Type 2 diabetes recommendations: the move toward an evidence informed consensus

Boden Institute of Obesity
Nutrition and Exercise
University of Sydney

Type 2 diabetes recommendations: the move toward an evidenceinformed consensus

by S. Colagiuri , Australia

Diabetes has reached epidemic proportions throughout the world. There is, however, strong evidence that the diabetes burden can be reduced by improving diabetes management. Despite this, the care received by many people with diabetes is less than optimal worldwide. Guidelines are an essential tool for addressing this situation. The International Diabetes Federation (IDF) has developed global guidelines including a treatment algorithm for people with type 2 diabetes. Limitations in the evidence base mean that recommendations and guidance are best described as evidence- informed consensus. While there is an extensive range of blood glucose– lowering therapies, availability and cost limits access to many of these options in many middle- and low-income countries. IDF guidance balances these important considerations with efficacy and safety. The usual approach recommended in the IDF algorithm is use of metformin as first-line therapy followed by a sulfonylurea when a second agent becomes necessary, and moving to a third oral agent or insulin if glycemic targets are not achieved. The generic IDF treatment algorithm is not proscriptive, but rather is formulated as a template for local adaptation by individual countries which do not have their own algorithms.

Medicographia. 2013;35:9-14 (see French abstract on page 14)

Diabetes has reached epidemic proportions and is a major global burden, especially in developing countries.1 Type 2 diabetes is associated with significant morbidity and decreased life expectancy due to its complications, which include heart disease, stroke, amputation, blindness, and kidney failure. It diminishes quality of life, impacts on employment and life opportunities, and has wide-ranging economic implications for the individual, the family, and society. There is considerable evidence that the diabetes burden can be reduced by improving diabetes management. Despite the available evidence, the care received by many people with diabetes is less than optimal worldwide.2 Guidelines are an essential tool for addressing this situation. A focus of the International Diabetes Federation (IDF) is to provide globally relevant guidance to improve the quality and consistency of diabetes care through the development and implementation of guidelines.

The evidence framework

Diabetes care is complex, involving a range of interventions, including education, lifestyle modification (diet, physical activity), medications for control of blood glucose and risk factors for cardiovascular disease, and ongoing monitoring and review. Ide- ally, intervention, especially pharmacotherapy, would be based on demonstrating a benefit in reducing morbidity and premature mortality; however, few interventions have data on these end points. Instead, potential benefits are based on demonstrating a favorable effect on improving intermediate outcomes, such as lowering glycated hemoglobin (HbA1c). Any benefits should be balanced against the occurrence of undesirable effects, including hypoglycemia, weight gain, and treatment side effects. Other considerations that are important from an IDF perspective include availability and cost of therapies. On an individual level, clinical decision making requires more than just taking into account efficacy of a particular treatment. Factors which influence the treatment used in a particular patient include contraindications, potential side effects, patient preference, local availability and prescribing restrictions, and cost to the individual and health care system.

The benefits of intervention

The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated that tighter blood glucose control reduced complications in people with newly diagnosed type 2 diabetes. 3 The intensively treated group had significantly fewer microvascular complications and lower incidence of the composite end point compared with the conventionally treated group. The Kumamoto study4 confirmed the benefits of intensive treatment in reducing the development or progression of microvascular complications. Microvascular benefits of improved glycemic control were also shown in ACCORD (Action to Control CardiOvascular Risk in Diabetes study),5,6 ADVANCE (Action in Diabetes and Vascular disease: Preter- Ax and DiamicroN MR Controlled Evaluation),7 and the VADT (Veterans Affairs Diabetes Trial).8 These studies failed to show a benefit on macrovascular complications. In the ACCORD study, two secondary outcomes were significant: an increase in mortality and a decrease in nonfatal myocardial infarction were observed in the intensively treated group.5 However, a subsequent meta-analysis incorporating these major studies showed a significantly reduced risk of major cardiovascular events and myocardial infarction, but no reduction in all-cause mortality or cardiovascular death.9

