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Drug Review - Sulphonylureas

Sulphonylureas

Classification

Gliclazide MR: The SU of choice

Mode of action and pharmacology

Glycaemic efficacy

Hypoglycaemia

Weight

Microvascular and macrovascular outcomes

Pleiotropic effects and non-glycaemic benefits

The choice of SU

Indications for use

Dosing and prescribing

 

Sulphonylureas (SUs) were first described in 1942 by the chemist Marcel Janbon when he observed that the sulphonamide antibiotics caused hypoglycaemia in animals.1 Tolbutamide was developed in 1956 and glibenclamide in 1966. SUs have good glucose-lowering efficacy and safety, having been in clinical use for more than sixty years.2

CLASSIFICATION

SUs are traditionally classified as 1st or 2nd generation:

1st generation SUs include acetohexamide, tolbutamide, chlorpropamide, tolbutamide and tolazamide. Their use has been limited by side effects. Chlorpropamide is the only one still available in South Africa (Hypomide® and Diabitex®) but is no longer in use.

2nd generation SUs include glibenclamide, gliclazide (standard and modified-release), glipizide and glimepiride. These have a more nonpolar, lipophilic side chain, which results in a marked increase in their affinity for the SU receptor and hypoglycaemic potency (e.g. glibenclamide is 200 times more potent than tolbutamide).3 All 2nd generation SUs are available in South Africa. There is no justification, pharmacological or otherwise, for classifying some SUs as 3rd generation.

Despite all SUs being classed together because of their chemistry and primary mode of action, it has become clear that these drugs are quite different in their effects. Controversies relating to specific agents have inappropriately been applied to the class as a whole. 

Note that glibenclamide is referred to as glyburide in the United States (US) and that gliclazide is not available in the US and some European countries. This has limited the number of trials where gliclazide is used as a comparator.

GLICLAZIDE MR: THE SU OF CHOICE

The 2012 SEMDSA guideline recommendation was that “glibenclamide therapy be phased out in favour of the other second generation SUs”. 

The SEMDSA Guideline Expert Committee has considered all of the SU data and now strongly recommends that gliclazide modified-release should be the SU of choice at primary health care level. The reasons for this decision will be reviewed below.

MODE OF ACTION AND PHARMACOLOGY2,4,5,6,7,8,9

(This section contains optional supplementary reading)

All SUs are insulin secretagogues; they lower blood glucose through glucose-independent stimulation of insulin secretion from the pancreatic ß-cell.

They induce insulin release by binding to specific receptors on ATP-sensitive potassium (KATP) channels. KATP channels consist of two sub units, namely a SU receptor (SUR) sub unit and a pore forming sub unit (Kir6.x). Each sub unit has 2 isoforms (SUR1 & SUR2 and Kir6.1 & Kir6.2).

The SUR isoform in the pancreatic ß-cell is SUR1. The binding of SUs to SUR1 leads to closure of the potassium channel, prevents potassium efflux and results in membrane depolarisation. This in turn leads to calcium influx, and the release of stored insulin from the ß-cell.9

Individual SUs differ in their affinity, specificity and binding to the SU receptor. Gliclazide, like glipizide and nateglinide, binds specifically and reversibly to pancreatic ß-cell SUR1 sub units at the A binding site. 

Glibenclamide and glimepiride bind SUR1 and SUR2 sub units (at both the A and B binding sites) irreversibly and non-specifically in a variety of tissues, including cardiac muscle.4,5,10 Blocking the KATP channel on cardiac myocytes inhibits ischaemic pre-conditioning in animal models, and is a potential mechanism by which SUs may worsen cardiac outcomes.11,12 

The tissue distribution of KATP subunit isoforms and their interactions with second generation SUs is shown in Table I below.

