Diamicron (gliclazide) MR the secretagogue with clinical benefits beyond insulin secretion






Manuel RUIZ,
Servier International
Paris, FRANCE

Diamicron (gliclazide) MR: the secretagogue with clinical benefits beyond insulin secretion


by M. Ruiz, France



Diabetes is a major public health issue. In 2011, it was responsible for 8.2% of global mortality from any cause in people 20-79 years of age. In particular, it was responsible for 10%of vascular deaths (from coronary heart disease, stroke, and other vascular causes), 50% of end-stage kidney disease, and 11% of total health care expenditures in the world. Moreover, the prevalence of diabetes continues to grow rapidly and should reach 9.9% of the world population in 2030. Recent international guidelines from the American Diabetes Association/European Association for the Study of Diabetes and the International Diabetes Federation agree on an HbA1c goal of <7%. Unfortunately, not enough patients achieve optimal glucose control and maintain it over the long term. Thus, challenges in type 2 diabetes management consist of controlling blood glucose, maintaining this control over the long term, and preventing the development of microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular complications (myocardial infarction, peripheral arterial disease, and stroke). Beyond its secretagogue effect, which provides powerful control of blood glucose, Diamicron MR (gliclazide modified release) 60 mg has specific properties that make it a therapeutic option of choice in preventing decline in β-cell function and reducing the development of diabetic nephropathy or cardiovascular complications.

Medicographia. 2013;35:81-89 (see French abstract on page 89)


Diamicron (gliclazide) MR 60 mg: unique clinical benefits

_ Intensive glycemic control
Lowering blood glucose in order to reduce the risk of microvascular and macrovascular complications remains a major focus of type 2 diabetes therapy, as mentioned in the latest American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) guidelines.1 The various classes of noninsulin glucose-lowering drugs have different levels of efficacy in terms of glycated hemoglobin (HbA1c) reduction: high for metformin, sulfonylurea, thiazolidinedione, and glucagon-like peptide-1 (GLP-1); and intermediate for dipeptidyl peptidase-4 (DPP-4) inhibitor.1 The antidiabetic Diamicron MR (gliclazide modified release) 60 mg has proven its efficacy in monotherapy or in combination therapy in many clinical studies.

The GUIDE study (GlUcose control In type 2 diabetes: Diamicron MR versus glimEpiride) was carried out in 845 type 2 diabetic patients according to a double-blind, 27-week, parallel-group design. At the end of the follow-up, HbA1c had decreased by 1.3% in newly diagnosed patients treated with gliclazide MR in monotherapy.2 In the same study, the efficacy of gliclazide MR in combination with metformin was also analyzed. The addition of gliclazideMR to treatment regimens in patients uncontrolled by metformin led to a further significant 1.0% reduction in HbA1c (HbA1c lowered from 8.4% to 7.4%).

The ADVANCE study (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) was conducted in 11 140 patients highly representative of those seen in daily clinical practice: mean age was 66 yearsold, mean duration of diabetes was 8 years, HbA1c=7.5%, 32% had a history of macrovascular disease, and 10% had microvascular disease. At the end of the 5-year follow-up, the intensive strategy based on gliclazide MR had lowered HbA1c by 1.0%, from 7.5% to 6.5%, and 80% of the patients had achieved an HbA1c equal to or below 7%. Over 70% of the patients were taking the maximum dose of 120 mg of gliclazide MR.3,4

A subanalysis of the ADVANCE study, aiming to examine the efficacy of the intensive gliclazide MR–based strategy showed that the efficacy of gliclazide MR was consistent across a wide variety of patient subgroups, defined by HbA1c, body mass index, duration of the disease, age, or previous treatment and treatment regimen at time of entry into the study. It is important to note that very large reductions in HbA1c level (up to 4%) relative to baseline levels at entry were observed.4

_ Sustained glycemic control
Sustained glycemic control remains a major issue in the management of type 2 diabetes. In the UKPDS (United Kingdom Prospective Study), the secondary failure rate of treatment was 44% after 6 years of diabetes.5 Riedel et al, in a retrospective study of 579 type 2 diabetic patients, found that 41.5% of patients who initially achieved target HbA1c experienced secondary failure of treatment; the mean time to this occurrence was1.3 years.6





