INTRODUCTIONSulfonylureas (SUs) have been available for the treatment of type 2 diabetes mellitus (T2DM) patients since 1950s and still occupy a central position in all international guidelines for diabetes management. With improved understanding of pathophysiology of T2DM and introduction of a number of newer oral agents, there is need to critically re-evaluate the effectiveness and safety of SUs, to assess their place in current management of T2DM. Sulfonylureas have the advantage of multiple formulations, low costs, minimal side effects, demonstrated efficacy in controlling hyperglycemia and reducing microvascular complications. However, recently concern has been raised with respect to their possible adverse effects. In addition to documented increase in risk of hypoglycemia, SUs are believed to favor the development b-cell apoptosis and b-cell exhaustion, endothelial dysfunction with increased risk for ischemic complications and possibly an increased mortality risk. This review attempts to analyze the advantages and disadvantages of available SUs with the purpose of providing a critical appraisal of the role of SUs in the modern treatment of T2DM.

BACKGROUNDSulfonylureas, the oldest noninsulin drug class presently available for the treatment of T2DM, have been the main pharmacologic approach for treatment of T2DM for many decades because of their reliable efficacy in newly diagnosed patients, limited side effects (mainly hypoglycemia) and low cost. While first generation SUs chlorpropamide and tolbuta-mide are obsolete, second generation SUs glibenclamide (glyburide), glipizide, gliclazide and glimepiride are still mainstay of pharmacotherapy for managing T2DM in India. Sulfonylureas improve glucose levels by stimulating insulin secretion by pancreatic b-cell, with elevated circulating insulin levels partially overcoming peripheral insulin resistance. They act by binding to the SU receptor subunit of adenosine triphosphate-sensitive K+ channels (KATP), reducing K+ efflux and thereby causing depolarization of cell membrane which in turn leads to calcium influx and increased release of insulin from b-cells (Figure 1).1

EFFICACY OF SULFONYLUREASSulfonylureas are possibly the most potent oral agents available for managing T2DM (Table 1). Clinical trials have shown an average reduction of glycosylated hemoglobin (HbA1c) of around 1–2% with SUs, similar to that seen with metformin and greater than other oral hypoglycemic agents.2

They are effective both as monotherapy and in combination with agents that have different mechanisms of antihyperglycemic action.

As add on therapy with metformin, SUs treatment has been shown to cause a greater reduction of HbA1c than thiazolidinedione’s and a similar effect as insulin.3

ISSUES WITH SULFONYLUREA USAGEDespite a documented efficacy, low cost and decades of clinical experience backing their usage, SUs in recent times have raised some concerns which tend to limit their use in treating T2DM patients. One, despite their remarkable efficacy in controlling glycemia, patients on SU monotherapy experience a progressive loss of glucose control. Secondly, there are documented side effects of weight gain and risk of hypoglycemia. Studies have also shown that there may be increased cardiovascular risk associated with SU usage. We will try to address these issues one by one and finally try to arrive at a conclusion regarding what should be the positioning of SUs in present day scenario.

BETA-CELL EXHAUSTION

Clinical EvidenceData from United Kingdom Prospective Diabetes Study (UKPDS) clearly showed that after initial improvement in the glycemic control, use of glibenclamide and chlorpropamide was associated with a progressive deterioration of glycemic control.4 Improvement in glycemic control was associated with an initial increase in the homeostasis model assessment b-cell function index that was followed by a progressive and linear reduction.5 This same phenomenon, however, is noted in patients in conventional treatment arm and those taking metformin, a drug that does not increase insulin secretion and also in patients taking insulin (Figure 2). Therefore, failure or worsening of glycemic control may simply be a fundamental feature of T2DM itself resulting from progressive loss of b-cell function, that is not substantially affected by the type of therapy used. On the contrary, data from A Diabetes Outcome Progression Trial (ADOPT) study clearly showed that SUs provide less durable glycemic control as compared to metformin and rosiglitazone.6

Experimental EvidenceLoss of b-cell mass and function has raised concern regarding the use of SUs for treatment of T2DM. Studies have shown that these agents may induce apoptosis in b-cell lines and rodent islets and also in isolated human islets.7,8 However, repaglinide and nateglinide did not induce b-cell apoptosis especially at low concentrations. On 4-day exposure of the islets to secretagogues, b-cell apoptosis was apparent for all secretogogues.