Table I: Tissue distribution of SU receptors4,5,10

Tissue
 		 SUR/Kir Isoform
 		 Blocked by
 
Pancreatic ß-cell SUR1A/Kir6.2
SUR1B/Kir6.2		 All SUs and meglitinides Glibenclamide, glimepiride
Cardiac muscle SUR2A/Kir6.2 Glibenclamide, glimepiride
Skeletal muscle SUR2A/Kir6.2 Glibenclamide, glimepiride
Vascular smooth muscle SUR2B/Kir6.1 Glibenclamide, glimepiride
Non-vascular smooth muscle SUR2A/Kir6.2 Glibenclamide
Brain SUR12B/Kir6.2 -

 

Gliclazide blocks SUR1A reversibly and this action is credited for its lower hypoglycaemic potential. Although glimepiride is non-specific in its interaction with the SUR sub unit, it has a lower affinity for the SUR than glibenclamide. This is believed to result in lower inhibition of KATP channels and less hypoglycaemic potential.13,14

Apart from KATP binding, all SUs except gliclazide also interact with exchange protein directly activated by cAMP (Epac2), which induces additional glucose-independent insulin exocytosis.7

The tissue specificity, reversible binding and lack of Epac2 interaction of gliclazide is credited chemically to its fewer hydrophobic domains and the lack of a benzamide moiety, and provides a pharmacological expectation for lower rates of hypoglycaemia and better cardiovascular (CV) safety.

The pharmacology of the second-generation SUs is summarised in the Table II below.

Note that:

  1. Glibenclamide and glimepiride have active metabolites with hypoglycaemic potential; gliclazide does not
  2. Despite similar metabolism and excretion to other SUs, glibenclamide has also been reported to accumulate in pancreatic ß-cells and to continue to stimulate insulin secretion during hypoglycaemia, leading to delayed recovery15,16

GLYCAEMIC EFFICACY 

A 2014 Cochrane systematic review and meta-analysis of randomised clinical trials found no difference in the glycaemic efficacy of second generation SU monotherapy when compared with metformin monotherapy.23

A 2013 meta-analysis of SU monotherapy trials found a mean HbA1c  reduction  of  -1.5%  compared  to  placebo.24  However this meta-analysis included 1st generation SUs, studies of short duration (three months or longer) and some trials had a very small number of participants. Other meta-analyses consistently show  an approximate 1% reduction  in  HbA1c  with  second generation SUs when used as monotherapy or combination therapy with non-insulin agents.25,26,27,28

Two systematic reviews and meta-analyses of gliclazide studies demonstrated equivalent, if not slightly better, glycaemic efficacy compared with other SUs.29,30

The most recent network meta-analysis of comparative efficacies of glucose lowering drugs (GLDs) reports the following mean [95% CI] HbA1c reductions for SUs:28

As monotherapy (vs. placebo): -0.83 [-0.64 to -1.02]

As dual therapy: -1.25% [-0.76 to -1.72]

Table II: Comparison of second-generation SU drugs in available in South Africa


 		 Glibenclamide17
 		 Gliclazide18
 		 Gliclazide-MR18
 		 Glimepiride19
 		 Glipizide20
 
Chemical structure
 		 Benzamide and sulphonyl moiety
 		 Sulphonyl moiety only; fewer hydrophobic domains
 		 Benzamide and sulphonyl moiety
 
ß-cell (SUR1) and cardiac (SUR2A) selectivity
 		 Non-selective
 		 Selective for SUR1A; reversible binding
 		 Non-Selective  Selective for SUR1
Epac2 binding 
 		 Yes No Yes
Protein binding 
 		 99% 95% >99% >90%
Peak concentration (hours)
 		 3-4 4-6 6-12 2-3 1-3
Elimination half-life (hours)
 		 10-16 10-12 16 5-8 2-4
Metabolism
 		 Hepatic Hepatic  Hepatic 
Metobolites 2 active metabolites21 6 inactive metabolites  2 metabolites; 1 active metabolites  Inactive 
Excretion of metobolites 50% renal
50% biliary 		 60-70% renal
10-20% biliary 		 60% renal
40% biliary
 		 80% kidney
20% biliary 
Duration of action2
 		 16-24 hours 10-24 hours 24 hours 16-24 hours  12-24 hours 
Tablet size 
 		 5 mg 80 mg 30-60 mg 1, 2 & 4 mg  5 mg 
Minimum daily dose  2.5 mg 40 mg 30 mg 1 mg 
 
