Consensus Recommendations on Sulfonylurea and Sulfonylurea Combinations in the Management of Type 2 Diabetes Mellitus – International Task Force

Abstract

For decades, sulfonylureas (SUs) have been important drugs in the antidiabetic therapeutic armamentarium. They have been used as monotherapy as well as combination therapy. Focus on newer drugs and concerns about the risk of severe hypoglycemia and weight gain with some SUs have led to discussion on their safety and utility. It has to be borne in mind that the adverse events associated with SUs should not be ascribed to the whole class, as many modern SUs, such as glimepiride and gliclazide modified release, are associated with better safety profiles. Furthermore, individualization of treatment, using SUs in combination with other drugs, backed with careful monitoring and patient education, ensures maximum benefits with minimal side effects. The current guidelines, developed by experts from Africa, Asia, and the Middle East, promote the safe and smart use of SUs in combination with other glucose-lowering drugs.

EXECUTIVE SUMMARY

Sulfonylureas (SUs) in oral combination therapy:

• A1. Modern SUs (glimepiride and gliclazide modified release [MR]) are effective and safe second-line agents in patients who have not achieved predecided glycemic targets with metformin monotherapy (Grade A; evidence level [EL] 1)

• A2. Modern SUs are effective and safe as initial therapy if used in combination with lifestyle modification and metformin, in patients with a baseline glycated hemoglobin ≥7.5% (Grade A; EL 1)

• A3. SUs may be considered for use in combination with all classes of oral antidiabetic drugs except glinides (Grade A, EL1)

• A4. If not used earlier, modern SUs may be preferred as third-line agents for the management of uncontrolled diabetes with dual combination therapy, owing to better safety profile than older SUs (Grade A, EL 1)

• A5. Fixed-dose combinations (FDCs) containing SUs reduce cost, offer convenience, and improve patient adherence (Grade B; EL 1); hence, FDCs with varying strengths of SU + metformin should be made available, while SU + other drugs may be considered (Grade A; EL 4).

Comparative assessment as dual therapy with metformin:

• B1. Compared to metformin uptitration beyond half-maximal dose, the addition of SU to metformin demonstrates better glucose-lowering efficacy, safety, and tolerability (Grade A, EL 1)

• B2. Compared to pioglitazone, SUs demonstrate good glucose-lowering efficacy with significantly lower risk of weight gain (Grade A, EL 1)

• B3. Compared to dipeptidyl peptidase 4 inhibitors, SUs demonstrate better and more durable glucose-lowering efficacy; however, the likelihood of increase in body weight and risk of hypoglycemia should be taken into consideration (Grade A, EL 1)

• B4. Compared to sodium glucose co-transporter 2 inhibitors, SUs show noninferior glycemic control; however, safety criteria need to be considered while preferring either class (Grade A, EL 1)

• B5. Compared to glucagon-like peptide 1 receptor agonists, SUs show similar glycemic efficacy, with acceptable safety at lower cost (Grade A, EL 1).

SU and insulin combination:

• C1. Modern SUs may be continued, with appropriate precaution, when basal insulin is initiated (Grade A; EL1)

• C2. Modern SUs may be continued, in the antipodal meal, if premixed insulin is initiated once daily (Grade A; EL1)

• C3. Short-acting SUs, or glinides, may be continued or added to the third meal, with appropriate glucose monitoring if premixed insulin is initiated twice daily (Grade B; EL 1).

Use in special populations:

• D1. Combinations containing modern SUs can be used in elderly patients as they are associated with low risk of hypoglycemia (Grade A; EL 1)

• D2. SUs (glibenclamide) may be used in the glycemic control of neonatal diabetes (KCNJ11, ABCC8 gene mutations) and Maturity-Onset Diabetes of the Young 3 (MODY 3) (Grade A; EL 3)

• D3. The evidence base for the use of SUs in adolescents with type 2 diabetes is limited (Grade A; EL 4)

• D4. There is insufficient evidence to recommend the use of SUs, as monotherapy or in combination, to be used during pregnancy and lactation (Grade A; EL 2).

Use in comorbid conditions:

• E1. There is insufficient evidence to suggest that modern SUs increase cardiovascular (CV) risk. Modern SUs are preferred over conventional SUs in patients with diabetes and cardiovascular disease (CVD) (Grade A; EL 1)

• E2. Among SUs, short-acting drugs, especially those metabolized in the liver (glipizide), should be preferred in patients with moderate/severe renal impairment. In mild/moderate renal impairment, modern SUs may also be used, preferably at lower doses (Grade A; EL 3)

• E3. Reductions of SU dose and/or longer intervals between dosing are recommended in patients with mild/moderate hepatic impairment (Grade B; EL 4).