The benefits of multifactorial intervention were demonstrated in the Steno-2 study.10,11 Subjects in the intensive therapy group received multifactorial treatment including behavior modification and pharmacological therapy for hyperglycemia, hypertension, and dyslipidemia, while the conventional group was treated according to national guidelines. Intensive therapy significantly reduced cardiovascular disease, nephropathy, retinopathy, and autonomic neuropathy by about 50%. The benefits of intervention are observed not only during the study period, but also continue for several years after the intensive intervention—the so-called legacy effect. In the UKPDS posttrial monitoring study, subjects were observed for up to 10 years.12 In the sulfonylurea/insulin groups, risk reduction persisted at 10 years for any diabetes-related end point and microvascular disease, and significant risk reductions for myocardial infarction and death from any cause emerged over time. In the metformin group, significant risk reductions persisted over the 10 years. In the Steno-2 study, by 5 years’ post intervention, a significant reduction in risk of death in the intensively treated group emerged compared with usual care.11

Choosing a pharmacological intervention

The range of pharmacological agents for the control of blood glucose continues to increase. The evidence base for deciding on a particular treatment or combination is limited by a lack of evidence directly comparing many of the choices. For example, if metformin is accepted as first-line pharmacotherapy, as advocated by many guidelines, and a second agent is required, then there are six therapeutic classes of blood glucose– lowering agents from which to choose: sulfonylureas (including glinides), α-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide- 1 receptor agonists (GLP-1 RA), and insulin. If adequate glucose control is not achieved and a third agent is required, there are five classes of agents from which to choose. This means there are 30 therapeutic options (6 × 5) for triple therapy. The options increase dramatically if different agents in each class are taken into account. There are at least three different types of sulfonylureas, four DPP-4 inhibitors, two GLP-1 RAs, and three broad insulin regimens, ie, 2160 (30 x 3 x 4 x 2 x 3) possible combinations for triple therapy, and clearly not all of these have been compared. It is encouraging that with the newer classes of agents a broader approach is being used to undertake direct comparative studies.

Most of the data relating to pharmaceutical interventions are based on efficacy in improving blood glucose, which is generally similar between agents, depending on whether the agent is used as first-, second-, or third-line therapy. Therefore, ultimately, individual treatment choices are more often based on other considerations. These include unwanted consequences such as risk of hypoglycemia and weight gain, which are inevitable with insulin, but differ between other agents and between studies. Cost to the individual, the health care system, and society is an important consideration, and cheaper, well established, and efficacious treatments (eg, metformin and sulfonylureas) continue to be widely used and recommended in guidelines globally.

The IDF approach

The IDF is an umbrella international nongovernmental organization of over 200 national diabetes associations in over 160 countries and has been leading the global diabetes community since 1950. The IDF’s mission is to promote diabetes care, prevention, and a cure worldwide.

The IDF Clinical Guidelines Task Force focuses on developing guidelines and clinical care recommendations which are globally relevant.13 Clinical management guidelines are a routine part of clinical practice and are an essential starting point for improving clinical care. Their recommendations synthesize the evidence to identify practices and processes of diabetes care that lead to better outcomes. Similarly, guideline recommendations establish standards and benchmarks that can assist policy makers to allocate resources judiciously and assess the need for services and workforce development to achieve desired standards of care and, ultimately, improved health outcomes.14

_ Evidence-informed consensus
Developing guidelines, including treatment algorithms, is complex for several reasons. While guideline recommendations are based on best available evidence, it is clear that treatment guidance cannot be truly evidence-based because of a lack of studies comparing all available options of treatment combination. Because of this limitation, IDF guidance is best described as evidence-informed consensus which seeks to balance available evidence with other important individual, practical, and societal considerations.

_ “Levels of care” approach
All people with diabetes should have access to the broad range of diabetes services and therapies, and no person should be denied any element of effective diabetes care. However, it is recognized that in many parts of the world, the implementation of particular standards of care is limited by lack of resources. The IDF has developed a practical approach to promote the implementation of cost-effective evidence-informed care in settings between which resources vary widely. The approach adopted by the IDF has been to give advice according to three levels of care.13

Recommended care is evidence-based care which is costeffective in most countries with a well-developed service base, and with health care funding systems consuming a significant part of national wealth. Recommended care should be available to all people with diabetes and the aim of any health care system should be to achieve this level of care. However, in recognition of the considerable variations in resources throughout the world, other levels of care are described which acknowledge low- and high-resource situations.