ADOPT (A Diabetes Outcome Progression Trial), conducted in 4360 patients, showed a cumulative incidence of secondary failure of 21% with metformin, 34% with glyburide, and 15% with rosiglitazone at 5 years.7 Finally, in another retrospective analysis, the incidence of therapeutic failure (HbA1c_8%) in 2220 patients was assessed in primary care practices in the United Kingdom.8 The results showed that 68% of patients who initially achieved an HbA1c level of less than 7.0% had an HbA1c level that exceeded 8.0% within 4 years.

Progressive decline in β-cell function, leading to a decline in insulin secretion, is recognized to play a major role in the deterioration of glycemic control over the long term in type 2 diabetes.9 Thus, antidiabetic treatments that protect β-cell function may represent a valid therapeutic option to reduce secondary failure of glycemic control.

In the ADVANCE study, the HbA1c target of ≤6.5% was achieved with an intensive strategy based on gliclazide MR, and this effect was obtained progressively over 36 months and remained stable thereafter, delaying the use of insulin by up to 44 months after randomization.3 This has also been documented in previous studies comparing gliclazide MR with other sulfonylureas, including one with glibenclamide.10 This study investigated the time interval before the initiation of insulin therapy, and found a significantly longer interval before the initiation of insulin with gliclazide (mean 14.5 years) than with glibenclamide (mean 8 years), along with better blood glucose control, as shown by HbA1c values (6.8%vs 7.4%, respectively; P<0.0001). The authors conclude that these benefits might be explained by the direct protective effect of gliclazide MR 60 mg on pancreatic β-cell function. _ Protection of β-cell mass and function
A decrease in β-cell mass, mainly due to apoptosis, is crucial in the development and progression of type 2 diabetes. The effect of different oral antidiabetic agents on this process has been widely studied, and the results are heterogeneous according to the drug used. It has been shown that exposure of isolated rodent islets, cells from a β-cell line, or human islets in culture to tolbutamide, glibenclamide, and glimepiride increases β-cell apoptosis.11,12 By contrast, gliclazide has been shown to have the unique property to reduce β-cell apoptosis. In a study conducted with a human β-cell line (MIN6), exposure to various concentrations of gliclazide for 48 hours did not affect the number of apoptotic cells (Figure 1).11 Another study demonstrated that in human β cells exposed to an intermittent high glucose concentration, gliclazide enhanced expression of the β-cell differentiation factor PDX-1 (pancreatic and duodenal homeobox 1) and the cell proliferation marker Ki-67.


Figure 1
Figure 1. Effect of sulfonylureas and nateglinide on apoptosis in MIN6 cells.

The MIN6 cells were incubated with test media containing 1% fetal bovine serum and 5.5 mmol/L glucose with glibenclamide, gliclazide, glimepiride, and nateglinide at a concentration of 10 μmol/L. After 48 hours of incubation, apoptosis was evaluated by TUNEL assay (terminal deoxynucleotidyl transferase dUTP nick end labeling).
A) Representative images of apoptotic cells. Arrows indicate brown-colored TUNEL-positive cells. B) Quantitative analysis of the rates of apoptotic cells induced by sulfonylureas and nateglinide. Data are expressed as mean percentage of control ± SEM (n=4). *P˂0.01 vs control. #P˂0.01 vs glibenclamide-treated MIN6 cells.
Abbreviations: Cont, control; Glib, glibenclamide; Glic, gliclazide; Glim, glimepiride; Nate, nateglinide.
After reference 11: Sawada et al. Metabolism. 2008;57(8):1038-1045. © 2008, Elsevier Inc.



