Evidence-based benefits of a selective secretagogue: Diamicron MR 60 mg





Brant DE FANTI,PhD
Servier International
Suresnes, FRANCE

Evidence-based benefits of
a selective secretagogue:
Diamicron MR 60 mg

 

by B. De Fanti, France

Treatment of type 2 diabetes needs to address disease progression and balance the pharmacological efforts that lower hyperglycemia against the increased risks of hypoglycemia and weight gain. Furthermore, as patients with type 2 diabetes are at increased risk of cardiovascular morbidity and mortality, treatment strategies should focus not only on reducing hyperglycemia, which decreases the risk of microvascular complications and probably also macrovascular complications, but also on controlling other cardiovascular risk factors and improving lifestyle factors. Findings show that greater benefits are obtained through an intensive target-driven approach to glucose control earlier in the life course of the patient. Modified-release gliclazide (gliclazide MR) has been shown to effectively lower HbA1c, with sustained glycemic control over time. In addition to its effective glucose-lowering action, gliclazide MR has been shown to significantly reduce the incidence of clinically relevant renal complications and is associated with the lowest risk of hypoglycemia and cardiovascular mortality among sulfonylureas. In view of its favorable risk-benefit balance and potential cardiovascular advantages, the Dutch Type 2 Diabetes Management Guidelines recently recommended gliclazide (rather than sulfonylureas as a class) as a preferred second treatment option.

Medicographia. 2016;38:77-87 (see French abstract on page 87)

Type 2 diabetes is one of the most prevalent and costly chronic medical conditions worldwide, incurring significant burdens on individuals, society, and health care systems. The global burden of diabetes has increased from 153 million people affected in 1980 to 387 million in 2014, and is expected to increase by a further 205 million over the next 20 years.1

Type 2 diabetes is associated with long-term complications and reduced quality of life and life expectancy, and can result in a wide range of complications with repercussions for both the individuals and health care systems. People with type 2 diabetes have almost a twofold excess cardiovascular risk, including coronary artery disease (leading to heart attacks and/or angina); lower extremity peripheral artery disease (leading to amputations); and carotid artery disease (strokes, dementia).2 In addition, prolonged hyperglycemia can lead to irreversible microvascular complications such as diabetic retinopathy, nephropathy, and neuropathy. The risk of death for adults with diabetes is 50% higher than for adults without diabetes and it is estimated that, globally, diabetes accounts for approximately 8.4% of deaths in adults aged 20-79 years, almost 5.1 million deaths annually.1 The presence of diabetic complications can lead to a 5- fold increase in a patient’s costs and people with diabetes can experience prolonged stays in hospital.3 Approximately 50% of people newly diagnosed with type 2 diabetes already have complications, so it is critical to implement some form of early intervention.

As patients with type 2 diabetes have an elevated risk of cardiovascular disorders, the treatment of this disease is multifactorial. Multiple vascular risk factors and wide-ranging complications make diabetes care complex and time-consuming, and many areas of health care services must be involved for optimal management. This means that treatment should focus not only on reducing hyperglycemia, which decreases the risk of microvascular complications and probably also macrovascular complications, but also on controlling other cardiovascular risk factors, such as smoking, hypertension, and dyslipidemia, and improving lifestyle factors, such as diet and exercise regimen to lose weight.4

The risks of arterial disease and microvascular complications in people with diabetes are related to the extent of hyperglycemia over time. Because type 2 diabetes is a progressive condition, with secretion of insulin decreasing over time, the need for blood glucose–lowering therapy becomes imperative and inevitable. A comprehensive approach to blood glucose management incorporating education, assessment, self-monitoring, and pharmacological strategies is required to facilitate optimal care. Evidence points to an increased risk of long-term complications associated with higher HbA1c levels, increasing with each 1% rise in HbA1c levels, and correspondingly decreasing with each 1% fall in HbA1c levels.

There is a general consensus that tight glycemic control is beneficial in reducing the risks associated with type 2 diabetes. Current guidelines now recommend that clinicians adopt an individualized approach to diabetes care that is tailored to the patient’s needs and circumstances, taking into account their personal preferences, comorbidities, risks of polypharmacy, and their ability to benefit from long-term interventions due to reduced life expectancy. The benefits, side effects, and relative cost-effectiveness differ among pharmacological classes, and to a lesser extent between individual drugs within the same class. The choice, order, and combination in which these treatments are used reflect consideration of their efficacy in glycemic control and prevention of microvascular and/or arterial damage, as well as their risks of side effects.

Mode of action of sulfonylureas

Type 2 diabetes results from two main pathological processes: insulin resistance and pancreatic β-cell dysfunction. Today, there are more therapy options for managing type 2 diabetes than ever before. As the first available oral glucose-lowering agents, sulfonylureas have a 60-year record of use, and there is substantial evidence of their efficacy, safety, and benefits in terms of quality-adjusted life-years at a significantly lower cost.5-8 The second-generation sulfonylureas such as glipizide, glibenclamide, gliclazide, and glimepiride, are still at the core of type 2 diabetes management with an early place in therapeutic algorithms. They are widely used around the world, accounting for up to 20% of newly initiated oral therapies, either as monotherapy or in combination, for treatment of type 2 diabetes.9