SUs in combination and Ramadan:

• F1. Modern SUs may be used in combination with other drugs during Ramadan, with appropriate counseling and dose modification (Grade A; EL 3)

• F2. Individuals on once-daily SU should take their medication at Iftar (evening meal) (Grade A; EL 3)

• F3. Individuals on twice-daily SU may shift the morning dose to Iftar and half of the evening dose to Suhur (morning meal) (Grade A; EL 4)

• F4. Patients on SU and premixed insulin should consider reducing the dose of either drug or shifting from premix to low-peak basal insulin during Ramadan (Grade A; EL 4)

• F5. Dose titration during Ramadan should be based on twice-weekly or weekly glucose monitoring (Grade A; EL 3).

INTRODUCTION

Epidemiology and burden of diabetes

Type 2 diabetes mellitus (T2DM), a progressive metabolic disorder, is continuously gaining the status of a potential epidemic in the world. According to the 2015 global estimates of International Diabetes Federation (IDF), about 415 million people (1 in 11 adults) have been shown to present with diabetes and is expected to reach 642 million (1 in 10 adults) by 2040.[1] Moreover, around 318 million adults are associated with impaired glucose tolerance, who are at a high risk of developing diabetes in the future. The 2015 regional fact sheet of IDF estimates the prevalence to be 10.7%, 8.5%, and 3.2% in the Middle East and North Africa (MENA), South East Asia (SEA), and African regions, respectively.[1] This increasing burden of the disease may contribute to increased rate of complications, reduction of quality of life, and premature mortality. As per the 2016 World Health Organization (WHO) global report on diabetes, the high blood glucose age-standardized mortality rates are 139.6, 115.3, and 111.3/100,000 in WHO Eastern Mediterranean, South-East Asia, and African regions, respectively.[2]

Prescription pattern of oral antidiabetic drugs

Tight glycemic control reduces the associated complications and improves the quality of life in patients with T2DM. The United Kingdom Prospective Diabetes Study trial reported that each 1% reduction of glycated hemoglobin (A1C) decreases approximately 12%–43% risk of diabetes-related mortality and morbidity.[3] Numerous antidiabetic agents are currently available as monotherapy or in combination therapy for the treatment of T2DM. However, oral antidiabetic drugs (OADs) still dominate the prescribing pattern (56.4%) followed by insulin alone (43.6%).[4,5] Furthermore, sulfonylureas (SUs) alone or in combination with metformin have been the most commonly prescribed OADs in some Afro-Asian countries.[6,7,8,9]

SUs can be classified either according to their hierarchy of development (conventional and modern SUs) or based on the duration of action (short-, intermediate-, and long-acting). The classification has been described in Table 1. This helps to avoid confusion during their use and can be effectively utilized in patients with variable clinical scenario.

Table 1.

Classification of sulfonylureas

Situational analysis of sulfonylureas

The conventional or modern SUs are widely used as second-line agents in the management of T2DM in most countries of Africa, MENA, and SEA region due to low cost and high efficacy. Among all, the combination of glimepiride (GLIM) and metformin is available in most of these countries. The National List of Essential Medicines (NLEM) in different countries containing SUs along with metformin is shown in Table 2. In 2015, the Indian NLEM was updated to align with the current treatment guidelines. Where more drugs were available within a therapeutic class, the core committee considered the best-suited one after due deliberation and careful evaluation of their relative safety, efficacy, and cost. Accordingly, glibenclamide (GLIB) has been replaced with GLIM in the diabetes section.[10] Tolbutamide (TOLB) and chlorpropamide (CHOL) are still used in Sri Lanka and Tanzania, respectively; gliquidone is available in Indonesia and Egypt. Fixed-dose combinations (FDCs) containing either conventional or modern SUs are available in most of the countries in Africa, MENA, and SEA regions except Oman and Sri Lanka. Furthermore, basal or premix insulin in combination with SUs is also prescribed for the management of T2DM in different parts of the world. A complete list of situational analysis of SUs in participating countries is summarized in Table 3.

Table 2.

Sulfonylureas listed in the National List of Essential Medicines of different countries in Africa, Middle East and North Africa, and South East Asian region

Table 3.