Clinical Trials to Clinical Practice: Role of Sulfonylureas in Today’s Practice

Brij Mohan Makkar, Deepak Gupta, Ajay Gainda

Chapter 87

394

Therapeutics Section 11

Studies in isolated human islets cultured in the presence of therapeutic concentrations of glimepiride, glibenclamide, or chlor-propamide have shown that insulin content decreased significantly after culture with all 3 SUs.9 Insulin responsiveness to glucose was preserved in islets incubated with glimepiride, but not when islets were preincubated with glibenclamide or chlorpropamide. These alterations were reverted by additional 48-hour incubation in drug-free conditions. In the UKPDS, the loss of b-cell function was not unique for SUs and also occurred at the same rate in other treatment arms, suggesting that other factors had to be at work. The most apparent factor is hyperglycemia per se, as it is concomitantly present. The toxic effect of hyperglycemia on the b-cell is now well documented.10,11

Figure 1: Schematic representation of the effect of SUs on pancreatic β-cells and cardiac myocytes. Sulfonylureas bind to sulfonylurea receptor proteins (SURs), subunits of the KATP channels. Drug binding inhibits KATP channel mediated K+ efflux, triggering a cascade of events leading to glucose-independent insulin release from pancreatic β-cells, but also to impaired ischemic preconditioning in cardiac myocytes. Adenosine triphosphate-sensitive K+ channel inhibition in other cells and tissue types may also contribute to the overall effects of individual SUs.Source: Gore MO, McGuire DK. Resolving drug effects from class effects among drugs for type 2 diabetes mellitus: more support for cardiovascular outcomes assessment. Euro Heart J. 2011;32(15):1832-4.

TABLE 1 │ Effect of oral hypoglycemics on glucose levels

Agent class Average fall in fasting plasma glucose

Average fall in HbA1c (%)

mg/dL mmol/L 0.8–2.0

Sulfonylureas 60–70 3.3–3.9 0.5–2.0

Meglitinides 65–75 3.6–4.2 1.5–2.0

Biguanide (Metformin)

50–70 2.8–3.9 1.4–2.6

Thiazolidinediones 60–80 3.3–4.3 1.4–2.6

a-Glucosidase 25–30 1.9–2.2 0.7–1.0

395

Chapter 87 Clinical Trials to Clinical Practice: Role of Sulfonylureas...Section 11

Incubation of human islets in the presence of 22.2 mmol/L glucose is associated with significant oxidative stress and marked impairment of glucose-stimulated insulin release which can be blocked by concomitant incubation with an antioxidant compound such as glutathione.11 Thus, agents with a similar antioxidant effect, may have a beneficial action in preventing loss of b-cell. Gliclazide is known to be a general free radical scavenger.12 A recent study in mouse MIN6 b-cells showed that gliclazide protected MIN6 cells from the cell death induced by H2O2, whereas glibenclamide had no significant effect (Figure 3).13

A similar experiment has been replicated in isolated human islets.14 Incubation of human islets in the presence of therapeutic concentrations of gliclazide was associated with significant reduction in nitrotyrosine content, a marker of apoptosis, while glibenclamide did not show this effect.

Long-term EfficacyThe UKPDS illustrates the progressive nature of T2DM with insidious rises in HbA1c with time as a result of b-cell loss irrespective of the agents used (Figure 2).4 As the hypoglycemic effect of SUs is secondary to increased insulin secretion, an adequate b-cell mass is needed. Beta-cell exhaustion is a part of the natural history of progression in T2DM which reduces the efficacy of SUs over the course of time. Results from the UKPDS also suggest that the “failure” rate may not be similar in all SUs. Chlorpropamide was noted to have a higher failure rate than glibenclamide.4 Gliclazide has also been shown to have a lower failure rate than glibenclamide orglipizide.15 It is important to bear in mind that SUs do not appear to either increase or decrease the underlying rate of b-cell function decline.