Maximum dose  10 mg BD 160 mg BD 120 mg OD 8 mg OD
 		 20 mg BD
 
Cheapest generic SEP* for maximum dose22
 		 R35.00 R93.00 R123.00 R315.00
 		 N/A
 
Originator SEP* for maximum dose22
 		 Euglucon® R426.00
Daonil®
R572.00
 		 Diamicron® R177.00
 		 Diamicron® R231.00 Amaryl®
R938.00
 		 Minidiab®
R868.00

 

SUR=SU receptor; Epac= exchange protein directly activated by cAMP ; OD=once daily; BD= two times a day; SEP= single exit price; *Issued by Department of Health and updated periodically as per South African regulations. For updated prices please consult The South African Medicines Price Registry. §Discontinued as at 2017.

HYPOGLYCAEMIA 

General
Inherent trial bias, publication bias, incomplete reporting and varying definitions of hypoglycaemia (less than 3.9, 3.5, 3.3, 3.1 and 2.8 mmol/L) hamper direct comparisons of the rates of hypoglycaemia across different randomised controlled trials (RCTs). Changing the cut point that defines hypoglycaemia can have a dramatic effect on results.31

Observational and epidemiological data have identified severe hypoglycaemia as a risk factor for poorer CV and mortality outcomes, though causality has not been proven.32 The clinical significance of mild and moderate hypoglycaemia on clinical outcomes in type 2 diabetes is not known, but it is a predictor for severe hypoglycaemia and must therefore be avoided. Severe or major hypoglycaemia in a trial setting has usually been defined as blood glucose <2.8 mmol/L and/or hypoglycaemia that requires external assistance.

SUs are consistently associated with higher rates of any hypoglycaemia when compared with metformin monotherapy.23,28 This is reflective of its mode of action as glucose- independent insulin secretagogues. Data from UKPDS showed that 17% of SU treated patients reported hypoglycaemia,33 and over 10 years 1.4% to 2.5% of glibenclamide treated patients experienced at least one episode of severe hypoglycaemia per year.34,35 A meta-analysis of SU RCTs revealed that 10% of users reported hypoglycaemia (<3.1 mmol/L).36

Hypoglycaemia data from RCTs  can  be  misleading  because  they often exclude high-risk patients in favour of more highly motivated patients, and have more intensive monitoring. A more real-world systematic review and meta-analysis from population based studies showed that the for treatment regimens that included a SU, the prevalence of mild-to-moderate and severe hypoglycaemia was 30% and 5% respectively. The incidence was 200 mild-to-moderate events/100 person-years and 1.0 severe event/100 person-years.37

Comparison of SUs
Glibenclamide has been consistently associated with a higher hypoglycaemia risk among the second-generation SUs, particularly in older persons and in those with renal impairment.38,39,40,41,42 This has led to its removal from the World Health Organisations Essential Medicines List. The American Geriatrics Society’s Beers Criteria lists a strong recommendation based on high quality evidence that glibenclamide be avoided in the elderly due to the potential risks.44 In the meta-analysis by Gangji et al. the estimated increased relative risk for hypoglycaemia with glibenclamide versus other SUs was 1.83 [95% CI 1.35–2.49].41

Gliclazide and glimepiride has been reported to have an eight- fold lower hypoglycaemic risk than glibenclamide.42,45 In a head- to-head comparison the European GUIDE study demonstrated that gliclazide modified-release also had lower rates of hypoglycaemia (BG < 3.0 mmol/l) than glimepiride with similar glycaemic efficacy. No episodes of severe hypoglycaemia were noted in this study.46 

The table below lists the estimated hypoglycaemic risk with second-generation SUs.47

Table III: Rates of severe hypoglycaemia with SUs (<2.8mmol/L)47

SU
 		 Prevalence (proportion of patients)
 		 Incidence (episodes/100-patient years)
 
Gliclazide
 		 4.6% 0.86
Glipizide
 		 8.0% 8.70
Glimepiride
 		 11.5% 0.87
Glibenclamide
 		 24% 16.00


Systematic reviews and meta-analyses that included gliclazide (including the modified-release formulation), compared to other SUs and oral glucose lowering drugs, have confirmed that it has the lowest hypoglycaemic potential in its class, with equal if not better glycaemic efficacy.29,30,36 

However the number of severe hypoglycaemic events in these studies was extremely low with  all therapies. The Schopman meta-analysis specifically examined hypoglycaemia outcomes and found that 10% of SU users experienced mild hypoglycaemia (defined as BG < 3.1 mmol/L) and 0.8% experienced severe hypoglycaemia (requiring external assistance). 