The use of sulfonylureas to treat type 2 diabetes is based on their insulinotropic action on the pancreatic βcells. Their primary mechanism of action is to close ATP-sensitive potassium (KATP) channels in the plasma membrane of βcells, initiating a chain of events which results in insulin release.10 More recent studies have shown that the β-cell KATP channel is a complex of two proteins: a pore-forming subunit (Kir6.2) and a drug-binding subunit that functions as the receptor for sulfonylureas (sulfonylurea receptor 1 [SUR1]).11 It is the binding of the sulfonylurea to the common SUR receptor on β cells that causes the closure of the KATP channels and inhibition of potassium efflux, leading to membrane depolarization and influx of calcium. The SUR1 receptor contains two high-affinity binding sites, one that accepts a sulfonyl moiety and one that accepts a benzamide moiety. Studies of cloned channels have revealed that most sulfonylureas (glibenclamide, glipizide, and glimepiride) possess both sulfonyl and benzamide moieties (Figure 1) and interact with both binding sites, creating a tight and nonreversible bond to the SUR1 receptor.12 Gliclazide, however, has no benzamide moiety and only binds to the sulfonyl site and so dissociates from the receptor more freely. These different binding behaviors result in different insulin secretion profiles, where the rapidly reversible interaction with gliclazide results in pulsatile stimulation.13 The consequence of prolonged binding, as with glimepiride, glipizide, and glibenclamide, is prolonged cell stimulation and uncontrolled insulin secretion.14

Figure 1
Figure 1. Molecular structure of sulfonylureas.

This different binding behavior also has an impact on tissue selectivity and safety. KATP channels are found at high density in a variety of cell types other than the β cell, including cardiac, smooth, and skeletal muscle. Those sulfonylureas that contain both sulfonylurea and benzamide moieties (glipizide, glibenclamide, and glimepiride) bind and block both SUR1 and SUR2 KATP channels while, gliclazide blocks the SUR1 KATP channels in the β cell, but not SUR2A or SUR2B in cardiac or smooth muscle.12,14-16

Gliclazide’s selectivity for the pancreatic β cell is important because the KATP channels in the heart are normally closed and open only in response to metabolic stress, such as that which occurs during ischemia.17,18 In the presence of cardiac ischemia, intracellular ATP levels drop, opening the cardiac muscle KATP channels and resulting in vasodilatation and decreased myocardial oxygen consumption, thereby minimizing tissue injury and protecting myocardial function. Nonselective pharmacological agents that close the cardiac SUR2A KATP channels oppose this ischemic preconditioning, effectively preventing this inherent protective effect and have the potential to increase cardiovascular risk in patients with diabetes.19

More recent studies focused on glucagon-like peptide-1 (GLP- 1) signaling have demonstrated a critical role for Epac2A (a cAMP binding protein) in the insulin secretory effect of incretins.20 The incretin GLP-1, secreted from the intestine upon meal ingestion, amplifies insulin secretion by binding to its specific receptors on pancreatic β cells, increasing the intracellular cAMP, and leading to the activation of both protein kinase A (PKA) and Epac2A/Rap1 signaling pathways.

Epac2A has also been found to be a direct target of certain sulfonylureas and it was shown that activation of Epac2A/ Rap1 signaling can potentiate sulfonylurea-induced insulin secretion.21

The combination of an incretin and a sulfonylurea (glibenclamide or glimepiride) has been shown to synergistically stimulate insulin secretion at a basal level of glucose concentration through Epac2A/Rap1 signaling.22 Gliclazide is unique among sulfonylureas in that its effect is not influenced by Epac2A/ Rap1 signaling, and these differences in the action of various sulfonylureas on Epac2A may well account for the clinical differences observed in the combinatorial effects of incretin and sulfonylureas. The incidence of hypoglycemia when a dipeptidyl peptidase-4 (DPP-4) inhibitor is combined with gliclazide is significantly lower than when it is combined with glibenclamide or glimepiride.23 These findings on the role of Epac2A/ Rap1 signaling in the over secretion of insulin observed with combination therapies suggest an additional mechanism for the differences observed in hypoglycemic risk depending on the sulfonylurea and its structure.

Glucose-lowering efficacy

Clinical experience with sulfonylureas
The degree of blood glucose lowering seen with sulfonylureas depends on the initial hyperglycemia, with a greater effect being seen in those with the highest initial glucose concentrations. Sulfonylureas have a long-standing evidence base for providing long-lasting improvement in blood glucose control.24 In placebo comparator studies, sulfonylurea treatment was found to reduce the fasting glycemia by 20 mg/dL to 40 mg/ dL and HbA1c by 1.0 % to 2.0%,4,25 and a meta-analysis of 27 randomized clinical trials comparing different drugs added to metformin found that sulfonylurea treatment was associated with a greater reduction of HbA1c than thiazolidinediones, and a similar effect to that of insulin.26 A recent systematic review and meta-analysis found sulfonylurea monotherapy to lower HbA1c by an average of 1.5%, similar to the reduction in HbA1c seen with metformin.27 Two more recent meta-analyses of randomized controlled studies have shown that gliclazide was slightly more effective in lowering HbA1c than other oral glucose- lowering agents, with a weighted mean difference between comparator of -0.11% to -0.13% (Figure 2).28,29

Figure 2
Figure 2.
Forest plot
of change in
HbA1c comparing
treatment
with gliclazide
with other oral
antidiabetic
drugs in 19
randomized
controlled trials.

Abbreviations: CI,
confidence interval;
HbA1c, glycated
hemoglobin.
Please see reference
28 for complete
details on
the trials cited in
this figure.
After reference 28:
Landman et al.
PLoS One. 2014;
9(2):e82880.
© 2014, Landman
et al.

The UKPDS study (United Kingdom Prospective Diabetes Study) illustrated the progressive nature of type 2 diabetes with escalating rises in HbA1c over time as a result of progressive β-cell loss. While there were concerns that sulfonylureas might accelerate β-cell loss by stimulating an already strained islet, no differences in the rate of glycemic deterioration were observed between agents. As the glucose-lowering effect of sulfonylureas is secondary to increased insulin secretion, an adequate β-cell mass is needed. As more and more β cells are lost as part of the natural history of progression in type 2 diabetes, the efficacy of treatments are also reduced over the course of time.