HYPOGLYCEMIAHypoglycemia represents a major clinical concern relating to SU use. Studies indicate that 10–20% patients get symptomatic hypoglycemia, though the incidence of severe hypoglycemia may be much lower.4,16 Over the 10-year follow-up period, UKPDS showed that the annual incidence of patients experiencing at least one hypoglycemic event was 11.0%, 17.7% and 36.5% with chlorpropamide, glibenclamide

and insulin, respectively. However, major events were seen in only 1.0%, 1.4% and 1.8%, respectively. The relative risk of severe hypoglycemia in the UKPDS is much lower than the 27% observed in intensively treated type 1 diabetic patients reported by the Diabetes Control and Complications Trial (DCCT) despite similar glycemic control (Figure 4).17 Nonetheless, severe hypoglycemic episodes are likely to be more protracted and associated with greater mortality when induced by SUs than with insulin.18

Hypoglycemia in T2DM tends to be more common among specific groups of patients, namely, older individuals and patients treated with polypharmacy. Concomitant use of insulin and SU-potentiating drugs was also associated with an increased risk of hypoglycemia. Long-acting SUs such as chlorpropamide and glyburide are more likely to cause hypoglycemia.19

The variation in hypoglycemic risk is the likely consequence of differences in duration, timing, dose equivalence and potency of hypoglycemic action of the individual agents. Glimepiride, a newer SU has been shown to cause fewer hypoglycemic reactions compared with glibenclamide (105 vs 150 episodes),20 possibly because of a better modulation of insulin release, as a function of prevalent plasma glucose concentrations. More recently, Glucosamine Unum in Die (Once A Day) Efficacy (GUIDE) study comparing gliclazide modified release (MR) 30–120

Figure 2: United Kingdom Prospective Diabetes Study 34–progressive loss of glycemic control irrespective of agent used * Therapy with Gylburide, Chlorpropamide, Metformin or insulin assigned if fasting plasma glucose (FPG) more than 15 mmol/L or symptoms of hyperglycemia Overweight patients Cohort, median values.Source: Adapted from United Kingdom Prospective Diabetes 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(9131):854-65.

Figure 3: Viability of MIN6 beta-cell exposed to H2O2 in the presence of gliclazide (5 mmol/L) or glibenclamide (5 mmol/L). Similar results were obtained with 1 mmol/L gliclazide or glibenclamide. Source: Del Prato S, Pulizzi N. The place of sulfonylureas in the therapy for type 2 diabetes mellitus. Metabolism. 2006;55(5 Suppl 1):S20-7.

Figure 4: Relative risk of hypoglycemia in T1DM patients in DCCT compared to T2DM patients in UKPDS

396

Therapeutics Section 11

mg daily and glimepiride 1–6 mg daily as monotherapy or in combi-nation with their current treatment (metformin or an a-glucosidase inhibitor), showed no hypoglycemia requiring external assistance for similar HbA1c reduction in both groups and irrespective of age.21 Nonetheless, hypoglycemia with a blood glucose level of less than 3 mmol/L occurred significantly less frequently with gliclazide MR (3.7% patients) compared with glimepiride (8.9% patients; P = .003). The latter findings outline the need for careful phenotyping of the patient, a search for all conditions that may precipitate SU-mediated hypoglycemia and accurate selection of the agent to be used. If all these procedures are followed, the risk-benefit ratio for the use of a SU is not any worse than that of other oral hypoglycemic agents.