The authors suggest that beyond protection against β-cell apoptosis, gliclazide may also positively influence β-cell regeneration.13

_ Kidney protection
Renal disease is the most frequent complication for type 2 diabetic patients. Approximately 24.9% of patients develop microalbuminuria, 5%-20% develop macroalbuminuria, and 20%, a renal functional impairment (moderate to severe: estimated glomerular filtration rate <60 mL/min).14-16 In most Western populations, diabetes is the leading cause of endstage kidney disease (ESKD),17 and about 20%of diabetic patients die from kidney disease.18

Diabetic nephropathy contributes to the burden of morbidity, increases the risk of premature death and affects the quality of life of the patients. In addition, renal impairment alters handling, and therefore effectiveness, of antidiabetic drugs by modifying pharmacokinetic and pharmacodynamic parameters. Thus, preventing kidney disease in patients is another major issue in the management of type 2 diabetes. The effectiveness of gliclazide MR 60 mg throughout the clinical course of kidney disease has been demonstrated, from the earliest stage (microalbuminuria) to the latest stage (ESKD). In the ADVANCE study, the strategy based on gliclazide MR reduced the riskof new-onsetmicroalbuminuria by 9% (P=0.02),macroalbuminuria by 30% (P<0.001), new or worsening nephropa- thy by 21% (P=0.006), and ESKD by 65% (P=0.02).3,19,20 Also, it is noteworthy that the intensive strategy based on gliclazide MR used in ADVANCE is the only one demonstrated to lead to significant reduction in ESKD. The UKPDS 33,21 UKPDS 34,22 ACCORD (Action toControlCardiOvascular Risk in Diabetes),23 and VADT (Veterans Affairs Diabetes Trial)24 all failed to demonstrate significant effects on ESKD (Figure 2, page 83).25


Figure 2
Figure 2. Pooled risk ratios, with 95% confidence interval, by trial for end-stage kidney disease (ESKD).

Abbreviations: ACCORD, Action to Control CardiOvascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; CI, confidence interval; M-H, Mantel-Haenszel test; UKPDS 33, 34, United Kingdom Prospective Diabetes Study 33,34; VADT, Veterans Affairs
Diabetes Trial.
After reference 25: Coca et al. Arch Intern Med. 2012;172(10):761-769. © 2012, American Medical Association.



Moreover, gliclazide MR has been demonstrated to lead to regression of albuminuria by one stage in 62% of patients with albuminuria at baseline, with the majority achieving normoalbuminuria.20 All these results show that gliclazide MR 60 mg is effective in delaying or disrupting the long process of diabetic kidney disease in patients with type 2 diabetes. Even more interesting, gliclazide MR 60 mg is considered in the guidelines from the National Kidney Foundation Kidney Disease Outcomes Quality Initiative to be a preferred sulfonylurea in patients with chronic kidney disease, because it does not have active metabolites and does not increase the risk of hypoglycemia (Table I).26 The major route of elimination of gliclazide MR 60 mg and its metabolites is via the urine. Studies with radiolabeling indicate 60% to 70% urinary, and 10% to 20% fecal excretion. In the urine, hydroxymethyl and carboxymethyl, 6 α-, 7 α-, 6 β-, and 7 β-hydroxyl radicals, and 2 O-glucuronide conjugates are found, with only trace quantities of unchanged active ingredient.27


Table I
Table I. Dosing adjustments by chronic kidney disease stage for drugs used to treat hyperglycemia. Adapted from the National Kidney
Foundation.

Abbreviations: ACCORD, Action to Control CardiOvascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; CKD, chronic kidney disease; GFR, glomerular filtration rate; SCr, serine creatinine; UKPDS, United Kingdom Prospective Diabetes Study; VADT,
Veterans Affairs Diabetes Trial.
Adapted from reference 26: KDOQI. Am J Kidney Dis. 2007;49(2 suppl 2):S12-S154. © 2007, Elsevier.



Figure 3
Figure 3. Effects of more-intensive versus less-intensive glycemic control on cardiovascular death.

Abbreviations: CI, confidence interval; HbA1c,
glycated hemoglobin. For trial names, see Figure 2 legend.
After reference 32: Turnbull et al. Diabetologia. 2009;52:2288-2298. © 2009, Springer-Verlag.