In the ORIGIN trial (Outcome Reduction with an Initial Glargine Intervention), patients in the standard therapy group were treated mainly with metformin and a sulfonylurea, and glycemic control was maintained at an average HbA1c of 6.5% for 6 years.30 Overall, sulfonylureas do not appear to either increase or decrease the underlying rate of β-cell function decline, but results suggest that the “therapeutic failure” rate may not be similar in all sulfonylureas.

In the ADOPT study (A Diabetes Outcome Progression Trial), subjects treated with glibenclamide had the highest fasting glucose, HbA1c, insulin resistance, and failure rate of monotherapy. The therapeutic failure rate with gliclazide has been shown to be significantly lower than that of glibenclamide or glipizide.31 The ADVANCE trial (Action in Diabetes and Vascular disease: PreterAx and Dia-microN MR Controlled Evaluation) lowered the average HbA1c level to 6.5% in a broad range of patients with type 2 diabetes using an intensive gliclazide MR (Diamicron MR)–based glucose-control strategy, which was maintained (with 4 out of 5 patients attaining an HbA1c≤7%) with no deterioration for a mean of 5 years.<sup<32 Gliclazide’s durability of efficacy has also been documented in a study demonstrating that the delay before insulin dependency (period until the start of insulin treatment) was significantly longer in patients with type 2 diabetes treated with gliclazide (14.5 years) than in those treated with glibenclamide (8 years).33

Extrapancreatic effects

Chronic oxidative stress is proposed to be a key component in the pathogenesis of diabetes as well as in the development of its complications.34 βCells are extremely sensitive to oxidative stress and the excessive levels of reactive oxygen species (ROS) produced by chronic exposure to hyperglycemia is one of the main contributors to the deterioration of β-cell function over time.35,36 Gliclazide, with its free radical– scavenging aminoazabicyclo-octyl ring grafted on the sulfonylurea group, appears to be the only sulfonylurea that can reduce ROS production and apoptosis in β cells.37 Experiments in isolated islets exposed to various concentrations of sulfonylureas found an absence of β-cell apoptosis with exposure to gliclazide, whereas with glibenclamide and glimepiride the numbers of apoptotic cells were significantly increased.38 Moreover, only gliclazide prevented high glucose–induced apoptosis in human β cells.39

The free radical–scavenging properties of gliclazide may also help restore endothelial function and reduce platelet activity.40 Antiplatelet therapy has an established role in the management of people with cardiovascular disease, although its role in primary prevention for people without existing cardiovascular disease is less clear. By decreasing plasminogen activator inhibitor and enhancing fibrinolysis, gliclazide can inhibit platelet aggregation and thrombosis as well as lower blood viscosity, contributing to the prevention of microangiopathy.41

Tolerability

Tight glycemic control is essential in order to prevent or delay diabetes complications, but hypoglycemia is the foremost clinical concern when intensifying the treatment.3,42 Moderate hypoglycemia induces cognitive impairment42 and can interfere with many complex attention tasks relevant to everyday life, while recurrent severe hypoglycemia may induce more grave and long-term consequences.43,44 The glucose-lowering effect of sulfonylureas can lead to a severe hypoglycemic event in about 1 in every 100 persons per year.45 In the 10-year follow- up analysis of the UKPDS study, the annual incidence of at least one hypoglycemic event experienced by patients taking sulfonylureas was found to be less than half that occurring with insulin (17.7% vs 36.5%), while rates of major hypoglycemic episodes per year were 0.7% with conventional treatment, 1.4% with glibenclamide, and 1.8% with insulin.3

An intensive target-driven approach can, however, safely reduce the risk of complications in high-risk patients. As demonstrated in the ADVANCE trial, patients treated with gliclazide MR benefited from a significant reduction in combined macrovascular and microvascular complications (-10%, P=0.01), which was largely linked to a significant protection against new or worsening nephropathy (-21%, P=0.006).32 The rate of severe hypoglycemic events was only 0.7 event per 100 patients per year in the gliclazide MR active group and 0.4 event per 100 patients per year in the standard-control group. The low rate observed in the intensive group is particularly reassuring considering that 40% of patients were also on insulin therapy.

Individual sulfonylureas differ in their hypoglycemic potential, mainly due to their half-life and time of action and their affinity and binding behavior to the SUR1receptor on β cells.46 A lower incidence of hypoglycemia has been reported with gliclazide than with other sulfonylureas in several studies. The GUIDE study (GlUcose control In type 2 diabetes: Diamicron modified release versus glimepiride), a 52-week double-blind comparison of gliclazide MR and glimepiride (the two most frequently used once-daily sulfonylureas in type 2 diabetes treatment), demonstrated that for similar reductions in HbA1c the proportion of patients experiencing hypoglycemic episodes was more than twice higher with glimepiride (8.9%) than with gliclazide MR (3.7%).47 Moreover, the particularly low incidence of hypoglycemia in the gliclazide MR–treated patients with only moderately elevated baseline HbA1c (≤7%), a group generally considered at higher risk for hypoglycemia, reinforces the value of gliclazide MR use to achieve the currently recommended aggressive HbA1c targets (between 6.5% and 7%).