BODY WEIGHT GAINImprovement in glycemic control is often associated with some degree of weight gain, a collateral effect common to many anti-diabetic treatments including insulin, thiazolidinedione’s, and SUs.4,22 Of the three options, SUs seem to be associated with much less increase in body weight. In the UKPDS, after 10 years of follow-up, the mean body weight change ranged from a minimum of 1.7 kg for glibenclamide to a maximum of 2.6 kg for chlorpropamide.4 In spite of the fact that body weight gain may be seen as an undesirable effect, the change in body weight should nevertheless be considered in a more comprehensive risk-to-benefit ratio. Increase in body weight during the UKPDS occurred together with achievement and maintenance of good glycemic control and significant reduction in all diabetes-related events, microangiopathy and, to some extent, macroangiopathy.4

Glimepiride has been claimed to be at least neutral with respect to body weight and weight reduction has been observed by some authors.23,24 Body weight neutrality has been reported with other SUs, particularly with extended-release glipizide and gliclazide MR.21,25 Altogether, these findings may suggest that body weight gain in response to SU therapy may have been overemphasized and that more accurate choice of the agent may allow an easier control of body weight, even in overweight T2DM patients.

SELECTIVITYDuring the past several years, the potential adverse effect of SUs on myocardial ischemic preconditioning has emerged as an important concern.26 The actual importance of this issue in clinical practice remains unclear, but it has possibly been exaggerated. Sulfonylureas act by binding of KATP channels on b-cells. Different SUs have differ-ent cross-reactivity with cardiovascular KATP channels (Figure 1).26 Pharmacologic agents closing these channels oppose ischemic preconditioning and this effect has raised concern of a possible deleterious effect of SU treatment with respect to cardiovascular mortality. In addition to animal experiments, recent human studies also support interference of some SUs on cardiac function under ischemic challenge.27-29 Thus, in response to dipyridamole stress, T2DM patients treated with glibenclamide compared with insulin had much worse myocardial function.30 More recently, Lee and Chou showed that protection by preconditioning occurred in T2DM patients treated with glimepiride, but not when glibenclamide was used.31 This different selectivity confirms previous experimental findings.27,28 A recent study looking at the effects of short-term and long-term treatment with glibenclamide and gliclazide on forearm post-ischemic reactive hyperemia (RH) in type 2 diabetic patients showed that after short-term administration of gliclazide (80 mg) or glibenclamide (5 mg), RH was not influenced.32,33 However, after 4 weeks of treatment, glibenclamide induced a significant (P = .004) reduction in RH. Gliclazide, conversely, did not induce a reduction in RH. Although this difference is most probably based on different

SU receptor binding, other mechanisms may contribute to this protective effect. Studies have also shown that different SU molecules may have different effects. Several studies have shown that gliclazide also possesses hemorheologic properties, reduces platelet reactivity, stimulates endothelial prostacyclin synthesis and increases fibrinolysis, possibly because of reduction in oxidative stress.34,35 A study of oxidative parameters with gliclazide in T2DM patients showed that administration of either MR or standard gliclazide resulted in a fall in 8-isoprostanes, a marker of lipid oxidation and an increase in the antioxidant parameters total plasma antioxidant capacity, superoxide dismutase and thiols. Most likely, this property is due to gliclazide’s free radical-scavenging ability that relates to the unique aminoazabicyclo-octane ring grafted onto the SU.36

MORTALITY RISKDespite the extensive use of SUs, few randomized studies have assessed long-term mortality outcomes related to monotherapy with individual SUs.4,37 The University Group Diabetes Program (UGDP) was possibly the first study to document that tolbutamide was associated with increased total and cardiovascular mortality, causing the premature discontinuation of the tolbutamide arm in the study.37 On the contrary, the initial UKPDS study found no effect of other older SUs, i.e. chlorpropamide and glibenclamide on macrovascular disease complications or mortality.4 Few observational studies have reported glibenclamide causing increase in overall and cardiovascular mortality when compared with gliclazide and glimepiride,38,39 whereas a recent large observational study comparing glibenclamide with glimepiride did not confirm increased risk.40