A complete list of situational analysis of sulfonylureas and sulfonylurea combinations in participating countries

RATIONALE AND METHODOLOGY

Pathophysiological basis

During the course of treatment, progressive nature of T2DM with a gradual decline in the functional β-cells leads to continuing the decrease in the glucose-lowering efficacy of OADs over time.[11] Evidence suggests that early combination therapy with intensive glycemic control can be an effective approach for better preservation of β-cell function, which may quickly attain the target glycemic level and reduce diabetic-related complications.[12,13,14,15,16,17] Early introduction of combination therapy also reduces complications associated with uptitration of monotherapies. The delay in stepping up from monotherapy to combination therapy in the step-wise approach contributes to long periods of hyperglycemia and an increased risk of macro- and microvascular complications.[18]

Pharmaceutical advances

Metformin produces its antihyperglycemic action without affecting the insulin secretion; hence, it is beneficial in combining metformin with insulin secretagog, like an SU. Among OADs available as add-on therapies to metformin, modern SUs can be considered as an ideal option owing to their high efficacy, relative cardiovascular (CV) safety, and low cost. The risk of hypoglycemia and weight gain can be minimized using modern SUs such as GLIM and gliclazide (GLIC) modified release (MR) with fewer side effects and better efficacy, which also has contributed to their wider use. Furthermore, combination therapies show a greater blood glucose-lowering effect than that of a single agent, which has been demonstrated in a number of studies and has resulted in the marketing of FDC preparations.[11,19]

Methodology

The current consensus reviews the recent evidence on SUs and presents evidence-based recommendations on the use of SUs and their combination for the management of T2DM. In order to impart the highest possible evidence base for the use of SUs in combination in the management of T2DM, a systematic review of the literature was initiated. Existing guidelines, meta-analyses, systematic reviews, randomized controlled trials (RCTs), non-RCTs, and key cited articles relating to T2DM management were reviewed and recommendations were framed. Recommendations for each section of the consensus statement were discussed by the expert panels and where there was a little or no evidence, the panel relied on logical empiricism and consensus to make their recommendations. The current consensus is developed in accordance with the American Association of Clinical Endocrinologists protocol for standardized production of clinical practice guidelines.[20] Recommendations are based on clinical importance (graded as A: strong, B: intermediate, C: weak, and D: no evidence based), which were coupled with four intuitive levels of evidence (1 = “at least one RCT or meta-analysis of RCTs,” 2 = “at least one nonrandomized or noncontrolled, prospective epidemiological study,” 3 = “cross-sectional or observational or surveillance or pilot study,” and 4 = “existing guideline or consensus expert opinion on extensive patient experience or review”) [Table 4.]

Table 4.

Evidence and recommendation grading according to the American Association of Clinical Endocrinologists guideline

SULFONYLUREAS AND TYPE 2 DIABETES MELLITUS

History

SUs have been a cornerstone in the T2DM management for the past 60 years. TOLB was the first SU marketed in the 1950s. This was followed by the introduction of the other first-generation agents such as CHOL, acetohexamide, and tolazamide. The next advancement in SU therapy was the development of potent second-generation agents such as GLIB and glipizide (GLIP) in the year 1984 in the United States. Furthermore, GLIM, a third-generation agent with eminent characteristics, was released into the market in the year 1995.[21,22,23] SUs with respect to their generation, history of development, duration of action, and other pharmacokinetic/pharmacodynamics profiles are described in Table 5.[5]

Table 5.

Sulfonylureas with respect to their generation, history of development, duration of action, and other pharmacokinetic/pharmacodynamic profile (adapted from)

Mechanism of action and differential effects of sulfonylureas

SUs have been categorized as insulin secretagogs. They act by stimulating the pancreatic β-cells to secrete insulin. SUs mainly bind to the SU receptors (SURs), a subunit of potassium ATP-dependent (K_ATP) channels located in the β-cell membrane, which eventually blocks the potassium channels and facilitates the influx Ca²⁺ into the cell. This leads to cell depolarization and subsequently accelerates insulin exocytosis [Figure 1a].[5,23] Furthermore, owing to their cell-mediated and nonglucose-mediated action, all SUs are more effective in the early stages of T2DM when the β-cell function is to its greatest ability.[11,24] All the SUs are eliminated by liver and kidney and well tolerated by adult patients; however, hypoglycemia and weight gain are the concerns with conventional SUs.[25,26]

Figure 1.

Mechanism of action of sulfonylureas. (a) General mechanism of action of all sulfonylureas. (b) Differential mechanism of action of gliclazide

