What do guidelines recommend? 

The updated American Diabetes Association (ADA) pharmacological guidelines (2022) state that first-line therapy depends on:  Patient-centred treatment factors (eg comorbidities), and management needs (minimise hypoglycaemia, minimise weight gain/promote weight loss, cost, and access), but generally include metformin and comprehensive lifestyle modification.² 

However, because of the progressive nature of T2DM (HbA1c increases by ∼1% every two years) patients often fail to reach targets with monotherapy and treatment has to be intensified.³  

Studies have shown that intensification cannot be achieved by increasing the therapeutic dose of metformin - thus, a combined approach with other OADs with different mechanisms of action should be incorporated in the treatment plan.⁴ 

Numerous guidelines, including the latest ADA guideline, and the 2017 International Diabetes Federation (IDF) clinical practice recommendations for managing T2DM in primary care, recommend SUs as monotherapy (if metformin is not tolerated) or as combination therapy.⁵  

In 2018, an International Task Force released comprehensive consensus recommendations on SUs in the management of T2DM promoting the use of these agents because of their efficacy, safety, and cost effectiveness profile⁷  and in 2019, the World Health Organization included SUs along with metformin and insulin on their model list of essential medicines 2019 for patients living with diabetes.⁵ 

SUs are divided into three groups:^6,8  

1. First-generation: Includes chlorpropamide, tolazamide, and tolbutamide. Known to have longer half-lives, higher risk of hypoglycaemia, and slower onset of action, compared to second-generation SUs 
2. Second-generation: Includes glipizide, glimepiride, and glyburide. Second-generation SUs are preferred over first-generation agents 
3. Third-generation: Includes gliclazide modified release (MR), which has been shown to possess high glucose-lowering efficacy, few side effects other than mild hypoglycaemia, offers CV and renal safety and only has to be administered once-daily. 

Gliclazide specifically suggested in guidelines 

According to Kalra et al, new guidelines specifically suggest gliclazide as second-line treatment, instead of SUs as a class, based on its safety and efficacy profile.⁵   

Numerous studies have confirmed the safety and efficacy of SUs in the treatment of patients living with T2DM with or without cardiovascular disease (CVDs). More recently (2018), the safety and effectiveness of gliclazide MR were evaluated in the real-world ObsErvationAl Study to analYse titration of Diamicron MR 60mg in daily clinical practice in a large population with uncontrolled T2DM (EASYDia) study.^1,8  

Following six months of progressive uptitration, individuals in the EASYDia cohort experienced significantly improved glycaemic control, mild weight loss and rare events of hypoglycemia.¹  

Gliclazide MR compared to other OADs 

Colagiuri et al (2018) conducted a comprehensive review of gliclazide MR, SUs and other OADs. These are some of their key findings:⁸  

