Lim Su Chi, MD, PhD
Khoo Teck Puat Hospital - Alexandra Health
90 Yishun Central, Singapore 768828
E-Mail:lim.su.chi@alexandrahealth.com.sg
e-ISSN 2308-118x
Printed in the Philippines
Copyright © 2011 by the JAFES
Received February 25, 2011. Accepted May 3, 2011.
The Singapore clinical practice guidelines (CPG) on diabetes mellitus were first drawn up in 1999. The main aim of the guidelines was to help physicians make sound clinical decisions on the management of diabetes mellitus by presenting up-to-date information on diagnosis, classification, treatment, outcomes and follow-up. The guidelines contained detailed recommendations on many aspects of diabetes care including the screening and diagnosis of diabetes, classification of diabetes, lifestyle modifications, pharmacotherapy, management of diabetic complications, and treatment of associated metabolic disorders. Diabetes management in special populations including children and adolescents, and pregnant women, were also detailed. The CPG was last revised in 2006. Since then, there has been a phenomenal rate of development of knowledge and an explosion of data challenging many traditional notions of diabetes. Therefore, a new working committee has been set up to update the Singapore diabetes mellitus CPG targeted for publication in 2012. In this manuscript, we aim to discuss briefly selected key issues that are likely to be extensively reviewed in our next CPG.
The 2006 guidelines endorsed the long-held diagnostic criteria of diabetes: random glucose ≥11.1 mmol/L (in the presence of symptoms), fasting plasma glucose (FPG) ≥7.0 mmol/L and 2-hour post-load plasma glucose (2HPG) in an oral glucose tolerance test (OGTT) of ≥11.1 mmol/L.
Recently, the American Diabetes Association (ADA) included the use of glycated hemoglobin (HbA1C) threshold ≥6.5% to diagnose diabetes.1
Epidemiological studies have demonstrated a relationship between risk of retinopathy and HbA 1C , similar to FPG and 2 HPG. The convenience of performing HbA 1C testing without the need for fasting, and purported reduced day-to-day fluctuations related to stress and illnesses, lend further support to utilizing HbA 1C as a diagnostic test. There are, however, some legitimate concerns. These include limited availability or standardization of the test, especially in developing countries; higher cost; systematic differences dependent on ethnicity; 2 and the effect of anemia and hemoglobinopathies on HbA 1C. Currently, most of the laboratories in Singapore perform HbA 1C certified by the National Glycohemoglobin Standardization Program (NGSP), standardized to the Diabetes Control and Complications Trial (DCCT) reference assay. The test is also widely available in Singapore. It is anticipated that the use of HbA 1C as a diagnostic test for diabetes will be carefully considered.
The 2006 guidelines described glycemic targets of HbA1C 4.5 to 6.4% as “ideal,” 6.5 to 7.0% as “optimal,” 7.1 to 8.0% as “suboptimal,” and > 8.0% as “unacceptable.” The recent Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the Veterans Affairs Diabetes Trial (VADT) have challenged existing paradigms. 3-5 These trials were designed to study the effects of intensive (aiming to achieve near-euglycemia) versus conventional therapy on cardiovascular outcomes in subjects with longstanding type 2 diabetes. Within the period of follow up—although these three trials demonstrated varying degrees of benefit, albeit modest, on the onset or progression of microvascular outcomes—none showed any benefit of intensive control with regard to macrovascular outcomes. Moreover, results from ACCORD showed a significant increase in total (hazard ratio 1.22) and cardiovascular (hazard ratio 1.35) mortality with intensive therapy. These results were in contrast to the findings of the United Kingdom Prospective Diabetes Study (UKPDS), which demonstrated consistent benefits in both microvascular and macrovascular outcomes in intensively treated patients on long term follow up.6 Some reconciliation of inconsistent findings from these clinical trials may be possible upon consideration of the known pathophysiology of diabetes and its vascular complications. For instance, the patient profile of UKPDS, consisting mainly of newly diagnosed diabetics, was different from the longstanding diabetic population of ADVANCE, ACCORD and VADT. This suggests that glycemic targets should be individualized based on age, duration of diabetes, and the presence of advanced vascular disease, amongst other factors.