_ Cardiovascular protection
Type 2 diabetic people have risks for coronary heart disease, myocardial infarction, and stroke that are at least two fold higher than in nondiabetics.28 It has been reported that 70% of type 2 diabetics die from cardiovascular causes.29 The relative risk of coronary heart disease or stroke has been estimated at 1.18 (95% confidence interval [CI], 1.10-1.26) for each 1% increase in HbA1c.30 With the constant growth of diabetes in the world, the burden of cardiovascular death will increase strongly in the coming years. A study of the Emerging Risk Factors Collaboration31 indicates that diabetes is responsible for 10% of vascular deaths in adults in developed countries, accounting for about 325 000 deaths per year. Considering these data, reduction in cardiovascular risk in type 2 diabetic patients is amajor challenge for the coming years. The CONTROL metaanalysis (COllaborators oN TRials Of Lowering glucose) has shown that every HbA1c reduction of 0.88% is associated with a significant relative risk reduction in major cardiovascular events (cardiovasculardeath, nonfatal stroke, or nonfatalmyocardial infarction) by 9%.32 This result is mainly driven by a 15% significant reduction in nonfatal myocardial infarction, whereas all-cause mortality and cardiovascular death were not significantly reduced.

In the ADVANCE trial, the intensive strategy based on gliclazide MR showed a clear trend in favor of a reduction in cardiovascular death by 12% (P=0.12).3 This result is even more relevant in light of the CONTROL meta-analysis, which reported a significant increase in cardiovascular mortality in the intensive arm of the ACCORD study (Figure 3).32

The positive trend observed in ADVANCE has been confirmed in recent data from two nationwide register studies including more than 70 000 patients with type 2 diabetes.

The first study, published in the European Heart Journal in June 2011, was performed in more than 9000 Danish type 2 diabetic patients who had experienced a previous myocardial infarction, and included a 9-year follow-up.33 All patients included were treated in monotherapy at baseline. Of the different medications, gliclazide MR was the only sulfonylurea that was associated with a positive trend toward reduction in the risk of cardiovascular death compared with metformin, which was considered the reference treatment: 13% reduction (P=0.40) (Figure 4).33


Figure 4
Figure 4. Hazard ratios (95% confidence intervals) for cardiovascular death in relation to monotherapies
with different glucose-lowering agents in patients with previous myocardial infarction.

Abbreviation: CI, confidence interval.
After reference 33: Schramm et al. Eur Heart J. 2011;32(15):1900-1908. © 2011, The Author. Published on behalf
of the European Society of Cardiology.



The second retrospective observational study was performed by Khalangot et al in 64 188 patients also treated in monotherapy with glibenclamide, gliclazide, or glimepiride, and followed over 6 years.34 Compared with glibenclamide, gliclazide MR was associated with lower risk of all-cause death (hazard ratio [HR] 0.33; 95% confidence interval [CI], 0.26-0.41) and cardiovascular mortality (HR 0.29; 95% CI, 0.21-0.38). The authors state that the better safety profile of gliclazide MR 60 mg and certain specific and unique vascular properties may explain these differences.

The Steno-2 follow-up study (intensive treatment with gliclazide as the sulfonylurea of choice versus conventional treatment), published in the New England Journal of Medicine in 2003, demonstrated a significant 53% reduction (P=0.01) in cardiovascular risk in the intensive-therapy group compared with the conventional-therapy group after 8 years.35 This difference is even more amplified at 13 years after a 5-year break from the study treatment. This cardiovascular benefit translates into a mortality rate that is cut by half.36

These unique clinical benefits of gliclazide MR 60 mg in terms of glycemic efficacy, β-cell preservation, and renal and cardiovascular protection may be explained in part, beyond its secretagogue effect, by its antioxidant properties. Indeed, chronic oxidative stress is postulated to be a key component in the pathogenesis of diabetes and the development of its complications.37-46 Oxidative stress occurs when production of oxidants or reactive oxygen species (ROS) exceeds local antioxidant capacity. In the case of diabetes, hyperglycemia amplifies the glycolysis pathway in cells and thus increases ROS production by the mitochondrial chain.