Sulfonylureas differ in their binding behavior to the pancreatic β SUR1 receptor due to their different chemical structures and the presence—or absence—of a second active site (besides the sulfonyl moiety). Gliclazide has a rapidly reversible interaction with the receptor while glibenclamide, glimepiride, and glipizide exhibit prolonged binding and cell stimulation, which results in differences in tolerability.13,14

In terms of tolerability, the particular interest of gliclazide was highlighted in a recent meta-analysis of 22 randomized controlled studies comparing individual sulfonylureas. The analysis of mild hypoglycemic events (defined as blood glucose ≤3.1 mmol/L) showed that hypoglycemia was experienced by 10 times fewer patients in those taking gliclazide than in those taking glimepiride (1.4% vs 15.5%, P<0.001)48 (Figure 3, page 82). Likewise, a significantly lower proportion of patients experienced severe hypoglycemia when taking gliclazide (0.1%) than patients taking glipizide (2.1%), glimepiride (0.9%), or glibenclamide (0.5%).48 In addition, a network metaanalysis of randomized controlled trials found that when added to metformin, gliclazide confers the lowest risk of hypoglycemia among the sulfonylureas. Gliclazide reduced the comparative risk of hypoglycemia of any severity by 56% vs glimepiride, 85% vs glipizide, and 86% vs glibenclamide.49 Certain patients with type 2 diabetes, such as the elderly, those with renal impairment, or those on polypharmacy are at increased risk of hypoglycemia.50 When caring for older adults with type 2 diabetes, particular consideration should be given to their broader health and social care needs. Older people are more likely to have coexisting conditions and to be on a greater number of medicines. The GUIDE study showed the same reduced risk with gliclazide versus glimepiride in older patients (>65 years) as that observed with younger patients. A more recent population-based retrospective cohort study evaluating the risk of hypoglycemia and all-cause mortality in older adults who were newly prescribed glibenclamide or gliclazide MR as monotherapy or in the presence of metformin found that gliclazide MR is associated with a significantly lower risk of hypoglycemia than glibenclamide.51 In matched comparison with glibenclamide, gliclazide was associated with a significantly reduced risk of severe hypoglycemia (8-fold reduction with monotherapy, and 6-fold reduction with bitherapy). Moreover, gliclazide MR treatment was associated with a significantly lower risk for hospital encounters with hypoglycemia than glibenclamide, all evidence supporting the current labeling where gliclazide MR is prescribed using the same dosing regimen recommended for patients under 65 years of age. These results in terms of efficacy and safety demonstrate that gliclazide is as effective as glibenclamide and glimepiride and more effective than glipizide in reducing HbA1c while causing less hypoglycemia than glibenclamide and glimepiride.52

Figure 3
Figure 3. Incidence of mild and severe hypoglycemia in patients
with type 2 diabetes treated with sulfonylureas.

Modified from reference 48: Schopman et al. Diabetes Metab Res Rev. 2014;
30(1)11-22. © 2013, John Wiley & Sons, Ltd.

Kidney impairment also impacts the choice and dosage of medication and the referral strategy. Chronic renal failure is a progressive loss of function of nephrons that gradually decreases overall kidney function. The risk of hypoglycemia is increased in patients with substantial decreases in glomerular filtration rate (chronic kidney disease [CKD] stages 4 and 5) due to decreased clearance of insulin and of some of the oral agents used to treat diabetes. Progressive falls in kidney function result in decreased clearances of the sulfonylureas or their active metabolites, necessitating a decrease in drug dosing to avoid hypoglycemia. Unlike glibenclamide and glimepiride, gliclazide is metabolized by the liver (not the kidney) and does not have active metabolites, so it can be safely used in patients with mild-to-moderate renal insufficiency with the same dosing regimen as in patients with normal renal function.47 Moreover, the guidelines from the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative considers gliclazide a preferred sulfonylurea in patients with chronic kidney disease, with no dose adjustment necessary even in CKD stages 3, 4, and 5, including in dialysis and transplant patients.53

Patients with type 2 diabetes that fast during Ramadan are also at increased risk of symptomatic and severe hypoglycemia, which can have an adverse effect on their quality of life, is a limiting factor in glycemic control, and forms an obstacle in compliance to medication and treatment. Current recommendations are largely based on expert opinion and not on scientific data derived from robust clinical trials. A recent meta-analysis of results from randomized trials comparing DPP-4 inhibitors and gliclazide (rather than the sulfonylurea class) highlighted similarly low risks of experiencing symptomatic hypoglycemia with either gliclazide or DPP-4 inhibitor, and pointed out that the proportion of patients reporting any hypoglycemic event in the gliclazide group was not statistically different than in the group of patients treated with sitagliptin or vildagliptin54 (Figures 4 and 5).

Two recent meta-analyses reexamined the evidence and came to similar conclusions: that the risk of severe or confirmed hypoglycemia is extremely low with gliclazide and that it has a much better safety profile than glibenclamide, glipizide, or glimepiride.28,29 An evaluation by an independent Dutch group validated their own country’s type 2 diabetes management guidelines, which specifically recommend gliclazide (“and not sulfonylureas as a group”) as the preferred second treatment option.55 Tissue selectivity and risk of hypoglycemia, which differ among sulfonylureas—with gliclazide consistently showing the lowest incidence—need to be considered when choosing a therapy.

Another major side effect that often limits the use of sulfonylureas is weight gain. In the UKPDS study, weight gain was significantly higher in the intensive group than in the conventional group, with patients assigned insulin gaining the greatest weight (4.0 kg) compared with those assigned glibenclamide (1.7 kg). Body weight was stable during the GUIDE study with mean changes from 83.1 to 83.6 kg and 83.7 to 84.3 kg on gliclazide MR and glimepiride, respectively, while the ADVANCE study showed that 5 years of intensive treatment with gliclazide MR resulted in no increase in body weight.32,47

Figure 4
Figure 4. Episodes
of symptomatic hypoglycemic
events with different
sulfonylureas and
dipeptidyl peptidase-4
(DPP-4) inhibitors in observational
randomized
studies during Ramadan
fasting.