Assessment of glycemic control utilizing traditional methods, including glycated hemoglobin and self monitoring of blood glucose (SMBG), were included in the 2006 guidelines. Recent advances in newer technology, particularly continuous blood glucose monitoring (CGM), and new data demonstrating its benefits in further improving glycemic control while limiting hypoglycemia, have supported the role of CGM in the management of type 1 diabetics on intensive insulin therapy.7 The next revision of the guidelines should perhaps incorporate these evolving technologies, which may serve an ancillary role in the management of diabetes.
The long term safety of anti-hyperglycemic agents—thiazolidinediones (TZDs) in particular (primarily relating to rosiglitazone)—has been the subject of intense discussion. Rosiglitazone was found to be associated with a significant increase in the risk of myocardial infarction and an increased risk of death from cardiovascular causes as reported by Nissen et al in 2007.8 The 2008 ADA and the European Association for the Study of Diabetes (EASD) consensus algorithm recommended against the use of rosiglitazone, owing to safety concerns and the availability of alternative therapies (pioglitazone in particular), which seemed not to share the same concerns. In 2010, the European Medicines Agency suspended sales of rosiglitazone. In the same year, the United States Food and Drug Administration (FDA) restricted its use to patients with type 2 diabetes who cannot achieve adequate glycemic control with other medications. Back in the 2006 guidelines, TZDs had an integral role as an oral therapeutic option for type 2 diabetes. Rosiglitazone was the only TZD available in Singapore at that time. Although rosiglitazone is still available in Singapore, it is unlikely to continue to play a major role as a therapeutic option for type 2 diabetes owing to its safety concerns. The other available TZD, pioglitazone, has its own share of issues including concerns with heart failure, fracture risk and, lately, bladder tumors.9 Therefore, the therapeutic placement of TZDs will be reviewed.
The other controversy, which has gathered significant attention in recent years, is with the insulin analog insulin glargine and mitogenicity. In an observational cohort study published in 2009, Hemkens et al reported that cancer incidence in patients on glargine was higher than expected, than in patients on human insulin.10 Other epidemiological data largely demonstrated no causal relationship between insulin glargine and cancer risk. 11,12 Some remain concerned because glargine has a higher affinity for insulin-like growth factor-1 (IGF-1) receptor compared to human insulin, which theoretically could alter mitogenic activity. There is, to date, insufficient evidence to make a recommendation against glargine. Therefore, the epidemiological observation only generates some hypotheses but is unable to establish causation. The CPG committee will carefully consider this issue.
While some therapeutic agents have been under scrutiny for their safety concerns, there have been several new classes of therapeutic agents that may play increasingly important roles in the management of diabetes. These include incretin-based treatment, such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs. These agents have gained increased use in part due to their favorable effect on weight and their postulated beneficial effect on beta-cell function in animal studies.13,14 The ADA and EASD consensus algorithm for the initiation and adjustment of therapy in 2008 endorsed the use of incretin-based therapeutic agents as an add-on to metformin, specifically when avoidance of hypoglycemia and weight loss are desirable.15
Novel technology and techniques have added new options to the treatment armamentarium for diabetes over the years. Insulin pump therapy has evolved to become an established form of intensive insulin therapy in type 1 diabetics. Studies exploring the utility of insulin pump therapy in type 2 diabetic patients have been steadily increasing.16,17 The advent of bariatric surgery as a possible option in the treatment of diabetes has presented a provocative challenge to the usual concepts in diabetes treatment.18 With the emergence of newer therapeutic options and novel concepts on diabetes care, a paradigm shift in the management algorithm of diabetes will be one of the key issues in our next CPG.