• In the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, mean body weight during the follow-up period was 0.7kg greater in the intensive control group (gliclazide MR and any other additional therapy to achieve HbA1c ≤6.5%) than in the standard glucose lowering group (treatment according to local guidelines [if a sulfonylurea was required it could be any agent except gliclazide]), but overall weight gain was negligible with gliclazide MR intensive therapy (0.1kg over five years of follow-up). 
• The ADVANCE study also demonstrated that an intensive strategy based on gliclazide MR to achieve mean HbA1c levels of 6.5% improved microvascular (especially renal) outcomes safely with no demonstrable increase in mortality.  
• The 10 year follow-up study of ADVANCE (ADVANCE-ON) showed long-term CV safety of intensive treatment with gliclazide MR and continued renal benefits (29 events vs 53 end-stage renal disease) compared to standard treatment. 
• The United Kingdom Prospective Diabetes Study (UKPDS) study randomised individuals to conventional glucose control with diet, or to intensive glucose lowering with a SUs (chlorpropamide, glibenclamide, glipizide) or insulin. The SUs  proved as effective as insulin in decreasing the risk of microvascular complications, although neither treatment had a statistically significant effect on macrovascular disease. However, the UKPDS long-term follow-up trial of the original UKPDS cohort found that those randomised to intensive glycaemic control using SUs or insulin during the 10 years of the study had a significant 15% lower risk for myocardial infarction (MI), a 24% lower risk for microvascular disease and a 13% reduction in death from any cause at the end of follow-up. 
• The Intensified Multifactorial Intervention in Patients With T2DM and Microalbuminuria study randomised  patients with T2DM and microalbuminuria to conventional therapy or intensive multifactorial intervention (metformin or gliclazide MR) to maintain HbA1c <6.5%. Follow-up was eight years. Some 44% of patients in the conventional-therapy group compared to 24% in the intensive-therapy group experienced a CV event. 
• A systematic review and network meta-analysis of controlled trials that included at least two SUs showed that all-cause and CV-related mortality was lower with gliclazide MR and glimepiride compared with glibenclamide. 
• Compared with metformin, over a median follow-up of 3.3 years, glimepiride, glibenclamide, glipizide and tolbutamide were associated with increased all-cause mortality in subjects with and without previous MI whereas gliclazide MR was not statistically different from metformin in both subjects without and with previous MI. 
• In the Double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients study, gliclazide MR and glimepiride were similarly effective in improving blood glucose control, but for gliclazide MR this was achieved with about 50% fewer hypoglycaemic episodes compared to glimepiride. 
• In ADVANCE, mean HbA1c was lowered to a target of ≤6.5% using an intensive gliclazide MR-based strategy. Four out of five patients attained an HbA1c <7% with no deterioration for a mean of five years. 
• Differences have been observed in hypoglycaemic risk among the different SUs which may be explained by variations in their pharmacological profiles. Glibenclamide and glimepiride are long-acting and the formation of active metabolites increases the risk for prolonged and severe hypoglycaemia, particularly in the elderly. The risk is significantly less with glipizide and gliclazide MR partly due to metabolism to inactive metabolites. 
• A meta-analysis of randomised controlled trials (RCTs) with a duration of 12–52 weeks compared the relative risk of hypoglycaemia with newer generation SUs when added to metformin monotherapy. With comparable reductions in HbA1c of -0.66 to -0.84%, gliclazide MR conferred the lowest risk of hypoglycaemia of any severity compared with glimepiride (odds ration [OR] 0.40), glibenclamide (OR 0.21) and glipizide MR (OR 0.22). 
• A meta-analysis of hypoglycaemia incidence in RCTs of SUs found that hypoglycaemia with glucose ≤3.1mmol/L was experienced by 10.1% of patients with any SUs, but only 1.4% of patients treated with gliclazide MR. Severe hypoglycaemia was experienced by 0.8% on any SUs and 0.1% on gliclazide MR. 
• Both gliclazide MR and glipizide have only inactive metabolites and their risk of increased hypoglycaemia with renal insufficiency is low and they may be safely used at estimated glomerular filtration rate levels >30 mL/min, and at reduced dose below this level with careful monitoring. The ADVANCE study showed that intensive glucose lowering based on gliclazide MR reduced the risk of new onset microalbuminuria by 9%, macroalbuminuria by 30%, new or worsening nephropathy by 21%, and end-stage renal disease (ESRD) by 65%. In addition, intensive glucose-lowering based on gliclazide MR led to regression of albuminuria by one stage in 62% of those with albuminuria at baseline, with the majority achieving normal albuminuria. A persistent benefit of gliclazide MR intensive glucose control with respect to ESRD was observed for 10 years after initiation of therapy. 

Conclusion 

According to Colagiuri et al, T2DM is no longer a pandemic only of economically affluent countries but is also a major problem in the developing world. More than ever, cost effective and safe therapies to lower blood glucose levels are required.⁸  

OADs still dominate the prescribing pattern (56.4%) followed by insulin alone (43.6%). SUs alone or in combination with metformin have been the most commonly prescribed OADs in some African and Asian countries, stressed Kalra et al.⁷ 

Gliclazide MR is associated with a low risk of hypoglycaemia, is weight neutral, offer CV safety benefits, and is associated with favourable renal outcomes - especially in patients with CKD. Furthermore, gliclazide MR has been shown to protects β-cells by acting specifically on the pancreatic SU receptor 1, thus delaying the development of secondary treatment failure.⁵   

References 

1. Leiter LA, Shestakova MV, Satman I. Effectiveness of gliclazide MR 60 mg in the management of type 2 diabetes: analyses from the EASYDia trial. Diabetol Metab Syndr, 2018. 
2.  American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycaemic treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care 2022;45(Suppl. 1):S125–S143. 
3. Fonseca VA. Defining and characterizing the progression of type 2 diabetes. Diabetes Care, 2009. 
4. Qian D, Zhang T, Zhang P. Comparison of Oral Antidiabetic Drugs as Add-On Treatments in Patients with Type 2 Diabetes Uncontrolled on Metformin: A Network Meta-Analysis. Diabetes Therapy, 2018. 
5. Kalra S, Unnikrishnan AG, Bantwal G, et al. The Position of Gliclazide in the Evolving Landscapes and Disease Continuum of T2DM: A Collaborative Delphi Survey-Based Consensus from India. Diabetes Ther, 2021. 
6.  Costello RA, Nicolas S, Shivkumar A. Sulfonylureas. [Updated 2022 May 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK513225/ 
7.  Kalra S, Bahendeka S, Sahay R, et al. Consensus Recommendations on Sulfonylurea and Sulfonylurea Combinations in the Management of Type 2 Diabetes Mellitus - International Task Force. Indian J Endocrinol Metab, 2018. 
8.  Colagiuri S, Matthews D, Leiter LA, et al. The place of gliclazide MR in the evolving type 2 diabetes landscape: A comparison with other sulfonylureas and newer oral antihyperglycemic agents. Diabetes Research and Clinical Practice, 2018.