Please see reference 54 for
complete details on the studies
cited in this figure.
After data from reference 54:
Mbanya et al. Diabetes Res
Clin Pract. 2015;109(2):
226-232.

Figure 5
Figure 5. Pooled analysis of randomized trials comparing the
number of patients who experienced at least one hypoglycemic
event while under treatment with gliclazide in comparison to
DPP-4 (dipeptidyl peptidase-4) inhibitors during Ramadan.

Please see reference 54 for complete details on the studies cited in this figure.
Modified from reference 54: Mbanya et al. Diabetes Res Clin Pract. 2015;
109(2):226-232. © 2015, Elsevier Ireland Ltd.

 

Cardiovascular safety

Although data on cardiovascular morbidity and mortality during treatment with sulfonylureas are contrasting, a meta-analysis of 62 randomized clinical trials reporting major cardiovascular events with sulfonylureas versus various comparators detected no signal for cardiovascular risk, with an overall odds ratio (OR) for major cardiovascular events with sulfonylurea treatment versus comparators of 1.08 (95% CI, 0.86- 1.36).56

Data do suggest, however, that different sulfonylureas might have a different impact on morbidity and mortality.57 A population- based case-control study showed a significantly increased risk of myocardial infarction in subjects using glibenclamide, but not gliclazide or glimepiride.58 Among patients with type 2 diabetes receiving combinations of metformin and sulfonylureas, a significantly higher all-cause mortality was observed in those treated with glibenclamide in comparison wi gliclazide.59 A retrospective analysis of 21 325 patients with type 2 diabetes followed over 5.5 years found that gliclazide was associated with a significantly reduced risk of acute coronary syndrome-related hospitalization compared with glibenclamide60 (Figure 6, page 84).

Evidence from numerous randomized controlled studies provides a high level of proof that, across the different comparator classes, sulfonylureas are safe in terms of total and cardiovascular mortality.61,62 That gliclazide, in particular, is safe was supported by a Danish observational study that compared the cardiovascular risk across the sulfonylureas and showed a reduced cardiovascular risk with gliclazide, and went as far as to suggest a specific protective effect of metformin and gliclazide.63

The mechanisms involved could include the previously mentioned greater selectivity of gliclazide for pancreatic—rather than myocardial—sulfonylureas receptors.64 Alternatively, the fibrinolytic properties of gliclazide, independent of its glucose lowering action, could confer a greater cardiovascular protection.65 Furthermore, a lower incidence of hypoglycemia along with weight neutrality have been documented with gliclazide in comparison with other sulfonylureas.66,67

Definitive evidence of gliclazide’s cardiovascular safety comes from the ADVANCE study where for 5 years, 91% of patients in the intensive group received gliclazide MR with 71% at the maximum dose of 120 mg. Whatever the parameter measured, whether it was major cardiovascular events, stroke, myocardial infarction, heart failure resulting in hospitalization or death, all-cause mortality, or cardiovascular death, targeting more intensive glucose lowering with a gliclazide MR–based strategy showed absolutely no evidence of harm.68 There was even a 12% numerical trend for a reduction in the risk of cardiovascular death, unlike any of the recent DPP-4 inhibitor outcome studies despite their being designed and powered for superiority.32,69-71

Figure 5
Figure 6. Risk of acute coronary syndrome in patients with type 2 diabetes mellitus
treated with glibenclamide vs gliclazide.

Abbreviations: ACS, acute coronary syndrome; CI, confidence interval; OR, odds ratio.
Modified from reference 60: Abdelmoneim et al. Diabetes Obes Metab. 2014;16(1):22-29. © 2013,
John Wiley & Sons Ltd.

 

Renal benefits

Given the major role of hyperglycemia in the development of microvascular complications, reducing blood glucose plays a critical role in their prevention. Large randomized controlled trials have demonstrated a reduction in microvascular complications with intensive glycemic control. Extra attention, however, is needed for kidney protection72 because reduced kidney function and albuminuria increase the risk of cardiovascular morbidity, kidney failure, and mortality.73-75

Diabetic nephropathy, a common microvascular complication of diabetes caused by damage secondary to hyperglycemia in small blood vessels, is one of the most significant long-term complications in terms of morbidity and mortality for individual patients with diabetes, and is the single most common cause of end-stage renal disease (ESRD) in adults in western countries.76,77 Over the last decades there has been a dramatic increase in the proportion of ESRD patients affected by diabetes, and this increase is largely due to type 2 diabetes. Among all patients who started kidney-replacement therapy in 2012, approximately 50% had diabetic kidney disease.78 The incidence of chronic kidney impairment is expected to increase in the future, because type 2 diabetes is developing at an increasingly younger age and life expectancy has increased due to improved treatment for cardiovascular risk factors.79,80

Intensive glycemic control has been shown to decrease the risk of developing diabetic kidney disease as well as delaying and/or preventing its progression. The benefit of intensive glucose control in the prevention of microalbuminuria has been shown in type 1 diabetes by the DCCT trial (Diabetes Control and Complications Trial)81 and in its long term follow-up (EDIC [Epidemiology of Diabetes Interventions and Complications]).82 The UKPDS study documented the benefit of intensive glucose control in reducing microalbuminuria in patients with type 2 diabetes.3 The ADVANCE trial more recently confirmed these findings, demonstrating the efficacy of tight glycemic control in reducing the risk of development and progression of diabetic nephropathy (from microalbuminuria to proteinuria and from proteinuria to ESRD).32

Gliclazide-based intensive glucose control was effective in delaying or disrupting the progression of diabetic kidney disease in patients with type 2 diabetes, where the development of macroalbuminuria—a well-established biomarker of increased cardiovascular risk—was significantly reduced by 30%, and the risk of ESRD—a clinically relevant hard endpoint—was significantly reduced by 65%.83 Furthermore, the long-term follow-up of this trial (ADVANCE-ON) demonstrated a sustained risk reduction over 10 years for dialysis and renal transplant,84 and showed that when intensive glucose control is begun early before diabetic kidney disease develops too far, by preventing early structural changes, these benefits can be maintained over the long-term.83 Thus, intensive glycemic control with gliclazide MR is effective not only in preventing the development of diabetic nephropathy, but also in slowing its progression.