The management of diabetic microvascular complications, including diabetic nephropathy and eye complications, was well highlighted in the 2006 guidelines. The recommended use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in the treatment of microalbuminuria or overt nephropathy is established practice applicable even to this day. Over the years, several trials have demonstrated additional albuminuria-lowering benefits with dual blockade of the renin-angiotensin system (RAS) using both ACE inhibitors and ARBs.19,20 With dual blockade, studies showing better long-term renal and cardiovascular outcomes are still lacking, and an increased risk of hyperkalemia has also been described. Nevertheless, dual blockade remains a viable option should patients have persistently significant proteinuria despite optimization of a single RAS-blocking agent. Furthermore, the direct renin inhibitor aliskiren has been approved by FDA for the treatment of hypertension since 2007. Although its role in the prevention of progression of diabetic nephropathy is unknown, data demonstrating its albuminuria-lowering properties has been promising.21 Studies also demonstrating additive proteinuria-lowering benefits with the use of spironolactone, an aldosterone antagonist, have been mounting.22,23 These additional agents offer a wider range of options in the management of diabetic nephropathy and should be addressed in the next revision to the Singapore guidelines.
Screening for diabetic retinopathy, and management of systemic risk factors for prevention of progression of diabetic retinopathy (including glycemic control, blood pressure control and treatment of hyperlipidemia), were well-detailed in the 2006 guidelines. Intensive diabetes management achieving near normoglycemia has been shown to prevent or delay the onset and progression of retinopathy.24 Lowering of blood pressure is also well established in reducing the progression of retinopathy.25 However, the role of treatment of hyperlipidemia has not clearly been linked to retardation of progression of retinopathy. In recent years, a reduced need for laser treatment for diabetic retinopathy was demonstrated in patients treated with fenofibrate.26 Retardation of progression of diabetic retinopathy with fenofibrate was also observed in the ACCORD Eye Study.27 Further data confirming the benefits of fibrates in primary prevention and progression of retinopathy are highly anticipated and will undoubtedly have an impact on the management of dyslipidemia in the near future.
The 2006 guidelines included recommendations on the management of women with pre-gestational and gestational diabetes mellitus (GDM). Guidelines on screening for, and detection of, gestational diabetes; glycemic control; and intrapartum and postnatal management; were highlighted. Traditionally, the term “gestational diabetes” was used to define women with onset or first recognition of abnormal glucose tolerance during pregnancy. With the continuing rise in incidence of diabetic patients presenting at an earlier age, it is inevitable to see an increasing trend of patients with diabetes during pregnancy. Diabetes may even antedate pregnancy. With the advent of data from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) and the ADA have recently revised guidelines on the diagnosis and classification of diabetes in pregnancy. The classification of “overt diabetes” has been proposed for diabetes detected on initial antenatal visit using the standard diagnostic test. Revised 75-gram OGTT criteria for diagnosis of GDM using any one positive criterion (fasting glucose ≥ 5.1 mmol/L, 1-hour post-load glucose ≥ 10.0 mmol/L or 2-hour post-load glucose ≥ 8.5 mmol/L) has been endorsed.28 Besides changes to the diagnostic criteria, data demonstrating the safety of oral hypoglycemic agents in pregnancy, particularly metformin and glibenclamide, have been increasing in recent years. 29,30 The use of the rapid-acting insulin analogs, lispro and aspart, has also been shown to have acceptable safety profiles and minimal transfer across the placenta, without evidence of teratogenesis.31,32 Guidelines on glycemic targets including premeal capillary glucose, peak post-prandial glucose and HbA1C targets for pre-existing type 1 or 2 diabetic women who become pregnant have been updated recently.33 The relevance and adoptability of these changes will be considered by the new CPG committee.
In the few years since the last revision to the Singapore diabetes CPG in 2006, there has been an astounding avalanche of data challenging traditional notions and bringing new perspectives to diabetes. It is timely that the guidelines be updated to reflect the latest developments and consensus in diabetes care. The challenge lies in adapting this considerable body of data and recommendations to the local setting, making them relevant to local practitioners. Diabetes is a rapidly developing field where exciting new information continues to challenge old practices. We look forward to the next revision to the Singapore Diabetes Mellitus CPG and hope that it will continue to enormously assist our local practitioners in enhancing their care for the diabetic population of Singapore.
The full article of the 2006 Guidelines is no longer available at the Singapore Ministry of Health website as it is currently under review.
1. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care. 2009 July;32(7):1327-34.
2. Ziemer DC, Kolm P, Weintraub WS, Vaccarino V, Rhee MK, Twombly JG, et al. Glucose-independent, black-white differences in hemoglobin A1c levels: a cross-sectional analysis of 2 studies. Ann Intern Med. 2010 Jun 15;152(12):770–7.
3. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560-72.
4. Gerstein HC, Riddle MC, Kendall DM, Cohen RM, Goland R, Feinglos MN, et al; ACCORD Study Group. Glycemia treatment strategies in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol. 2007 Jun 18;99(12A):34i-43i.
5. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360(2):129-39.
6. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008 Oct 9; 359(15):1577-89.
7. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med. 2008 Oct 2;359(14):1464-76.
8. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007 Jun 14; 356(24):2457-71.
9. Dormandy J, Bhattacharya M, van Troostenburg de Bruyn AR; PROACTIVE Investigators. Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROACTIVE. Drug Saf. 2009;32(3):187-202.
10. Hemkens LG, Grouven U, Bender R, Günster C, Gutschmidt S, Selke GW, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009 Sep;52(9):1732-44.
11. Jonasson JM, Ljung R, Talbäck M, Haglund B, Gudbjörnstdòttir S, Steineck G. Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia. 2009 Sep;52(9):1745-54.
12. Colhoun HM, SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia. 2009 Sep;52(9):1755-65.
13. Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 1999 Dec;48(12):2270-6.
14. Stoffers DA, Desai BM, DeLeon DD, Simmons RA. Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat. Diabetes. 2003 Mar;52(3):734-40.
15. 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 Jan;32(1):193-203.
16. Wainstein J, Metzger M, Boaz M, Minuchin O, Cohen Y, Yaffe A, et al. Insulin pump therapy vs. multiple daily injections in obese type 2 diabetic patients. Diabet Med. 2005 Aug;22(8):1037-46.
17. Raskin P, Bode BW, Marks JB, Hirsch IB, Weinstein RL, McGill JB, et al. Continuous subcutaneous insulin infusion and multiple daily injection therapy are equally effective in type 2 diabetes: a randomized, parallel-group, 24-week study. Diabetes Care. 2003 Sep;26(9):2598–603.
18. Pories WJ, Swanson MS, MacDonald KG, Long SB, Morris PG, Brown BM, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995 Sep;222(3):339-52.
19. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ. 2000 Dec 9;321(7274):1440-4.
20. Song JH, Cha SH, Lee HJ, Lee SW, Park GH, Lee SW, et al. Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-beta in type 2 diabetic patients with advanced kidney disease. Nephrol Dial Transplant. 2006 Mar;21(3):683-9.
21. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK; AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008 Jun 5;358(23):2433-46.
22. van den Meiracker AH, Baggen RG, Pauli S, Lindemans A, Vulto AG, Poldermans D, et al. Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function. J Hypertens. 2006 Nov;24(11):2285-92.
23. Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol. 2009 Dec;20(12):2641-50.
24. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837–53.
25. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998 Sep 12;317(7160):703–13.
26. Keech AC, Mitchell P, Summanen PA, O’Day J, Davis TM, Moffitt MS, et al; FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet. 2007 Nov 17;370(9600):1687-97.
27. ACCORD Study Group; ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010 Jul 15;363(3):233-44.
28. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, Damm P, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010 Mar;33(3):676-82.
29. Gilbert C, Valois M, Koren G. Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis. Fertil Steril. 2006 Sep;86(3):658-63.
30. Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000 Oct 19;343(16):1134-8.
31. Wyatt JW, Frias JL, Hoyme HE, Jovanovic L, Kaaja R, Brown F, et al. Congenital anomaly rate in offspring of mothers with diabetes treated with insulin lispro during pregnancy. Diabet Med. 2005 Jun;22(6):803-7.
32. Hod M, Damm P, Kaaja R, Visser GJ, Dunne F, Demidova I, et al; Insulin Aspart Pregnancy Study Group. Fetal and perinatal outcomes in type 1 diabetes pregnancy: a randomized study comparing insulin aspart with human insulin in 322 subjects. Am J Obstet Gynecol. 2008 Feb;198(2):186.e1-7.
33. Kitzmiller JL, Block JM, Brown FM, Catalano PM, Conway DL, Coustan DR, et al. Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for care. Diabetes Care. 2008 May;31(5):1060-79.
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