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study of ~11,000 T2DM patients with high-risk of cardiovascular disease (CVD) demonstrated no harm with respect to cardiovascular risk or mortality in patients treated with gliclazide MR in the intensive control arm.41

In a recent nationwide Danish registry-based observational study, Schramm et al. reported most insulin sensitizers (ISs); including glimepiride, glibenclamide, glipizide and tolbutamide, seem to be associated with increased mortality and cardiovascular risk compared with metformin, while gliclazide and repaglinide appear to be associated with a lower risk than other ISs.42

In interpreting these data, it is of key importance to note that the observation of less benefit with most SUs compared with metformin should not be interpreted as causing harm, as metformin has an estimated risk reduction of approximately 40% for major adverse cardiac events and death compared with placebo.43 When comparing outcomes associated with SUs against metformin, hazard ratios of up to 1.7 would suggest treatment effects similar to or better than placebo, especially when considered in the context of favorable effects on microvascular disease risk associated with improved glucose control.44

TRANSLATING EVIDENCE INTO CLINICAL PRACTICEIn depth analysis of the vast literature on SUs suggests that SUs are not only efficacious in the management of T2DM, they are also the most potent and the cheapest agents available. The side effects of hypoglycemia and weight gain do not appear to take away all the benefit of significant HbA1c reduction and reduction in the risk of microvascular complications. Also, when used in combination with metformin, as is recommended by most guidelines, weight gain is not a big problem. Also, by making judicious choice of which SU agent to use, drawbacks of older SUs can be overcome. There is data to suggest

397

Chapter 87 Clinical Trials to Clinical Practice: Role of Sulfonylureas...Section 11

that some of these drugs may provide persistent glycemic control, while limiting the risk of hypoglycemia and weight gain. Once-daily SUs such as glimepiride and gliclazide MR may have much less interference with vasculature ensuring neutrality on the endothelial function and no adverse effect on ischemic preconditioning. Hemorheologic effects of gliclazide MR together with an antioxidant action might provide an antiatherogenic advantage.

RECOMMENDATIONS FROM APEX ORGANIZATIONSFindings from major trials of glucose control in patients with T2DM and the approval of novel medications have prompted revised treatment algorithms from all major diabetes organizations. However, despite availability of newer molecules, all treatment guidelines still recommend starting with metformin in most patients on diagnosis of T2DM, and SUs are very much part of the choice available for initiation or as second add on agents and are especially preferred where cost of therapy is a consideration.45-47

CONCLUSIONSulfonylureas still occupy a central position in the recommendations of all the guidelines for treatment of T2DM and are likely to continue to be a reliable and effective treatment, particularly as combination therapy. Advancement in the formulation and established non-glucose lowering properties of specific SU agents still provide an opportunity for effective treatment of T2DM. Given the fact that insulin resistance and defective insulin secretion contribute to development and progression of hyperglycemia, in individuals with a prevalent defect in insulin secretion, use of a SU may sound a better choice as a front-line treatment. The use of once-daily administration and the choice of SU agents that may not exert further stress on the b-cell and are associated with beneficial properties other than a glucose-lowering effect may then confer specific advantages. Low cost of therapy, a consideration of immense importance in India is another major advantage which may be of help in getting the large population of diabetes in country to improve their glycemic control.

REFERENCES 1. Kramer W, Müller G, Geisen K. Characterization of the molecular mode

of action of the sulfonylurea, glimepiride, at beta-cells. Horm Metab Res. 1996;28(9):464-8.

2. Kar P, Holt RI. The effect of sulphonylureas on the microvascular and macrovascular complications of diabetes. Cardiovasc Drugs Ther. 2008;22(3):207-13.

3. Monami M, Lamanna C, Marchionni N, et al. Comparison of different drugs as add-on treatments to metformin in type 2 diabetes: a meta-analysis. Diabetes Res Clin Pract. 2008;79(2):196-203.