The affinity of SUs varies with different SUR subunits present in K_ATP channels.[5] It is reported that GLIB blocks both SUR₁ (pancreatic β-cells) and SUR₂ (cardiac and skeletal muscles) subunits with similar affinity. The modern SU, GLIM, blocks SUR₁ and preferentially the sarcolemmal SUR₂ while sparing the mitochondrial SUR. A number of studies, however, have demonstrated that GLIM does not have a negative impact on cardiac function and has less effect on the electrical properties of the heart.[27,28] GLIC and TOLB selectively block only SUR₁ compared to SUR₂.[29,30] The affinity of SUR₁ protein toward sulfonyl moiety is 100–1000 folds more compared to SUR₂ protein.[31] Furthermore, GLIC is the only SU which does not bind to the Epac2 receptor [Figure 1b][5], a stimulating factor for insulin exocytosis, which may confer a lower risk of hypoglycemia.[5,32] Similarly, GLIM also confers a low rate of hypoglycemia and weight gain than conventional SUs due to its lower binding affinity (2–3 folds) and quick association and dissociation with SUR proteins.[33,34,35] Furthermore, SUs inhibit the mitochondrial K_ATP channels in cardiac myocytes, which contributes to impairment of ischemic preconditioning; however, GLIM does not exert this effect and preserves myocardial ischemic preconditioning.[5] Moreover, a lesser pancreatic overstimulation and resultant low hypoglycemia by GLIC could be due to the restoration of the early insulin peak in response to glucose stimulation and higher reversibility of binding of GLIC to the SUR1 of β-cell.[36] In addition, modern SUs also exhibit certain pleiotropic effects such as insulin clearance, glucagon secretion, insulin sensitization, anti-oxidative effect, angiogenesis, vascular health, and ischemic preconditioning.[5]

Summary of guidelines recommending SUs and combinations for the management of type 2 diabetes mellitus

The addition of SUs has been the gold standard combination therapy for decades in patients who fail to achieve target glycemic control with metformin monotherapy.[37] In addition, pertaining to their low cost and high efficacy, SUs are widely used as a second-line agent in different regions of the world for the management of diabetes. Moreover, modern SUs such as GLIM and GLIC MR are preferred over other SUs in diabetic patients due to low risk of hypoglycemia and CV neutrality.[36,38,39,40] A summary of guidelines recommending SUs in combination therapy for the management of T2DM in various countries is depicted in Table 6.

Table 6.

Summary of guidelines recommending sulfonylureas and combination for management of type 2 diabetes mellitus

SULFONYLUREAS AND COMBINATIONS IN THE MANAGEMENT OF TYPE 2 DIABETES MELLITUS

Sulfonylurea + metformin

Mechanism

A combination of two drugs with the complementary mechanism of action may help in addressing multiple etiologies of hyperglycemia in patients with T2DM.[5] Metformin has insulin-sensitizing properties. It facilitates insulin uptake by the peripheral tissues and enhances the glucose utilization in adipose and intestinal tissues. SUs increase the sensitivity of β-cells to glucose and facilitate endogenous secretion of insulin. Furthermore, both metformin and SUs may reduce hepatic glucose overproduction by decreasing hepatic gluconeogenesis and glycogenolysis; however, the relative contribution of gluconeogenesis and glycogenolysis by metformin remains controversial.[56,57] Moreover, SUs may inhibit secretion of glucagon from islet cells[58] and also stimulates glycogen synthesis in the liver.[57] Diagrammatic representation of the complementary mechanism is shown in Figure 2.

Figure 2.

Complementary mechanism of action of sulfonylurea-metformin combination therapy

Glycemic efficacy

The addition of SUs to ongoing metformin monotherapy has shown good glycemic control with acceptable safety and tolerability in numerous meta-analyses and RCTs.

Sulfonylureas add-on to metformin versus metformin monotherapy

A meta-analysis of 15 RCTs each lasting <1 year compared metformin monotherapy with the combination of metformin and SUs. All included studies favored the combination arm over monotherapy for glycemic efficacy with a pooled between-group difference of 0.9% (95% confidence interval [CI]: 0.7%–1.2%).[59] In another meta-analysis, when SU was added to oral medication, A1C was reduced by 1.62% (95% CI: 1.00, 2.24; I² = 94.1%) in the SU group than in the comparator group.[60] A placebo-controlled study by Ahren et al. with a duration lasting up to 104 weeks compared metformin (>1500 mg daily) with the combination of metformin (≥1500 mg daily) plus GLIM (up to 4 mg daily). The study showed a between-group difference in A1C of 0.63% at the end, favoring the combination arm.[61] In a randomized, open-label, parallel group, multicenter trial, GLIM/metformin FDC therapy provided significantly greater adjusted mean decreases in A1C (−1.2 vs. −0.8%, P < 0.0001) and fasting plasma glucose (FPG) (−35.7 vs. −18.6 mg/dL, P < 0.0001) compared with metformin uptitration. Furthermore, a significantly greater proportion of patients with GLIM/metformin FDC therapy achieved A1C <7% (74.7 vs. 46.6%, P < 0.0001) at the end of the study.[62] In a multicentric epidemiologic surveillance protocol of 60 days, patients (n = 759) with T2DM were prospectively prescribed 1–2 tablets of GLIC 60 mg + metformin 500 mg during the course of daily practice. The study reported that 62.5% of patients had achieved the primary outcome (FPG of 90–130 mg/dL) at the end of the study. Mean (95% CI) FPG (mg/dL) decreased from baseline by 48.7 (45.0–51.4) with 1 tablet, by 71.3 (66.0–76.6) with 1½ tablets, and by 86.3 (75.7–96.9) with 2 tablets. Furthermore, the frequency of hypoglycemia was reported as 0.7%.[63]

A summary of published RCTs comparing the combinations of different SUs and metformin with metformin monotherapy in the management of T2DM is summarized in Table 7.