Limited care is the lowest level of care that anyone with diabetes should receive. It acknowledges that standard medical resources and fully trained health professionals are often unavailable in poorly funded health care systems. Nevertheless, this level of care aims to achieve with limited resources a high proportion of what can be achieved by recommended care.

Comprehensive care includes the most up-to-date and complete range of health technologies that can be offered to people with diabetes, with the aim of achieving best possible outcomes. However, the evidence base supporting the use of some of these expensive or new technologies is relatively weak.

IDF treatment algorithm

The generic IDF treatment algorithm (Figure 1, page 12)14 takes into consideration available evidence and differences in global availability, access, and cost of medications.13 The algorithm is not proscriptive, but rather is formulated as a template for local adaptation by individual countries which do not have their own algorithms. The algorithm will be continuously updated as new evidence, particularly the results of current outcomes studies, becomes available.

_ Usual and alternative approaches to therapeutic choice
There is a wide range of blood glucose–lowering agents; however, availability and access tomany of these is limited in many middle- and low-income countries. Treatment algorithms are intended to provide guidance on ways in which these therapies can be used either alone or in combination. The IDF algorithm is structured to provide a stepwise approach to intensifying therapy if blood glucose targets are not met. It also provides advice on what is considered a usual or alternative approach to selecting a therapy. The usual approach represents therapies which would usually be chosen first unless contraindicated. These therapies are effective, safe, relatively inexpensive, and widely available globally. The alternative approach indicates other therapeutic options which could be used if the usual approach therapies are contraindicated, not tolerated, or not considered suitable for a particular individual.

Lifestyle changes, including diet modification, increase in physical activity, weight reduction in those that are overweight, and smoking cessation, are essential components of the management of type 2 diabetes. This is recommended as the initial step in diabetes management. Subsequent treatment changes are based on failure to achieve target HbA1c after a 3-month period, taking into account tolerability and hypoglycemia. A recent systematic review compared effectiveness and safety of medications for type 2 diabetes, excluding α-glucosidase inhibitors and insulin.15 This review was limited by the lack of comparative studies allowing a comprehensive comparison of all medication classes and outcomes, especially newer agents. Most diabetes medications were similarly efficacious when used as monotherapy and decreased HbA1c levels by 1% (11 mmol/mol) although there were some exceptions. The strength of evidence was low or insufficient to support conclusions about the comparative effectiveness of diabetes medications on all-cause mortality, cardiovascular morbidity and mortality, and microvascular outcomes.

Figure 9
Figure 1. The IDF treatment algorithm.

After reference 14: International Diabetes Federation Web site. http://www.idf.org/. © 2012, International Diabetes Federation.

Metformin is generally considered the first-choice oral medication, unless contraindicated, eg, in the presence of renal impairment. This recommendation is based on metformin’s favorable effect on weight, low risk of hypoglycemia, and low cost, but gastrointestinal intolerance is common and the need to monitor renal function is problematic in many health systems. Long-term outcome data are limited. In a substudy of the UKPDS, in 342 overweight people, metformin resulted in a significantly greater risk reduction than those assigned intensive therapy with sulfonylurea or insulin for any diabetes related end point and all-cause mortality.16 However, a possible macrovascular benefit of metformin was not found in a recent meta-analysis of randomized clinical trials which examined the effect of metformin on cardiovascular events and mortality.17

Global alternatives to metformin as first-line therapy include sulfonylureas or α-glucosidase inhibitors. Sulfonylureas are commonly used and efficacious, but can be associated with weight gain and an increased risk of hypoglycemia. Outcome studies—the UKPDS3 and the ADVANCE study7—showed that intensive therapy with sulfonylurea-based treatment improved long-term outcomes. The ADVANCE study, which used gliclazide, achieved this without weight gain and with low rates of hypoglycemia.7