4. United Kingdom 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(9131):837-53

5. UKPDS Study Group. Overview of 6 years’ therapy of type 2 diabetes: a progressive disease. Diabetes. 1995;44(11):1249-58.

6. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427-43.

7. Efanova IB, Zaitsev SV, Zhivotovsky B, et al. Glucose and tolbutamide induce apoptosis in pancreatic beta-cells. A process dependent on intracellular Ca2+ concentration. J Biol Chem. 1998;273(50):33501-7.

8. Maedler K, Carr RD, Bosco D, et al. Sulfonylurea induced beta-cell apoptosis in cultured human islets. J Clin Endocrinol Metab. 2005;90(1):501-6.

9. Del Guerra S, Marselli L, Lupi R, et al. Effects of prolonged in vitro exposure to sulphonylureas on the function and survival of human islets. J Diabetes Complications. 2005;19(1):60-4.

10. Poitout V, Robertson RP. Minireview: secondary beta-cell failure in type 2 diabetes—a convergence of glucotoxicity and lipotoxicity. Endocrinology. 2002;143(2):339-42.

11. Del Prato S, Lupi R, Bugliani M, et al. Glucotoxicity in human pancreatic islets is mediated by oxidative stress: evidence for limited defense capacity. Diabetologia. 2004;47(Suppl 1):A39.

12. McGavin JK, Perry CM, Goa KL. Gliclazide modified release. Drugs. 2002;62(9):1357-64.

13. Kimoto K, Suzuki K, Kizaki T, et al. Gliclazide protects pan-creatic beta-cells from damage by hydrogen peroxide. Biochem Biophys Res Commun. 2003;303(1):112-9.

14. Grupillo M, Del Guerra S, Masini M, et al. Gliclazide protects isolated human islets from apoptosis induced by intermittent high glucose: the role of oxidative stress. Diabetologia. 2005;48(Suppl 1):A45.

15. Holman RR. Long-term efficacy of sulfonylureas. Metabolism. 2006;55(5 Suppl 1):S2-5.

16. Jennings AM, Wilson RM, Ward JD. Symptomatic hypoglycemia in NIDDM patients treated with oral hypoglycemic agents. Diabetes Care. 1989;12(3):203-8.

17. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-86.

18. Ferner RE, Neil HA. Sulphonylureas and hypoglycaemia. Br Med J (Clin Res Ed). 1988;296(6627):949-50.

19. Del Prato S, Pulizzi N. The place of sulfonylureas in the therapy for type 2 diabetes mellitus. Metabolism. 2006;55(5 Suppl 1): S20-7.

20. Draeger KE, Wernicke-Panten T, Lomp HJ, et al. Long-term treatment of type 2 diabetic patients with the new oral antidiabetic agent glimepiride (Amaryl): a double-blind comparison with glibenclamide. Horm Metab Res. 1996;28(9):419-25.

21. Schernthaner G, Grimaldi A, Di Mario U, et al. GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Invest. 2004;34(8):535-42.

22. United Kingdom Prospective Diabetes Study Group. United Kingdom Prospective Diabetes Study 24: a 6-year, randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. Ann Intern Med. 1998;128(3):165-75.

23. Martin S, Kolb H, Beuth J, et al. Change in patients’ body weight after 12 months of treatment with glimepiride or glibenclamide in type 2 diabetes: a multicentre retrospective cohort study. Diabetologia. 2003;46(12):1611-7.

24. Bugos C, Austin M, Atherton T, et al. Long-term treatment of type 2 diabetes mellitus with glimepiride is weight neutral: a meta-analysis. Diabetes Res Clin Pract. 2000;50(Suppl 1):S47.

25. Simonson DC, Kourides IA, Feinglos M, et al. Efficacy, safety, and dose-response characteristics of glipizide gastrointestinal therapeutic system on glycemic control and insulin secretion in NIDDM. Results of two multicentre, randomized, placebo-controlled clinical trials. Diabetes Care. 1997;20(4):597-606.