Table 7.

Summary of randomized controlled trials evaluating different sulfonylureas in combination with metformin compared to metformin monotherapy

Sulfonylureas versus thiazolidinedione as add-on to metformin

Compared to add-on therapies with other OADs, SUs as an add-on to metformin have shown a favorable glycemic control in terms of significant A1C reduction. A meta-analysis comparing the outcomes of thiazolidinedione (TZD) and SUs, both add-ons to metformin, reported a pooled between-group difference in A1C of −0.06% (95% CI: −0.19%–0.06%).[59] Furthermore, a multicentric randomized, parallel group, open-label, forced titration study reported that GLIM therapy resulted in a more rapid decline in A1C levels at weeks 6, 12, and 20 in comparison to pioglitazone (P < 0.05) in patients with uncontrolled glycemic level with metformin. A target A1C ≤7% was reached faster in the GLIM group (median, 80–90 days vs. 140–150 days [P = 0.024]).[72] Evidence reported no significant difference in glycemic parameters between GLIC and pioglitazone when added in patients with uncontrolled glycemic level with metformin monotherapy.[73,74]

Sulfonylureas versus dipeptidyl peptidase 4inhibitor as add-on to metformin

SUs compared to dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4I) when added to metformin are associated with a significantly greater reduction in A1C from baseline to 12 weeks (mean difference [MD]: 0.21; 95% CI: 0.06, 0.35) but no significant difference at 52 and 104 weeks (MD: 0.06 and 0.02, respectively, 95% CI: −0.03, 0.15 and −0.13, 0.18 respectively).[75] Furthermore, accumulated evidence from 14 RCTs (n > 10,000) reported that SUs were associated with a larger decline in A1C compared to DPP-4I (weighted mean difference [WMD]: 0.08, 95% CI: 0.03, 0.14, P = 0.001).[76] Moreover, a systematic review and meta-analysis reported that GLIM was associated with a 12% greater reduction in A1C compared to DPP-4I (WMD: −0.12; 95% CI: −0.16, −0.07), with a clinically irrelevant weight difference between the treatment (2.1 kg).[77] A 52-week RCT comparing GLIC and vildagliptin as a second-line agent reported a noninferiority of vildagliptin, with a mean change from A1C (−0.85% ± 0.06 vs. −0.81% ± 0.06).[78] Another 52-week RCT also demonstrated noninferiority of saxagliptin versus GLIP; adjusted mean changes from baseline A1C were 0.74% versus 0.80%; the between-group difference was 0.06% (95% CI: −0.05, 0.16).[79] However, in a population-based cohort study in Denmark (4734 patients), A1C reduction with SUs as a second-line agent was better compared to that of DPP-4I (1.2% vs. 0.8%).[80]

Sulfonylureas versus sodium glucose co-transporter 2 inhibitor as add-on to metformin

In a meta-analysis, the combination of metformin plus an SU with the combination of metformin plus a sodium-glucose co-transporter 2 inhibitor (SGLT-2I) was compared. The results supported the combination of metformin plus an SGLT-2I for A1C reduction (pooled between-group difference in A1C of 0.17%; 95% CI: 0.14%–0.20%).[59] In EMPA-REG-H2HSU-trial, a noninferiority trend in terms of change of A1C has been reported with empagliflozin when compared to GLIM at 104 weeks.[81] Furthermore, in CANTATA-SU trial, no difference in glycemic control was observed with less dose of canagliflozin and GLIM (canagliflozin 100 mg vs. GLIM 6–8 mg [MD − 0.01%]).[82] Similarly a 52-week, double-blind, active-controlled, noninferiority RCT reported a statistically noninferiority in adjusted mean A1C reduction with dapagliflozin (−0.52%) and GLIP (−0.52%) in T2DM patients with inadequate glycemic control with metformin.[83]