Although considered as a class, there may be intrinsic differences between the various sulfonylureas. Schramm et al18 examined mortality and cardiovascular risk associated with available insulin secretagogues compared with metformin in a nationwide Danish study. All-cause mortality, cardiovascular mortality, and a composite end point with the different medications were assessed over a median 3.3 years of follow-up. Compared with metformin, glimepiride, glibenclamide, glipizide, and tolbutamide were associated with increased all cause and cardiovascular mortality and increased incidence of the composite end point. Overall outcomes for gliclazide and repaglinide were not different from metformin. In addition, rates of hypoglycemia vary with different sulfonylureas, being lowest with gliclazide.19 These differences in rates of hypoglycemia are reflected in clinical trials comparing sulfonylureas and DPP-4 inhibitors added to metformin,20,21 and during fasting associated with Ramadan,22 in which gliclazide is associated with less hypoglycemia. α-Glucosidase inhibitors are widely used and popular in many, especially Asian, countries.23 Gastrointestinal side effects such as flatulence and diarrhea are frequent. Hanefeld et al24 performed ameta-analysis on the effect of the α-glucosidase inhibitor acarbose on cardiovascular events in seven randomized, placebo-controlled studies of at least 52 weeks’ duration and found significantly reduced risk for myocardial infarction and any cardiovascular event.

When monotherapy fails to achieve target glycemia, a second agent is required. Of the many options, the IDF recommends the addition of a sulfonylurea as the usual approach for people taking metformin. The alternative approach is touse an &alpga;-glucosidase inhibitor, a DPP-4 inhibitor, or a thiazolidinedione. Combination therapy decreases HbA1c levels more than monotherapy by about 1% (11 mmol/mol).15 A recent network meta-analysis compared blood glucose–lowering therapies added to metformin in short-term studies.25 Of the IDF second-line therapies, sulfonylureas and thiazolidinediones showed greater reductions in HbA1c than α-glucosidase inhibitors and DPP-4 inhibitors. Considering other relevant factors such as availability and cost, combined metformin and sulfonylurea therapy remains an effective and safe treatment which is widely used throughout the world.

Alternative second-line therapies include an α-glucosidase inhibitor or DPP-4 inhibitor. Both are effective when used in combination with metformin (or sulfonylurea) and lower HbA1c by approximately 0.7% (8 mmol/mol),25 have a low risk of hypoglycemia, and have favorable effects on weight. Thiazolidinediones effectively lower blood glucose, but their side effects and increasing safety concerns have seen their use decrease. Adverse effects include weight gain and fluid retention, which may result in peripheral edema and congestive heart failure. Increasingly recognized is the greater incidence of fractures, especially in females.26 Some regulatory authorities have acted in relation to possible adverse cardiovascular effects with rosiglitazone and a possible link with bladder cancer with pioglitazone. Although thiazolidinediones are included as an option in the IDF algorithm, other choices are favored.

If diabetes control remains unsatisfactory and a third agent is required, the usual approach options include either adding a third oral agent or commencing insulin. Options for a third oral agent include a DPP-4 inhibitor, an α-glucosidase inhibitor, or a thiazolidinedione. Few studies have compared adding a third agent or using insulin, but those which have show similar short-term effects on glycemic control.27

The efficacy of add-on blood glucose–lowering therapy in people with type 2 diabetes not controlled with metformin and a sulfonylurea was recently analyzed in randomized trials of at least 24 weeks’ duration.28 Compared with placebo, medication classes did not differ in effect on HbA1c level with reductions ranging from 0.7% (7 mmol/mol) with acarbose to 1.1% (12 mmol/mol) with insulin. Weight increase was seen with insulin and thiazolidinediones, and insulin resulted in twice the absolute number of severe hypoglycemic episodes compared with noninsulin blood glucose–lowering therapies.

The UKPDS established the effectiveness of intensive therapy based on insulin treatment in reducing vascular complications compared with conventional therapy.3 Insulin options include adding once-daily basal insulin or twice-daily premixed insulin, usually in combination with oral blood glucose–lowering medications. While there is ongoing debate about these two approaches, a recent systematic review reported the percentage of people reaching an HbA1c target of <7.0% (53 mmol/ mol) was similar. However, there was considerable heterogeneity between study results related to final insulin dose and use of oral medications; overall incidence of hypoglycemia was variable, but weight gain was less with basal insulin.29 The IDF algorithm lists GLP-1 RAs as an alternative third-line approach mainly on the basis of their limited global availability and their cost. GLP-1 RAs lower HbA1c by approximately 1% (11 mmol/mol) compared with placebo, and result in moderate and continuous weight loss and low rates of hypoglycemia, but are associated with gastrointestinal side effects, especially nausea and vomiting.15 There are some poorly supported data that the use of GLP-1 RAs may predispose to pancreatitis.