In addition, a recent observational study compared reliable (sustained doubling of serum creatinine levels from baseline) and clinically relevant (new-onset ESRD) long-term kidney outcomes. In a propensity score–matched analysis of patients with type 2 diabetes treated with either glimepiride or gliclazide for a median of 4.7 years, gliclazide offered significant renal protection compared with glimepiride in those patients effectively controlled (HbA1c<7%) on their respective treatment. That is, where glucose lowering is equivalent, the observation of beneficial outcomes for diabetic nephropathy suggests a distinctive renoprotective property of gliclazide above and beyond that of just glucose lowering.85 Moreover, as with the ADVANCE study, these results confirm that early initiation and maintenance of intensive treatment with gliclazide MR is the optimum strategy for the prevention of major, clinically relevant, complications later on.

Conclusions

Treatment of type 2 diabetes needs to address disease progression and balance the pharmacological efforts that lower hyperglycemia against the increased risks of hypoglycemia and weight gain. As patients with type 2 diabetes experience increased risk of cardiovascular morbidity and mortality over time, treatment strategies should ideally address cardiovascular risk factors including body weight, blood pressure, dyslipidemia, and renal function. Decreased mortality and decreased macrovascular and diabetes-related endpoints have been demonstrated in patients using metformin from the time of the diagnosis, supporting it as the first choice of oral blood glucose–lowering medicine. Medical treatment generally follows a stepwise approach, and while therapy may be initiated with metformin, if the HbA1c target is not achieved, international guidelines recognize that sulfonylureas are easy to administer, are low in cost, and are among the most potent of all oral antidiabetics. However, when selecting a treatment, clinicians need to consider the differences in risk.

Gliclazide MR has been shown to effectively lower HbA1c, with sustained glycemic control alongside an optimal safety profile in terms of weight gain and hypoglycemia (lowest risk of any sulfonylurea and comparable to that of a DPP-4 inhibitor). Glicazide MR–based intensive glucose control is the only therapeutic strategy to significantly reduce the incidence of clinically relevant renal complications and is thus effective in delaying and/or preventing the long process of diabetic kidney disease. In view of gliclazide’s complete cardiovascular safety and unmatched clinical evidence of benefits, the recent Dutch type 2 diabetes management guidelines specifically recommend gliclazide (rather than sulfonylureas as a class) as a preferred second treatment option. ■