Sulfonylureas versus glucagon-like peptide 1 analogs as add-on to metformin

The dose-dependent variability has been observed in terms of glycemic control between glucagon-like peptide-1 (GLP-1) analogs and SUs when added to metformin. A meta-analysis of several RCTs has found favorable outcomes with the combination of metformin plus SU despite submaximal doses of SUs being compared with maximal doses of daily exenatide (pooled between-group difference in A1C, −0.26%; 95% CI: −0.48%–0.03%).[59] In the LEAD-2 trial, liraglutide reported noninferiority in reduction of A1C compared to GLIM, both added on to metformin.[84] Similarly a 16-week RCT including patients from China, India, and South Korea reported that liraglutide 1.2 and 1.8 mg was noninferior to GLIM (mean A1C reduction: 1.36%, 1.45%, and 1.39%, respectively).[85] However, combination of metformin plus maximum dose of albiglutide (titrated to 50 mg weekly) compared to metformin plus submaximal dose of GLIM (titrated to 4 mg daily) favored the metformin plus albiglutide arm (A1C reduction, −0.9% vs. −0.3%) in HARMONY 3 trial.[61]

Sulfonylureas versus insulin as add-on to metformin

In DiaRegis registry (n = 3810), the addition of insulin reduced the A1C level more as compared to SU after the failure of metformin monotherapy in a duration of 2 years (−0.9 ± 2.0% vs. −0.6 ± 1.4%).[86]

Body weight

SU use is associated with weight gain, a secondary effect that also occurs with insulin, TZD, and glinides. Modern SUs such as GLIM and GLIC MR are associated with weight neutralizing/reducing effect compared to conventional SUs.[5] Furthermore, evidence suggests that GLIM may be the least in the class to endorse weight gain.[87,88] Nonetheless, weight gain associated with SUs may be due to improved utilization of consumed glucose and a subsequent reduction in glycosuria, thereby indicating reduction in glucotoxicity.[88]

An extra increment in body weight has been observed when SUs were added to ongoing metformin therapy.[59] When compared to TZD, a pooled mean between-group difference of 0.9 kg (95% CI: 0.4–1.3 kg) favored the combination of metformin plus SU.[59] Similarly, the addition of pioglitazone was associated with more weight gain (2.5 kg) than GLIC (1.2 kg) in patients with metformin.[89] Several meta-analyses and RCTs reported that metformin-SU combination was associated with more weight gain compared to metformin-DPP-4I combinations and metformin-SGLT-2I combinations; however, the difference was nonsignificant.[59,77] Zhang et al. reported that DPP-4I was associated with a reduction in body weight (WMD, −1.652 kg; 95% CI values here as –1.658, –1.646) compared to SUs.[90] Furthermore, in a 16-week prospective study, a variation of weight change has been observed between vildagliptin and GLIC (−0.3 kg vs. +1.4 kg, P = 0.048) after adding to metformin.[91] Similarly, in another trial, canagliflozin 100 and 300 mg and GLIM 6–8 mg/day were associated with −4.1%, −4.2%, and 0.9% reductions in body weight, respectively.[92] Furthermore, several RCTs reported a weight loss in patients with the combination of metformin and GLP-1 receptor agonists and weight gain in patients with the combination of metformin and SUs.[61,85,93,94] Compared to insulin, in BETA trial, addition of GLIM to metformin produced a less weight gain (mean between-group difference in weight of −1.7 kg, P = 0.02) in patients with T2DM.[95] In DiaRegis registry (n = 3810), the addition of insulin also reported increment of body weight from baseline as compared to SU after the failure of metformin monotherapy in a duration of 2 years (+0.8 ± 9.0 vs. −0.4 ± 4.8 kg).[86]

Safety and tolerability

Hypoglycemia is a primary clinical concern during the intensification of the antidiabetic regimen in patients with T2DM. The hypoglycemic potentials of SUs are different pertaining to their variable mode of action and pharmacokinetic and pharmacodynamic properties. Evidence suggests that modern SUs are associated with less risk of hypoglycemia compared to conventional SUs.[39,40,96,97] Furthermore, the European GUIDE (GlUcose control in type 2 diabetes: Diamicron MR vs. GLIM) study (n = 845) was the first double-blind, 27-week, parallel-group, large-scale, head-to-head study compared once-daily GLIC MR (maximum dose up to 120 mg) to once-daily GLIM (maximum dose up to 6 mg) either as monotherapy or in combination. Hypoglycemia occurred significantly lesser with GLIC MR compared to GLIM (3.7% vs. 8.9%, respectively, P = 0.003), though a higher number of patients reached A1C <6.5% with GLIM (17% vs. 2%) which may influence the hypoglycemic episodes. Moreover, no episodes of severe hypoglycemia were reported during the study in patients, reiterating the safety of both these modern SUs.[98] Kim et al. in their randomized, open-label, parallel group, multicentric study reported that patients with GLIM/metformin combination therapy experienced more hypoglycemia compared with metformin uptitration therapy (41% vs. 5.6%, P < 0.0001), but there was no serious hypoglycemia reported in any group.[62] In a 52-week RCT, patients taking GLIC or vildagliptin experienced similar incidence of any adverse events (~61%); however, GLIC patients had more serious adverse events (8.7% vs. 6.7%) and more vildagliptin patients discontinued as a result of an unsatisfactory effect (n = 22 vs. 13).[78]