26. O’Rourke B. Myocardial K(ATP) channels in preconditioning. Circ Res. 2000;87(10):845-55.

27. Lazdunski M. Ion channel effects of anti-diabetic sulfonylureas. Horm Metab Res. 1996;28(9):488-95.

28. Geisen K, Végh A, Krause E, et al. Cardiovascular effects of conventional sulfonylureas and glimepiride. Horm Metab Res. 1996;28(9):496-507.

29. Mocanu MM, Maddock HL, Baxter GF, et al. Glimepiride, a novel sulfonylurea, does not abolish myocardial protection afforded by either ischemic preconditioning or diazoxide. Circulation. 2001;103(25):3111-6.

30. Maddock HL, Siedlecka SM, Yellon DM. Myocardial protection from either ischaemic preconditioning or nicorandil is not blocked by gliclazide. Cardiovasc Drugs Ther. 2004;18(2): 113-9.

31. Scognamiglio R, Avogaro A, Vigili de Kreutzenberg S, et al. Effects of treatment with sulfonylurea drugs or insulin on ischemia-induced myocardial dysfunction in type 2 diabetes. Diabetes. 2002;51(3):808-12.

32. Lee TM, Chou TF. Impairment of myocardial protection in type 2 diabetic patients. J Clin Endocrinol Metab. 2003;88(2):531-7.

33. Klepzig H, Kober G, Matter C, et al. Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-con-trolled evaluation of glimepiride and glibenclamide. Eur Heart J. 1999;20(6):439-46.

398

Therapeutics Section 11

34. Wascher TC, Boes U. Forearm vascular reactivity is differentially influenced by gliclazide and glibenclamide in chronically treated type 2 diabetic patients. Clin Physiol Funct Imaging. 2005;25(1):40-6.

35. Renier G, Mamputu JC, Serri O. Benefits of gliclazide in the atherosclerotic process: decrease in monocyte adhesion to endothelial cells. Metabolism. 2003;52(8 Suppl 1):13-8.

36. Jennings PE. Vascular benefits of gliclazide beyond glycemic control. Metabolism. 2000;49(10 Suppl 2):17-20.

37. O’Brien RC, Luo M, Balazs N, et al. In vitro and in vivo antioxidant properties of gliclazide. J Diabetes Complications. 2000;14(4):201-6.

38. Meinert CL, Knatterud GL, Prout TE, et al. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes. 1970;19(Suppl):789-830.

39. Khalangot M, Tronko M, Kravchenko V, et al. Glibenclamide-related excess in total and cardiovascular mortality risks: data from large Ukrainian observational cohort study. Diabetes Res Clin Pract. 2009;86(3):247-53.

40. Monami M, Balzi D, Lamanna C, et al. Are sulphonylureas all the same? A cohort study on cardiovascular and cancer-related mortality. Diabetes Metab Res Rev. 2007;23(6):479-84.

41. Pantalone KM, Kattan MW, Yu C, et al. The risk of overall mortality in patients with type 2 diabetes receiving glipizide, glyburide, or

glimepiride monotherapy: a retrospective analysis. Diabetes Care. 2010;33(6):1224-9.

42. The ADVANCE collaborative group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): 2560-72.

43. Schramm TK, Gislason GH, Vaag A, et al. Mortality and cardiovascular risk associated with different secretogogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Euro Heart J. 2011;32(15):1900-8.

44. United Kingdom Prospective Diabetes 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(9131):854-65.

45. Gore MO, McGuire DK. Resolving drug effects from class effects among drugs for type 2 diabetes mellitus: more support for cardiovascular outcomes assessment. Euro Heart J. 2011;32(15):1832-4.

46. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglyce-mia in type 2 diabetes: a patient-centred approach. Position Statement of American Diabetes Association (ADA) and European Association for Study of Diabetes (EASD). Diabetologia. 2012;55(6):1577-96.

47. AACE/ACE Glycemic Control Algorithm. Endocr Pract. 2009;15(No. 6):543.