References
1. IDF Diabetes Atlas Group. Update of mortality attributable to diabetes for the IDF Diabetes Atlas: Estimates for the year 2013. Diabetes Res Clin Pract. 2015; 109(3):461-465.
2. The Emerging Risk Factors Collaboration; Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010; 375:2215-2222.
3. U.K. 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. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58(3):429-442.
5. Lebovitz HE. Clinical utility of oral hypoglycemic agents in the management of patients with noninsulin-dependent diabetes mellitus. Am J Med. 1983;75 (suppl 5B):94-99.
6. Kennedy DL, Piper JM, Baum C. Trends in use of oral hypoglycemic agents 1964-1986. Diabetes Care. 1988;11:558-562.
7. Melander A, Lebovitz HE, Faber OK. Sulfonylureas. Why, which, and how? Diabetes Care. 1990;13(suppl 3):18-25.
8. Zhang Y, McCoy RG, Mason JE, Smith SA, Shah ND, Denton BT. Secondline agents for glycemic control for type 2 diabetes: are newer agents better? Diabetes Care. 2014;37(5):1338-1345.
9. Desai NR, Shrank WH, Fischer MA, et al. Patterns of medication initiation in newly diagnosed diabetes mellitus: quality and cost implications. Am J Med. 2012;125(3):302.e1-e7.
10. Lebovitz HE, Feinglos MN. Sulfonylurea drugs: mechanism of antidiabetic action and therapeutic usefulness. Diabetes Care. 1978;1(3):189-198.
11. Bryan J, Crane A, Vila-Carriles WH, Babenko AP, Aguilar-Bryan L. Insulin secretagogues, sulfonylurea receptors and K(ATP) channels. Curr Pharm Des. 2005; 11(21):2699-2716.
12. Winkler M, Stephan D, Bieger S, Kuhner P, Wolff F, Quast U. Testing the bipartite model of the sulfonylurea receptor binding site: binding of A-, B-, and A + B-site ligands. J Pharmacol Exp Ther. 2007;322(2):701-708.
13. Gribble FM, Ashcroft FM. Differential sensitivity of beta-cell and extrapancreatic K(ATP) channels to gliclazide. Diabetologia. 1999;42(7):845-848.
14. Song DK, Ashcroft FM. Glimepiride block of cloned beta-cell, cardiac and smooth muscle KATP channels. Br J Pharmacol. 2001;133(1):193-199.
15. Gribble FM, Tucker SJ, Seino S, Ashcroft FM. Tissue specificity of sulfonylureas: studies on cloned cardiac and beta-cell K(ATP) channels. Diabetes. 1998;47 (9):1412-1418.
16. Seino S, Miki T. Physiological and pathophysiological roles of ATP-sensitive K+ channels. Prog Biophys Mol Biol. 2003;81(2):133-176.
17. Hiraoka M. Pathophysiological functions of ATP-sensitive K+ channels in myocardial ischemia. Jpn Heart J. 1997;38(3):297-315.
18. Abdelmoneim AS, Hasenbank SE, Seubert JM, Brocks DR, Light PE, Simpson SH. Variations in tissue selectivity amongst insulin secretagogues: a systematic review. Diabetes Obes Metab. 2012;14(2):130-138.
19. Riddle M. Sulphonylureas differ in effects on ischaemic preconditioning: is it time to retire Glyburide? J Clin Endocrinol Metab. 2003;88(2):528-530.
20. Seino S, Shibasaki T. PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol Rev. 2005; 85(4):1303-1342.
21. Zhang CL, Katoh M, Shibasaki T, et al. The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs. Science. 2009;325(5940)607-610.
22. Takahashi H, Shibasaki T, Park JH, et al. Role of Epac2A/Rap1 signaling in interplay between incretin and sulfonylurea in insulin secretion. Diabetes. 2015; 64(4)1262-1272.
23. Yabe D, Seino Y. Dipeptidyl peptidase-4 inhibitors 4 inhibitors and sulfonylureas for type 2 diabetes: Friend or Foe? J Diabetes Investig. 2014;5(5):475-477.
24. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA. 1999;281(21):2005-2012.
25. Nyenwe EA, Jerkins TW, Umpierrez GE, Kitabchi AE. Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metabolism. 2011;60(1):1-23.
26. Monami M, Lamanna C, Marchionni N, Mannucci E. 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.
27. Hirst JA, Farmer AJ, Dyar A, Lung TW, Stevens RJ. Estimating the effect of sulfonylurea on HbA1c in diabetes: A systematic review and meta‑analysis. Diabetologia. 2013;56(5):973-984.
28. Landman GW, de Bock GH, van Hateren KJ, et al. Safety and efficacy of gliclazide as treatment for type 2 diabetes: a systematic review and meta-analysis of randomized trials. PLoS One. 2014;9(2):e82880.
29. Chan SP, Colagiuri, S. Systematic review and meta-analysis of the efficacy and hypoglycemic safety of gliclazide versus other insulinotropic agents. Diabetes Res Clin Pract. 2015 Jul 9. pii: S0168-8227(15)00319-8. doi: 10.1016/j.diabres. 2015.07.002. [Epub]
30. ORIGIN Trial Investigators, Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319-328.
31. Holman RR. Long-term efficacy of sulfonylureas: a United Kingdom Prospective Diabetes Study perspective. Metabolism. 2006;55(5 suppl 1):S2-S5.
32. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
33. Satoh J, Takahashi K, Takizawa Y, et al. Secondary sulfonylurea failure: comparison of period until insulin treatment between diabetic patients treated with gliclazide and glibenclamide. Diabetes Res Clin Pract. 2005;70(3):291-297.
34. Ceriello A, Motz E. Is Oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol. 2004;24(5):816-823.
35. Robertson RP, Harmon J, Tran PO, Tanaka Y, Takahashi H. Glucose toxicity in β cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes. 2003;52(3):581-587.
36. Drews G, Krippeit-Drews P, Düfer M. Oxidative stress and beta-cell dysfunction. Pflugers Arch. 2010;460(4):703-718.
37. O’Brien RC, Luo M, Balazs N, Mercuri J. In vitro and in vivo antioxidant properties of gliclazide. J Diabetes Complications. 2000;14(4):201-206.
38. Sawada F, Inoguchi T, Tsubouchi H, et al. Differential effect of sulfonylureas on production of reactive oxygen species and apoptosis in cultured pancreatic betacell line, MIN6. Metabolism. 2008;57(8):1038-1045.
39. Del Guerra S, Grupillo M, Masini M, et al. Gliclazide protects human islet betacells from apoptosis induced by intermittent high glucose. Diabetes Metab Res Rev. 2007;23(3):234-238.
40. Pagano PJ, Griswold MC, Ravel D, Cohen RA. Vascular action of the hypoglycaemic agent gliclazide in diabetic rabbits. Diabetologia. 1998;41(1):9-15.
41. Konya H, Hasegawa Y, Hamaguchi T, et al. Effects of gliclazide on platelet aggregation and the plasminogen activator inhibitor type 1 level in patients with type 2 diabetes mellitus. Metabolism. 2010;59(9):1294-1299.
42. Cryer PE Hypoglycemia: Still the Limiting Factor in the Glycemic Management of Diabetes. Endocr Pract
. 2008;14(6):750-756.
43. Bakatselos SO. Hypoglycemia unawareness. Diabetes Res Clin Pract. 2011; 93(suppl 1):S92-S96.