Evidence shows an increase in hypoglycemia risk with SUs compared to other OADs when added to metformin monotherapy. The hypoglycemic risk, when compared with SUs, for TZD was as follows: pooled odds ratio (OR): 7.5; 95% CI: 4.0–13.8;[59] DPP-4I, risk ratio: 0.24, 95% CI: 0.21–0.27, P < 0.001;[76] and SGLT-2I, OR: 0.08 (95% CI: 0.03–0.17).[59] Furthermore, DPP-4I was associated with lower risk of total adverse events (Mantel–Haenszel odds ratio [MHOR]: 0.79; 95% CI: 0.72–0.87) and CV events (MHOR: 0.53; 95% CI: 0.32–0.87) compared with SUs.[90]

Several RCTs reported that the rate of genital and urinary tract infections was more common with SGLT-2I compared to SUs.[92,99] Furthermore, there were increased odds of genital infections for metformin plus SGLT-2I and differences in relative odds by gender were as follows: pooled OR: 5.2 (95% CI: 3.4–7.8) for women and pooled OR: 7.6 (95% CI: 4.0–14.4) for men.[59] Moreover, volume depletion was observed frequently with canagliflozin than GLIM.[92] Similarly, gastrointestinal events with liraglutide and exenatide[84,100] and diarrhea with albiglutide[61] were more commonly reported.

In a retrospective cohort study, 20,070 patients were newly treated with an SU, DPP-4I, or a TZD following metformin therapy failure. It was reported that the therapy failure at 1 year was 15% with SU, 23% with DPP-4I, and 8% with TZD.[101] Furthermore, multivariate analysis of the data showed that addition of a DPP-4I was associated with an increased risk of treatment failure (adjusted hazard ratio (aHR): 1.58; 95% CI: 1.48–1.68) compared to the SU group, while adding a TZD was associated with a adjusted hazard ratio (aHR: 0.45; 95% CI: 0.41–0.50).

Moreover, choice of drugs should be based on the risk of hypoglycemia in an individual patient; further details regarding this are provided in patient and dose selection sections in this article.

All-cause mortality and macrovascular complications

A meta-analysis including several RCTs demonstrated that SUs (GLIB, GLIP, GLIC, and GLIM) as an add-on to metformin were not associated with all-cause mortality (OR: 1.26; 95% CI: 0.94–1.68; I² = 0%) and CV mortality (OR: 1.40; 95% CI: 0.61–3.22; I² = 6%). Furthermore, among all SUs, GLIP was associated with increased all-cause and CV mortality, while the risk was least with GLIM (numerically, though did not achieve statistical significance).[38] Modern SUs show less CV mortality than conventional SUs due to more pancreatic selectivity action. A randomized, double-blind, crossover study of GLIC 80 mg twice daily and GLIM 2 mg once daily, each for 4 weeks as add-on therapy to metformin, found no evidence between SUR1-specific (GLIC) and nonspecific SU (GLIM) in differential effects on arterial distensibility, endothelial function, or vasodilator mechanisms.[102]

Metformin remains an ideal first-line agent and among the SUs, the relative safety of a GLIC makes it a preferred SU. In a population-based study on 107,806 patients from the Danish registry with a median follow-up of 3.3 years, Schramm et al. evaluated several mortality end points with different insulin secretagogs compared with metformin in patients with or without a previous history of myocardial infarction (MI).[103] The all-cause mortality was significantly higher with all SUs (GLIM: HR: 1.32, 95% CI: 1.24–1.40; GLIP: HR: 1.27, 95% CI: 1.17–1.38; and GLIB: HR: 1.19, 95% CI: 1.11–1.28) except GLIC (HR: 1.05, 95% CI: 0.94–1.16) in patients with a previous history of MI. Similar significant increase in all-cause mortality was observed with all SUs except GLIC in those with a previous history of MI. Furthermore, this was a retrospective study and therefore there is a likelihood of selection bias (patients on GLIM had a higher baseline risk and likely contributed to more morbidity and mortality). In another nationwide study on 202,272 Danish patients, GLIP, GLIB, GLIM, and TOLB appeared to be associated with an increased risk compared with GLIC when used in combination with metformin.[104]

When added to metformin, pioglitazone found to produce potential benefits in terms of improvements in specific lipid abnormalities compared to GLIC or GLIM.[74,89,105] Nonetheless, a single retrospective cohort study from a Veterans Affairs population with Medicare (n = 80,936) found a nonsignificant increase in the risk of stroke or MI (composite outcome) for SU-based versus TZD-based therapy: aHR: 1.15 (95% CI: 0.8–1.66; P = 0.46).[106]