Gliclazide users had the lowest rate of mild and severe hypoglycaemia (1.4% and 0.1% respectively). Equivalent figures for glimepiride was 15.5 and 0.9% respectively.36

The ADVANCE study randomised 11 140 type 2 diabetes patients with high CV risk, a mean age of 66 years and disease duration of 8 years to either intensive treatment using a gliclazide modified-release strategy (75% used a dose of 120 mg daily) or conventional therapy.70 

The intensive treatment group achieved an HbA1c of 6.5% over 5 years of follow-up. Despite this rather low glycaemic target for this population (by current standards), the rate of severe hypoglycaemia was 0.7 episodes/100 patients/year compared to 0.4 episodes/100 patients/year in the conventional treatment group whose mean HbA1c was 7.3%. 

The proportion of patients who experienced any hypoglycaemic episode was 53% for intensive gliclazide modified-release based treatment vs. 38% for conventional therapy. We therefore recommend  that even gliclazide modified-release, the SU with the lowest hypoglycaemic potential, be used with caution when the target HbA1c is 6.5% or less.70

Factors that increase the risk of hypoglycaemia include exercise, increased age, presence of co–morbidities, hypoglycaemia unawareness, missed meals, excessive dieting or weight loss, alcohol, and diabetes duration and renal impairment.36,48

Multiple reports from a single study group using a single database (United Kingdom Clinical Practice Research Database – UKCPRD) have questioned the superior safety of gliclazide.48,49,50,51,52 However, these are all observational studies, where gliclazide users are over-represented (80% of SU use is gliclazide), subjects are not matched, confounding by indication cannot be excluded, and residual confounding factors cannot be corrected for. Their data will need to be replicated in a controlled trial before being considered reliable.

WEIGHT

In a systematic review and meta-analysis, SU therapy was associated with a mean weight gain  of  2.31  kg  (95%   CI 1.31- 3.32).44 In the UKPDS, the mean weight gain in patients assigned glibenclamide therapy was 1.7 kg over 10 years. In the ADVANCE study using gliclazide, modified-release as the base therapy was not associated  with weight gain.70 The Landman et al.30 meta-analysis of gliclazide RCTs demonstrated a 0.47 kg mean weight gain when compared to controls.

MICROVASCULAR AND MACROVASCULAR OUTCOMES

Randomised controlled trials
In the UKPDS, intensive treatment with SUs (glibenclamide, chlorpropamide or glipizide) over 10 years in newly diagnosed diabetes resulted in a 0.9% HbA1c difference and a 25% reduction of microvascular complications compared to standard treatment, where pharmacological intervention only occurred when the fasting plasma glucose exceeded 15 mmol/L.34 In this RCT, these SUs had no macrovascular or mortality benefit compared to diet alone. This trial was designed to study the effect of intensive glycaemic control, and was not designed or powered to examine the safety of one drug class against another.53

The report of glibenclamide and chlorpropamide compared to metformin in obese patients (UKPDS 34 secondary analysis)35 has been discussed in the section on metformin (See: Hypoglycaemia). It is not possible to determine definitively from this study whether the better results with metformin was due to a beneficial effect of metformin or a harmful effect of glibenclamide and chlorpropamide, (the argument being that the benefits of HbA1c reduction on macrovascular disease and mortality with these SUs may have been negated by the harmful effects of these drugs). This has added to the speculation from the University Group Diabetes Program (UGDP), which reported (controversially) a higher CV mortality with tolbutamide, that SUs as a class have harmful CV effects.54