This overproduction of ROS seems to play a key role in the decline of β-cell function and pathogenesis of vascular complications of diabetes, such as kidney dysfunction and cardiovascular disease.13,37,40,47

_ Oxidative stress and &beta-cell failure
βCells are extremely sensitive to oxidative stress. Indeed, β cells have a very low intrinsic antioxidant capacity, because they are low in free-radical quenching (antioxidant) enzymes such as catalase, glutathione peroxidase, and superoxide dismutase.13 In case of chronic exposure to hyperglycemia, ROS produced in excessive levels constantly “bombard” β cells, and this phenomenon is one of the main hypotheses to explain deterioration of β-cell function over time in type 2 diabetes.48

Recent studies in type 2 diabetic animal models report that the progressive reduction in islet β cells is associated with excessive oxidative stress.38 Excessive apoptosis of β cells and defective insulin gene expression are both considered to be responsible for deterioration of insulin synthesis and secretion. This vicious circle contributes to the development and the progression of type 2 diabetes.

_Oxidative stress and kidney dysfunction
It is postulated that localized tissue oxidative stress is a key component in the development of diabetic nephropathy. There remains controversy, however, as to whether this is an early link between hyperglycemia and renal disease or whether this develops as a consequence of other primary pathogenic mechanisms. In the kidney, a number of pathways that generate ROS such as glycolysis, specific defects in the polyol pathway, uncoupling of nitric oxide (NO) synthase, xanthine oxidase, NAD(P)H oxidase, and advanced glycation have been identified as potentially major contributors to the pathogenesis of diabetic kidney disease. In addition, a unifying hypothesis has been proposed whereby mitochondrial production of ROS in response to chronic hyperglycemia may be the key initiator for each of these pathogenic pathways. This postulate emphasizes the importance of mitochondrial dysfunction in the progression and development of diabetes complications including nephropathy.49

_ Oxidative stress and cardiovascular complications
Oxidative stress induced by hyperglycemia increases cardiovascular complications by acting at several levels: increased vascular permeability, low-density lipoprotein (LDL) oxidation, prothrombotic activity, and through the inflammatory pathway.37-40 In particular, increased ROS production and reduced antioxidant defense promote LDL oxidation, which is an early step in the atherosclerotic process in diabetic patients. Additionally, oxidative stress and advanced glycation end product (AGE) deposition contribute to diabetic endothelial dysfunction, which has been described as the “choreographer” of diabetic vascular disease due to the microcirculatory changes it causes and its accelerating impact on macroangiopathic processes.50

Diamicron (gliclazide) MR 60 mg: powerful antioxidant properties

_ Scavenger of ROS
Gliclazide is known to be a powerful general free radical scavenger. In cell-free assays, it has been shown to scavenge superoxide radicals, hydroxyl radicals, and NO in a dose-dependent manner, whereas glibenclamide was without effect.51 This unique scavenging effect of gliclazide can be explained by its aminoazabicyclo-octyl ring, grafted onto the sulfonylurea group, which is thought to be a free radical scavenger.52 These results were confirmed in a study using a cultured β-cell line (MIN6) to compare the effect of various sulfonylureas (glibenclamide, glimepiride, and gliclazide) or nateglinide on oxidative stress.11 Only gliclazide was able to decrease production of intracellular ROS. All these findings show that gliclazide MR 60 mg is not only effective in reducing blood glucose, but is also effective in reducing oxidative stress.

_ Inhibition of LDL oxidation
Oxidation of LDL in diabetic patients is promoted by increased free radical production from glucose oxidation and reduce dantioxidant activity, and is an early step in the atherosclerotic process. The mechanisms by which gliclazide MR 60 mg influences atheroma development have been explored in ex vivo studies of LDL from type 2 diabetic subjects and controls.53 Gliclazide, at therapeutic concentrations, increased the lag time between exposure of LDL to pro-oxidant copper and the start of oxidation to a highly significant extent. This effect was more marked than that of equimolar vitamin C, and was not reproduced by glimepiride, glibenclamide, glipizide, or tolbutamide. Only gliclazide significantly increased the resistance of LDL to oxidation.

