S, Choe HM, Sweet BV. Managed care perspective on three new agents for type 2 diabetes. J Manag Care Pharm 2008;14:363‑80. Berlie H, Hurren KM, Pinelli NR. Glucagon‑like peptide‑1 receptor agonists as add‑on therapy to basal insulin in patients with type 2 diabetes: A systematic review. Diabetes Metab Syndr Obes 2012;5:165‑74. Neumiller JJ, Setter SM. Pharmacologic management of the older patient with type 2 diabetes mellitus. Am J Geriatr Pharmacother 2009;7:324‑42. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193‑203. Nathan DM. Clinical practice. Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med 2002;347:1342‑9. Hendra TJ. Starting insulin therapy in elderly patients. J R Soc Med 2002;95:453‑5. Bajwa SJ, Kalra S, Baruah M, Bajwa SK. Insulin injection guidelines for peri‑operative and critically ill patients. J Sci Soc 2013;40:68‑75. Kalra S, Balhara YP, Baruah MP, Chadha M, Chandalia HB, Chowdhury S, et al. Forum for injection techniques, India: The first Indian recommendations for best practice in insulin injection technique. Indian J Endocrinol Metab 2012;16:876‑85. Bajwa SJ, Kalra S, Baruah MP, Bajwa SK. An acute need for awareness of insulin injection guidelines in operative and intensive care units. Anesth Essays Res 2013;7:1‑3. Strojek K, Bebakar WM, Khutsoane DT, Pesic M, Mahelova S, Thomsen HF, et al. Once‑daily initiation with biphasic insulin aspart 30 versus insulin glargine in patients with type 2 diabetes inadequately controlled with oral drugs: An open‑label, multinational RCT. Curr Med Res Opin 2009;25:2887‑94. Joshi SR, Kalra S, Badgandi M, Rao YS, Chawla M. Designer insulins regimens in clinical practice‑pilot multicenter Indian study. J Assoc Physicians India 2005;53:775‑9. Unnikrishnan AG, Tibaldi J, Hadley‑Brown M, Krentz AJ, Ligthelm R, Damci T, et al. Practical guidance on intensification of insulin therapy with BIAsp 30: A consensus statement. Int J Clin Pract 2009;63:1571‑7. Wong J, Yue D. Starting insulin treatment in type 2 diabetes. Aust Preser 2004;27:93‑6. Floyd B, Chandra P, Hall S, Phillips C, Alema‑Mensah E, Strayhorn G, et al. Comparative analysis of the efficacy of continuous glucose monitoring and self‑monitoring of blood glucose in type 1 diabetes mellitus. J Diabetes Sci Technol 2012;6:1094‑102. Nomura K, Inoue K, Akimoto K. A two‑step screening, measurement of HbA1c in association with FPG, may be useful in predicting diabetes. PLoS One 2012;7:e36309. Herman WH, Ma Y, Uwaifo G, Haffner S, Kahn SE, Horton ES, et al. Diabetes Prevention Program Research Group. Differences in A1C by race and ethnicity among patients with impaired glucose tolerance in the Diabetes Prevention Program. Diabetes Care 2007;30:2453‑7. Alam T, Weintraub N, Weinreb J. What is the proper use of hemoglobin A1c monitoring in the elderly? J Am Med Dir Assoc 2006;7 Suppl 3:S60‑4, 59. Tessier D, Avila‑Funes JA, Aguilar‑Navarro S. Specific needs in the care of elderly with diabetes mellitus. Rev Invest Clin 2010;62:323‑6.
Journal of Pharmacy and Bioallied Sciences July-September 2014 Vol 6 Issue 3
54. Khalam A, Dilip C, Shinu C. Drug use evaluation of diabetes mellitus in hospitalized patients of a tertiary care referral hospital. J Basic Clin Physiol Pharmacol 2012;23:173‑7. 55. Association Diabetes Association. Standards of medical care in diabetes‑‑2012. Diabetes Care 2012;35 Suppl 1:S11‑63. 56. Sinclair AJ. Diabetes in the elderly: A perspective from the United Kingdom. Clin Geriatr Med 1999;15:225‑37. 57. Marquess JG. The elderly and diabetes: An age trend and an epidemic converging. Consult Pharm 2008;23 (Suppl B):5‑11. 58. Khan R, Foster GR, Chowdhury TA. Managing diabetes in patients with chronic liver disease. Postgrad Med 2012;124:130‑7. 59. Bhattacharyya SK, Else BA. Medical costs of managed care in patients with type 2 diabetes mellitus. Clin Ther 1999;21:2131‑42. 60. McCowen KC, Malhotra A, Bistrian BR. Stress‑induced hyperglycemia. Crit Care Clin 2001;17:107‑24. 61. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359‑67. 62. Lazar HL. How important is glycemic control during coronary artery bypass? Adv Surg 2012;46:219‑35. 63. Pichardo‑Lowden A, Gabbay RA. Management of hyperglycemia during the perioperative period. Curr Diab Rep 2012;12:108‑18. 64. Arinzon Z, Fidelman Z, Berner YN, Adunsky A. Infection‑related hypoglycemia in institutionalized demented patients: A comparative study of diabetic and nondiabetic patients. Arch Gerontol Geriatr 2007;45:191‑200. 65. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449‑61. 66. Brunkhorst FM, Engel C, Bloos F, Meier‑Hellmann A, Ragaller M, Weiler N, et al. German Competence Network Sepsis [SepNet]. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125‑39. 67. Bajwa SJ. Intensive care management of critically sick diabetic patients. Indian J Endocrinol Metab 2011;15:349‑50. 68. Bajwa SS, Kalra S. Glycaemic control in ICU. In: Bajaj S, et al. editors. Vol 1. Endocrine Society of India Manual of Clinical Endocrinology; 2012. p. 115‑23. 69. Kosiborod M, Inzucchi SE, Krumholz HM, Xiao L, Jones PG, Fiske S, et al. Glucometrics in patients hospitalized with acute myocardial infarction: Defining the optimal outcomes‑based measure of risk. Circulation 2008;117:1018‑27. 70. Deedwania P, Kosiborod M, Barrett E, Ceriello A, Isley W, Mazzone T, et al. American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism. Hyperglycemia and acute coronary syndrome: A scientific statement from the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 2008;117:1610‑9. 71. Pinto DS, Skolnick AH, Kirtane AJ, Murphy SA, Barron HV, Giugliano RP, et al. TIMI Study Group. U‑shaped relationship of blood glucose with adverse outcomes among patients with ST‑segment elevation myocardial infarction. J Am Coll Cardiol 2005;46:178‑80. 72. Svensson AM, McGuire DK, Abrahamsson P, Dellborg M. Association between hyper‑ and hypoglycaemia and 2 year all‑cause mortality risk in diabetic patients with acute coronary events. Eur Heart J 2005;26:1255‑61. 73. Malmberg K, Rydén L, Wedel H, Birkeland K, Bootsma A, Dickstein K, et al. DIGAMI 2 Investigators. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): Effects on mortality and morbidity. Eur Heart J 2005;26:650‑61. 74. Bajwa SS, Kalra S. Diabeto‑anaesthesia: A subspecialty needing endocrine introspection. Indian J Anaesth 2012;56:513‑7. 75. Reider J, Lin H, DiNardo M. Efficacy of a guideline for treatment of corticosteroid related hyperglycemia in the hospital. Diabetes 2008;57:A574. 76. Paiva I, Baptista C, Ribeiro C, Leitao P, Carvalheiro M. Diabetes in the elderly: Our reality. Acta Med Port 2006;19:79‑84.
Source of Support: Nil, Conflict of Interest: None declared.
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