The final step in the algorithm is to intensify insulin therapy with basal and mealtime insulins. Intensified insulin therapy in type 2 diabetes has been shown to improve metabolic control30 and improve clinical outcomes.4

Guideline implementation

The translation of guidelines into everyday practice remains a challenge. Many approaches have been used with varying success, but the most effective are multidimensional and locally specific.14 Greater support is needed for guideline implementation. Plans for implementation should be developed at the same time as the guidelines are being formulated and should be considered an integral part of the planning stage of guideline development. _

The author has received fees for participating in advisory boards or speaking engagements from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Glaxo- SmithKline, Merck & Co, Novartis, Novo Nordisk, Roche Diagnostics, and Servier.

1. Whiting DR, Guariguata L, Weil C, Shaw J. IDF Diabetes Atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011; 94:311-321.
2. Chan JC, Gagliardino JJ, Baik SH, et al; IDMPS Investigators. Multifaceted determinants for achieving glycemic control: the International Diabetes Management Practice Study (IDMPS). Diabetes Care. 2009;32:227-233.
3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
4. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.Diabetes Res Clin Pract. 1995;28:103-117.
5. ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.
6. Ismail-Beigi F, Craven T, Banerji MA, et al; ACCORD Trial Group. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376:419-430.
7. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
8. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular com plications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139.
9. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52:2288-2298.
10. Gæde P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393.
11. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes—Steno 2. N Engl J Med. 2008;358: 580-591.
12. 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;359:1577-1589.
13. Colagiuri S, Colagiuri R. How evidence-based medicine has shaped international guidelines over the past 25 years. Medicographia. 2010;33:42-46.
14. Treatment algorithm for people with type 2 diabetes. International Diabetes Federation Web site. http://www.idf.org/.
15. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154:602-613.
16. Prospective Diabetes UK Study (UKPDS) Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-865.
17. Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2011;13:221-228.
18. Schramm TK, Gislason GH, Vaag A, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J. 2011;32:1900-1908.
19. Tayek J. SUR receptor activity vs. incidence of hypoglycaemia and cardiovascular mortality with sulphonylurea therapy for diabetics. Diabetes Obes Metab. 2008;10:1128-1129.
20. Filozof C, Gautier JF. A comparison of efficacy and safety of vildagliptin and gliclazide in combination with metformin in patients with type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study. Diabet Med. 2010;27:318-326.
21. Seck T, Nauck M, Sheng D, et al. Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study. Int J Clin Pract. 2010;64:562-576.
22. Al Sifri S, Basiounny A, Echtay A, et al; 2010 Ramadan Study Group. The incidence of hypoglycaemia in Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan: a randomised trial. Int J Clin Pract. 2011;65:1132-1140.
23. Van de Laar FA, Lucassen PL, Akkermans RP, Van de Lisdonk EH, Rutten GE, Van Weel C. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005;2:CD003639.
24. Hanefeld M, Cagatay M, Petrowitsch T, Neuser D, Petzinna D, Rupp M. Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: metaanalysis of seven long-term studies. Eur Heart J. 2004;25:10-16.
25. Liu SC, Tu YK, Chien MN, Chien KL. Effect of antidiabetic agents added to metformin on glycemic control, hypoglycemia and weight change in patients with type 2 diabetes: a network meta-analysis. Diabetes Obes Metab. 2012; 14(9):810-820.
26. Kahn SE, Haffner SM, Heise MA; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355: 2427-2443.
27. Rosenstock J, Sugimoto D, Strange P, et al. Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients. Diabetes Care. 2006;29:554-559.
28. Gross JL, Kramer CK, Leitão CB, et al; Diabetes and Endocrinology Metaanalysis Group (DEMA). Effect of antihyperglycemic agents added to metformin and a sulfonylurea on glycemic control and weight gain in type 2 diabetes: a network meta-analysis. Ann Intern Med. 2011;154:672-679.
29. Giugliano D, Maiorino MI, Bellastela G, et al. Treatment regimens with insulin analogues and haemoglobin A1c target of <7% in type 2 diabetes: a systematic review. Diabetes Res Clin Pract. 2011;92:1-10.
30. Goudswaard AN, Furlong NJ, Valk GD, et al. Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2004;4:CD003418.

Keywords: evidence-informed consensus; guidelines; International Diabetes Federation; treatment algorithm; type 2 diabetes