The results were confirmed in vivo in a 10-month study in type 2 diabetic patients.53 Treatment with gliclazide improved all the parameters measured, with a fall in 8-isoprostanes, a marker of lipid oxidation, and an increase in the antioxidant parameters, such as total plasma antioxidant capacity (TPAC), superoxide dismutase (SOD), and thiols. Moreover, these changes were completely independent of HbA1c, which remained stable throughout the study.

_ Antiatherogenic effect
Antioxidant properties of gliclazide MR 60 mg may be especially pertinent concerning atherosclerosis and cardiovascular outcomes. This has been investigated in type 2 diabetic patients using ultrasonographic assessment of the carotid artery intima-media thickness (IMT) at the beginning and the end of a 3-year observation period.54 The patients were already receiving antidiabetic treatments on entry into the study: glibenclamide (n=59) and gliclazide (n=30). The results for the change in carotid artery IMT were adjusted for other factors, such as changes in HbA1c, lipid profile, and blood pressure. This analysis showed that the administration of gliclazide significantly (P<0.05) and independently reduced the progression of average IMT compared with glibenclamide. The investigators attribute the antiatherogenic effect of gliclazide to its free radical scavenging properties, its restorative action on endothelial function, and its reduction in platelet reactivity. This study demonstrates that gliclazide MR 60 mg can attenuate the progression of atherosclerosis in patients with type 2 diabetes.

Diamicron (gliclazide) MR 60 mg: a remarkable safety profile

The risk of hypoglycemia and weight gain in the management of type 2 diabetes remains a main issue and the effect of antidiabetic treatment on these parameters is a key element in drug selection.

_ Hypoglycemia
In the ADVANCE study, the intensive strategy based on gliclazide MR was associated with a very low risk of severe hypoglycemia: only 2.7%of the patients had at least one severe hypoglycemic episode.3 In ACCORD23 and the VADT,24 the rate of severe hypoglycemic events were 16.2% and 21.2%, respectively, in the intensive arm.

This observation has been confirmed recently in the Al Sifri study.55 The aim of this study was to assess the incidence of hypoglycemia with sulfonylureas (glibenclamide, glimepiride, and gliclazide) and the DPP-4 inhibitor (sitagliptin) in 1024 type 2 diabetic patients fasting during Ramadan. The proportion of patients who recorded one or more symptomatic hypoglycemic events was only 6.6%in the gliclazideMR group compared with 19.7%, 12.4%, and 6.7% in the glibenclamide, glimepiride, and sitagliptin groups, respectively.

_ Weight
In the ADVANCE study, there was no weight gain in the group with intensive glucose control based on gliclazide MR, even in the obese patients.4 The authors conclude that a possible explanation is that the sulfonylurea used in the intensive glucose control arm was gliclazide MR.

In the UKPDS,21ACCORD,23 and theVADT,24 the intensive strategy was associated with a weight gain of 1.7 kg, 3.5 kg, and 8.1 kg, respectively.

This unique safety profile of gliclazide MR 60 mg as regards hypoglycemia and weight compared with other sulfonylureas could be explained in part by its insulin secretion profile. Indeed, gliclazide MR restores the early peak of insulin secretion without inducing excess secretion of insulin during the second phase. The gliclazide MR–induced stimulatory effect on insulin release is reduced when the glucose level falls.56

Conclusion

Controlling blood glucose, maintaining this control over the long term, and preventing the development of microvascular and macrovascular complications are main challenges in type 2 diabetes management. Gliclazide MR 60 mg has an unmatched level of clinical evidence demonstrating powerful glycemic efficacy maintained over the long term, unique end stage kidney disease prevention, cardiovascular safety, and an optimal safety profile in terms of hypoglycemia and weight gain. Moreover, it is postulated that oxidative stress, which is abnormally high in type 2 diabetic patients, has a negative impact on progression of diabetes by reducing β-cell function, and the development of diabetic nephropathy and cardiovascular disease, particularly by increasing atherosclerosis. Gliclazide MR 60 mg, thanks to its unique chemical structure, reduces oxidative stress, increasing the resistance of LDL to oxidation and slowing the progression of atherosclerosis in type 2 diabetic patients. _


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Keywords: antioxidant; β cell; cardiovascular protection; gliclazide; HbA1c; kidney protection; sustained glucose control