The ADVANCE study, using a gliclazide modified-release strategy, demonstrated a significant reduction in microvascular outcomes (and therefore also the combined microvascular and macrovascular outcomes), driven mainly by the reduction in the incidence of nephropathy.70 Another study indicated potential renal risks for elderly patients using glimepiride versus gliclazide.39

Rosenstock et al. reviewed 15 published RCTs that were of ≥ a72 week duration and included SU therapy versus an active comparator (including metformin, DPP-4i, GLP-1RA, TZD and insulin), or as part of a treatment strategy.55 None of them reported an increased CV risk with SU use. However, some of the studies (e.g. UKPDS and ADVANCE) studied the effect of intensive control vs. less intensive control, and were not designed or powered to demonstrate safety of SUs against other therapies, so that any benefit (or lack of harm) might be credited to improved glycaemic control rather than the SU. In the studies that did target equivalent glycaemic control, none of them were powered to demonstrate CV safety, and there was inconsistency in CV event reporting and adjudication.

More formal systematic reviews and meta-analyses of RCTs examining the CV risk/safety of SUs have also generally not demonstrated an increased or reduced CV risk with second generation SUs23,28,41,56,57,58,59 (Table IV). One meta-analysis showed an increase in all-cause mortality,60 one showed a reduction in non-fatal CV events,23 and one showed a lower CV risk lower with DPP-4-inhibitors compared to SUs.61 However they suffer the same weaknesses of the underlying RCTs analysed, (design flaws, inadequate follow-up, selection-bias, inconsistent reporting of CV events, varying definitions and event adjudication, publication bias), and the heterogeneity in these analyses has generally been quite high, thus reducing their reliability.12

Observational Studies

Observational studies have the advantage of representing more “real-world” population data rather than the highly selected populations of industry-sponsored drug trials. Abdelmoneim et al. has listed the 68 published observational studies on SU use and CV outcomes to January 2015 in a supplementary table.12 Table IV summarises the meta-analyses of these observational studies, which, in contrast to extrapolated RCT data, mostly suggest an increased CV and mortality risk (up to 379%) with SU use.57,62,63 Abdelmoneim et al. discusses the inherent weaknesses of observational studies particularly in relation to SUs and CV outcomes.12

Data from observational studies can never be used as proof of causality; it merely generates a hypothesis that then needs to be proven in a suitably designed RCT. In the absence of such suitably designed trials, the strong signal from these observational studies cannot be ignored. One of the additional weaknesses of studies examining SUs and CV risk is that the SUs are often examined as a homogeneous class when in fact their pharmacology does differ. It is reassuring then, that the observational studies that report CV risk with different SUs have consistently reported better outcomes with gliclazide when compared to other SUs.64,65,66,67,68 The better CV safety of gliclazide has been confirmed in the meta- analysis by Simpson et al.58

In summary, the inherent weaknesses of both the meta-analyses of RCTs not designed to investigate the CV safety of SUs, and the weaknesses of observational studies means that there is no definitive answer as to the CV safety or risk of SUs as a class. 

The ongoing CAROLINA trial is comparing linagliptin and glimepiride in a dedicated CV safety design and will hopefully lend more clarity to this issue.55 In the meantime the balance of probabilities must rest with RCTs, which favour CV safety. The ADVANCE study rather than UKPDS more closely resembles the day-to-day use of SUs (as add-on therapy), and this trial did not show evidence of CV harm.70 

Even if the observational data on higher CV risk with SUs are true, from a meta-analysis the same data the risk with gliclazide is lower than glibenclamide and glimepiride, and not different to metformin.