44. Barendse S, Singh H, Frier BM, Speight J. The impact of hypoglycaemia on quality of life and related patient-reported outcomes in Type 2 diabetes: a narrative review. Diabet Med. 2012;29(3):293-302.
45. Leese GP, Wang J, Broomhall J, et al. Frequency of Severe Hypoglycemia Requiring Emergency Treatment in Type 1 and Type 2 Diabetes: A population-based study of health service resource use. Diabetes Care. 2003;26(4):1176-1180.
46. Proks P, Reimann F, Green N, Gribble F, Ashcroft F. Sulfonylurea stimulation of insulin secretion. Diabetes. 2002;51(suppl 3):S368-S376.
47. 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):535-542.
48. Schopman JE, Simon AC, Hoefnagel SJ, et al. The incidence of mild and severe hypoglycaemia in patients with type 2 diabetes mellitus treated with sulfonylureas: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2014;30(1)11-22.
49. Andersen SE, Christensen. The Risk of Hypoglycemia among Sulfonylureas Is Lowest with Gliclazide: A Network Meta-analysis of Randomized, Controlled Trials. Diabetes. 2014;63(suppl 1)A106.
50. Thulé PM, Umpierrez G. Sulfonylureas: a new look at old therapy. Curr Diab Rep. 2014;14(4):473.
51. Clemens KK, McArthur E, Dixon SN, Fleet JL, Hramiak I, Garg AX. The hypoglycemic risk of glyburide (glibenclamide) compared with modified-release gliclazide. Can J Diabetes. 2015;39(4):308-316.
52. World Health Organization. WHO Model List of Essential Medicines. 18th edition. http://www.who.int/medicines/publications/essentialmedicines/18th_EML_F inal_web_8Jul13.pdf. 2013. Accessed October 7, 2015.
53. National Kidney Foundation. Nelson RG, Tuttle KR, Bilous RW, et al. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update. Am J Kidney Dis. 2012;60(5):850-886.
54. Mbanya JC, Al-Sifri S, Abdel-Rahim A, Satman I. Incidence of hypoglycemia in patients with type 2 diabetes treated with gliclazide versus DPP-4 inhibitors during Ramadan: A meta-analytical approach. Diabetes Res Clin Pract. 2015;109 (2):226-232.
55. Rutten GEHM, De Grauw WJC, Nijpels G, et al. NHG-Standaard Diabetes mellitus type 2 (derde herziening). Huisarts Wet. 2013;56(10):512-525.
56. Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;15 (10):938-953.
57. Monami M, Luzzi C, Lamanna C, et al. Three-year mortality in diabetic patients treated with different combinations of insulin secretagogues and metformin. Diabetes Metab Res Rev. 2006;22(6):477-482.
58. Johnsen SP, Monster TB, Olsen ML, et al. Risk and short-term prognosis of myocardial infarction among users of antidiabetic drugs. Am J Ther. 2006;13(2): 134-140.
59. 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):479-484.
60. Abdelmoneim AS, Eurich DT, Gamble JM, et al. Risk of acute coronary events associated with glyburide compared with gliclazide use in patients with type 2 diabetes: a nested case-control study. Diabetes Obes Metab. 2014;16(1):22-29.
61. Hemmingsen B, Schroll JB, Wetterslev J, et al. Sulfonylurea versus metformin monotherapy in patients with type 2 diabetes: a Cochrane systematic review and meta-analysis of randomized clinical trials and trial sequential analysis. CMAJ Open. 2014;2(3):E162-E175.
62. Rados DV, Pinto LC, Remonti LR, Canani LH, Leitao CB, Gross JL. Sulphonylureas Are Not Associated with Increased Mortality: Meta-analysis and Trial Sequential Analysis of Randomized Clinical Trials. Diabetes. 2015;64(suppl 1):A5.
63. 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(15):1900-1908.
64. Gribble FM, Reimann F. Differential selectivity of insulin secretagogues: mechanisms, clinical implications, and drug interactions. J Diabetes Complications. 2003;17(2 suppl):11-15.
65. Gram J, Jespersen J. Increased fibrinolytic potential induced by gliclazide in types I and II diabetic patients. Am J Med. 1991;90(6A):62S-66S.
66. Tessier D, Dawson K, Tetrault JP, Bravo G, Meneilly GS. Glibenclamide vs gliclazide in type 2 diabetes of the elderly. Diabet Med. 1994;11(10):974-980.
67. Veitch PC, Clifton-Bligh RJ. Long-acting sulfonylureas – longacting hypoglycaemia. Med J Aust. 2004;180(2)84-85.
68. Control Group, Turnbull FM, Abraira C, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52(11):2288- 2298.
69. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. N Engl J Med. 2013;369(14): 1317-1326.
70. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-1335.
71. Green JB, Bethel MA, Armstrong PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;373(3):232-242.
72. Naushahi MJ, De Grauw WJ, Avery AJ, Van Gerwen WH, Van de Lisdonk EH, Van Weel C. Risk factors for development of impaired renal function in Type 2 diabetes mellitus patients in primary care. Diabet Med. 2004;21(10):1096-1101.
73. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003;63(1):225-232.
74. Bo S, Ciccone G, Rosato R, et al. Renal damage in patients with Type 2 diabetes: a strong predictor of mortality. Diabet Med. 2005;22(3):258-265.
75. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296-1305.
76. Fioretto P, Mauer M, Brocco E, et al. Patterns of renal injury in type 2 diabetic patients with microalbuminuria. Diabetologia. 1996;39(12):1569-1576.
77. Saran R, Li Y, Robinson B, Ayanian J, et al. US Renal Data System 2014 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis. 2015;65(6 Suppl 1):A7
78. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care. 2014;37(10):2864-2883.
79. Gregg EW, Li Y, Wang J, Burrows NR, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014;370(6):1514-1523.
80. Liyanage T, Ninomiya T, Jha V, et al. Worldwide access to treatment for end-stage kidney disease: a systematic review. Lancet. 2015;385(9981):1975-1982.
81. 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):977-986.
82. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA. 2003;290(16):2159-2167.
83. Perkovic V, ME Cooper, M Woodward, JP. Chalmers, M Marre, S Zoungas. ADVANCE-ON: Long-Term Benefits of Intensive Glucose Control for End- Stage Kidney Disease [Abstract]. J Am Soc Nephrol. 2014;25(Suppl):B1
84. Zoungas S, Chalmers J, Neal B, et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371(15):1392-1406.
85. Lee YH, Lee CJ, Lee HS, et al. Comparing kidney outcomes in type 2 diabetes treated with different sulphonylureas in real-life clinical practice. Diabetes Metab. 2015.41(3):208-215.

Keywords: cardiovascular safety, gliclazide, sulfonylurea, tolerability, type 2 diabetes