Table IV: Summary of meta-analyses of SUs and cardiovascular safety

Meta-analysis
 		 Type and no. of studies included
 		 SU vs. comparator
 		 Outcome examined
 		 Pooled point estimate [95%CI]§
 
Gangji et al., 200741 RCT (21) Glibenclamide vs secretagogues or insulin CV events 0.84 [0.56–1.26]
Selvin et al., 200856 RCT (5)
RCT (6)
RCT (5)		 SU vs no SU
SU vs no SU
SU vs no SU		 CV mortality
All Cause Mortality
CV morbidity		 0.92 [0.68 – 1.26]
0.90 [1.10 – 1.85]
0.89 [0.71 – 1.11]
Rao et al., 200862 Observational (4)
Observational (7)
Observational (5)		 SU+Met vs. diet, Met monotherapy, SU monotherapy CV Mortality
All-cause mortality
CV mortality and
hospitalisation		 1.29 [0.73 – 2.27]
1.19 [0.88 – 1.62]
1.43 [1.10 – 1.85]
Phung et al., 201357 Observational (9)
RCT (7)		 SU vs no SU
SU vs no SU		 CV Mortality
CV Mortality		 1.27 [1.18 – 1.34]
1.22 [0.63 – 2.39]
Monami et al., 201360 RCT (30)
RCT (37)		 SU vs no SU
SU vs no SU		 MACE
All-cause mortality		 1.08 [0.86 – 1.36]
1.22 [1.01 – 1.49]
Hemmingsen et al., 201323 RCT (3)
RCT (6)
RCT (6)		 SU monotherapy vs Met
SU monotherapy vs Met
SU monotherapy vs Met		 CV Mortality
All-cause mortality
CV Mortality		 1.47 [0.54 – 4.01]
0.98 [0.61 – 1.58]
0.67 [0.48 – 0.93]
Forst et al., 201363 Observational (4)
Observational (12)		 SU vs no SU
SU vs no SU		 CV Mortality
All-cause mortality		 2.72 [1.95 – 3.79]
1.92 [1.48 – 2.49]
Zhang et al., 201461 RCT (4) DPP-4i vs SU CV events 0.53 [0.32 – 0.87]
Simpson et al., 201558 RCT (7)
Observational (7)		 Glipizide vs glibenclamide
Glipizide vs glibenclamide
Glipizide vs glibenclamide		 CV Mortality
All Cause Mortality
CV Mortality
All Cause Mortality
CV Mortality
All Cause Mortality		 1.01 [0.72 – 1.43]
0.98 [0.80 – 1.19]
0.79 [0.57 – 1.11]
0.83 [0.68 – 1.00]
0.60 [0.45 – 0.84]
0.65 [0.53 – 0.79]
Rados et al., 201659 RCT (37)
RCT (37)
RCT (23)
RCT (23)		 SU vs no SU All Cause Mortality
CV Mortality
Myocardial infarction
Stroke		 1.12 [0.96 - 1.30]
1.12 [0.87 - 1.42]
0.92 [0.76 - 1.12]
1.16 [0.81 - 1.66]
Palmer et al.,201628 RCT (25)
RCT (26)		 SU monotherapy vs Met*
Dual therapy: Met + SU vs Met + non-SU**		 CV Mortality
All-cause mortality
CV Mortality
All-cause mortality		 1.25 [0.59 - 2.67]
1.19 [0.81 - 1.75]
1.00 Reference
1.00 Reference

 SU=SU; CI=confidence interval; RCT= randomised controlled trial; CV=cardiovascular; Met=metformin
§95% Values <1.00 favour SU safety; Confidence Interval: statistically significant if the interval does not cross 1.00 (bold italics)
*Other monotherapies (TZD, DPP-4i, SGLT2i,, AGI, meglitinides and placebo vs metformin were not significantly different to SU vs metformin)
**For 2nd line therapy, metformin + SU was used as reference; metformin + any one of TZD, DPP-4i, SGLT2i, GLP-1RA, meglitinides and placebo was not significantly different to the Met + SU combination

PLEIOTROPIC EFFECT AND NON-GLYCAEMIC BENEFITS

Gliclazide has been shown to have additional pleiotropic effects:18

1. Extra-pancreatic effects on glucose metabolism:

  • Increase peripheral insulin sensitivity and increases muscle glucose uptake by +35%, due to its effect on muscle glycogen synthetase and a post-transcriptional action on GLUT4 glucose carriers.
  • Decreases hepatic glucose production, leading to an improvement in fasting blood glucose levels

2. Haemovascular effects: Gliclazide decreases microthrombosis by two mechanisms which may be involved in complications of diabetes:

  • A partial inhibition of platelet aggregation and adhesion
  • A restoration of the vascular endothelium fibrinolytic activity with an increase in t-PA activity
  • Antioxidant effects: A controlled clinical study in diabetics has confirmed the antioxidant effects of gliclazide i.e. a reduction in plasma levels of lipid peroxides and an increase in the activity of erythrocyte superoxide dismutase

3. Cancers: Data about an increased cancer risk with SUs and insulin are unclear. Nevertheless, the cancer risk with gliclazide has been shown to be lower than insulin and other SUs.2,8

THE CHOICE OF SU

SUs are one of the more effective glucose lowering drugs that can improve glycaemic control rapidly. They are relatively inexpensive, have a long history of clinical use, and are relatively simple to use. 

Their clinical use predates the US Food and Drug Administration (FDA) regulatory requirement for proven CV safety,69 and there are no suitably designed trials that have examined this issue specifically. 

What we do know for now, is that there is at least some data to suggest that SUs may increase CV risk, and that there is a plausible mechanism by which this might occur (hypoglycaemia and SUR binding on cardiac myocyes). How then, can we best manage this potential risk? 

Firstly, we should use the SU with the lowest risk for hypoglycaemia. Secondly, we should favour SUs with proven outcomes and the best evidence for CV safety, especially when combined with metformin. 

Thirdly, a SU with the best renal safety is highly preferable to minimise inappropriate prescribing and dosing, particularly at primary care level. 

Fourthly, we should prefer, at least on theoretical grounds, a SU that does not interact with cardiac myocytes. Additional considerations would be potential non-glycaemic benefits, once daily dosing to improve compliance and adherence, and availability of cost-effective generic medicines.

Based on our review of the SU data, we make the following observations:

  1. Gliclazide and its modified-release formulation has demonstrated the lowest hypoglycaemic  potential  in  the  SU class, in head-to-head RCTs,46 meta-analyses29,30,36 and observational studies.45 The rate of severe hypoglycaemia with gliclazide is very low (estimated at 0.1%).
  2. The WHO has concluded that the adverse safety profile of glibenclamide, especially in older patients, warranted it being replaced by gliclazide on the WHO Essential Medicines List.43 The American Geriatrics Society makes a recommendation based on strong evidence that glibenclamide is unsafe and must not be used in older patients.44
  3. A gliclazide modified-release based intensive treatment strategy has proven microvascular benefit and macrovascular safety in a long term RCT that included older type 2 diabetes patients, patients at high CV risk, and those taking concomitant metformin therapy.70 Glimepiride may have adverse renal outcomes in some sub-populations of type 2 diabetes patients.39
  4. In observational studies and meta-analyses  of  SU-related  CV safety, gliclazide has been shown to have a better safety profile than glibenclamide and glimepiride.64,65,66,67,68
  5. There has been no evidence of an adverse safety signal with a gliclazide-metformin combination (as exists for glibenclamide).35
  6. The gliclazide dose does not require adjustment in CKD and can be used even in stage 5 CKD; glimepiride either should not be used or will need dose adjustments in Stage 3 CKD or worse; glibenclamide must not be used in stage 3 CKD or worse.71,72,73 (vide infra)
  7. Gliclazide and its modified-release formulation do not bind SUR2 on cardiac myocytes; this potentially harmful interaction therefore does not exist for gliclazide2,4,5,6,7,8,9  (and possibly explains it better CV safety).
  8. Gliclazide and its modified-release formulation have beneficial pleiotropic effects, not all of which are shared by the other SUs.
  9. Gliclazide MR is dosed once daily, reduces the pill burden and can improve adherence and compliance with therapy.
  10. Gliclazide MR is available in South Africa as cost-effective generic tablets. In  the  private  health  sector,  gliclazide MR is significantly less expensive than generic glimepiride tablets or glipizide. Using the most inexpensive formulations available at maximum recommended doses, glimepiride is currently 256% more expensive, while glipizide is 933% more expensive than gliclazide modified-release (Table II).22

Based on these observations we strongly recommend that gliclazide MR should be the SU of choice at primary care level and that glibenclamide must not be used at primary health care level.

INDICATIONS FOR USE 
SEMDSA recommends that gliclazide modified-release be considered for use only when the target HbA1c is greater than 6.5% in the following situations:
1. As monotherapy (first-line)

  • In patients who have intolerable side-effects with metformin and its extended-release formulation, or when metformin is contraindicated
  • In patients with symptoms attributable to hyperglycaemia when rapid symptom control is desirable, (these patients will often need initial dual therapy with metformin and gliclazide modified-release)
  • In non-obese patients, gliclazide modified-release is an acceptable alternative first-line therapy

2. As add on (second-line) to metformin or other initial drug therapy in patients not achieving or maintaining their glycaemic targets.
3. As a third glucose lowering drug in patients not achieving or maintaining their glycaemic targets on a two drug regimen that does not already include a SU.

DOSING AND PRESCRIBING  

Dosing

  1. The usual starting dose for gliclazide modified-release is 30 to 60 mg administered once daily with the morning meal. Consider starting with the higher dose when the HbA1c target is >0.5% from the patient’s prevailing HbA1c level.
  2. The dose can be escalated by 30 to 60 mg every 1 to 4 weeks, guided by fasting glucose levels
  3. The maximum dose is 120 mg administered once daily with the morning meal
  4. The 60 mg tablets are scored and can be broken to improve cost effectiveness

Prescribing in chronic kidney disease
Glibenclamide and glimepiride have active metabolites that accumulate when renal function is impaired. Gliclazide and glipizide do not have active metabolites. The most recent guidelines on SU dose adjustments in renal disease are summarised in the Table below.71,72,73

Table V: Renal dose adjustments for SUs71,72,73

CKD Stage / eGFR (ml/min/1.73m2)
 		 Stage 1-2
≥ 60
 		 Stage 3A and B
30-59
 		 Stage 4
15-29
 		 Stage 5
<15
 		 5D
On dialysis
 
Glibenclamide
 		 Normal dose
 
 		 Must not use
 
 
 
Glimepiride§
 		 Normal dose
 		 Caution – 1mg
 		 Reduce – 1mg
 		 1mg / Do not use
 		 Do not use
 
Glipizide
 		 Normal dose
 		 No dose adjustment
No dose adjustment
 
Gliclazide / MR
 		 Normal dose
 

§Differing recommendations for glimepiride:
Reference 57 (KDOQI): Glipizide is the preferred SU (gliclazide is not available in the USA). If using glimepiride, recommended dose is 1 mg for stage 3-5; not recommended for stage 5D.
Reference 58 (Hahr): Stage 3 – use with caution; Stage 4&5 – avoid use. Reference 59 (Arnouts): Stage 3&4 – reduce dose to 1mg; Stage 5 – do not use.

Special precautions and side effects

1. Hypoglycaemia

  • Use with caution when the target HbA1c is ≤ 6.5% as the risk of hypoglycaemia may be unacceptably high
  • If mild hypoglycaemia occurs unexpectedly (e.g. not due to unplanned missed meals or unplanned exercise), reduce the dose by 30 to 60 mg
  • A single episode of severe hypoglycaemia or recurrent episodes of mild hypoglycaemia would be a strong indication to switch to an alternative glucose lowering drug

2. Although renal dose adjustments may not be necessary with gliclazide modified-release, caution is still advised especially when the eGFR is < 30 ml/min/1.73m2. In any case, these patients must be managed at specialist care level, and not at primary care level.
3. Serious adverse drug reactions include pancytopenia, thrombocytopenia, hepatitis, cholestatic jaundice, pyrexia, pancreatitis and skin reactions. These are very rare
4. A history of allergy to sulphonamide antibiotics is not a contraindication to gliclazide modified-release use as the cross-reactivity is low74
5. All SUs are contra-indicated in advanced liver disease because of their hepatic metabolism and biliary excretion

Authors: Aslam Amod and Fraser J Pirie
Editors: Zaheer Bayat, Ankia Coetzee, Nazeer A Mohamed, Joel A Dave, Tanya E Kinvig

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Drugs mentioned

NeoHealth® ID 18520 · updated 9/28/2021