The pooled OR from five RCTs on mortality between DPP-4I and SUs, when added on to metformin, was 0.64 (95% CI: 0.27–1.51).[59] In the Danish National Registry, combination therapies with incretin-based drugs and metformin were compared with a combination of metformin and SU in T2DM for all-cause mortality, CV mortality, and combined end point of MI, stroke, and CV mortality. By keeping metformin + SU as a reference, the study demonstrated a significantly decreased risk of death among metformin plus DPP-4I users (n = 11,138) with a relative risk (RR) of 0.65 (0.54–0.80) for mortality, 0.57 (0.40–0.80) for CV mortality, and 0.70 (0.57–0.85) for the combined end point. For metformin + GLP-1 receptor agonist, the RR for mortality was 0.77 (0.51–1.17), for CV mortality was 0.89 (0.47–1.68), and for the combined end point was 0.82 (0.55–1.21).[104] However, a meta-analysis suggested that long-term all-cause mortality (which was low [< 1%] across studies) was similar for metformin plus SGLT-2I and metformin plus SU (pooled OR: 0.86; 95% CI: 0.29–2.55).[59] Moreover, a significant reduction in urine albumin was observed in the metformin plus exenatide arm (37.97%) compared to the metformin plus GLIM arm (5.76%).[107]

Nonetheless, in a meta-analysis of 301 clinical trials which utilized the glucose-lowering drugs including metformin, SUs, TZD, DPP-4I, alpha-glucosidase inhibitor (AGI), SGLT-2I, GLP-1 receptor agonists, meglitinides, and insulin either alone or in combination suggested no significant difference in the risk of CV mortality between the antidiabetic drugs.[108]

A summary of landmark trials comparing outcomes of SUs with other antidiabetic drugs as add-on therapy is summarized in Table 8.

Table 8.

Summary of landmark trials comparing outcomes of sulfonylureas in combination with other antidiabetic drugs

Sulfonylurea + other oral antidiabetic drugs

Mechanism

In patients with inadequate glycemic control on SUs, there are a number of OADs available which can be used in combination with an SU. However, the choice of therapy should be individualized based on patient characteristics, preferences, and cost. TZDs decrease insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Thus, the combination of SUs and TZD may be beneficial for supporting each other in T2DM.

DPP-4 inhibitors elevate cellular cyclic adenosine monophosphate (cAMP) levels in pancreatic β-cells, leading to potentiated insulin secretion. SUs mimic the glucose-induced K_ATP channel-dependent pathway. Therefore, an increase in cAMP induced by incretin therapy potentiates K_ATP channel-independent insulinotropic action by glucose.[111,112,113] Therefore, SUs and DPP-4I may be an effective combination for supporting inappropriate insulin secretion in T2DM; however, careful consideration is required when initiated in the elderly and/or patients with renal insufficiency.[113]

Glycemic efficacy

A combination therapy with SU and TZD resulted in remarkable glycemic control when compared to each monotherapy. A randomized, double-blind, placebo-controlled, multicentric study comparing the efficacy of add-on of GLIM to on-going rosiglitazone reported that combination therapy with GLIM produced greater reductions in A1C (mean [standard error (SE)]: −1.2% [0.1%] vs. −0.3% [02%]; P < 0.001) and FPG (mean [SE]: −24.4 [6.0] mg/dL vs. 5.9 [8.0] mg/dL; P < 0.006).[114] Similarly a 28-week, double-blind, parallel-group RCT revealed that GLIM/rosiglitazone FDC significantly reduced A1C (2.5 ± 1.4%) than rosiglitazone (1.8 ± 1.5%) or GLIM (1.7 ± 1.4%) monotherapy (model-adjusted mean treatment difference, P < 0.0001 vs. both rosiglitazone and GLIM).[115] Evidence suggests that treatment with a combination of pioglitazone and SUs provided extensive glycemic control as compared to baseline glycemic level; however, no significant difference was found when compared to metformin and SU-based combinations.[89,109,116]

In a multicentric, prospective, randomized, open-label study, patients who had an uncontrolled glycemic level with sitagliptin and low-dose GLIM were randomized to receive uptitration with either sitagliptin or GLIM. There was no significant difference in the A1C-lowering effects between the two groups. However, a significant A1C-lowering effect from baseline of GLIM uptitration was found (P < 0.01 vs. baseline).[117] Furthermore in a 52-week, prospective, single-arm study, sitagliptin and low dose GLIC or GLIM also reduced A1C by −0.80% (95% CI: −0.90 to −0.68) (P < 0.001) from baseline.[118]

In conditions where dual therapy failed to obtain optimal glycemic control, the addition of a third agent (SUs) could be helpful in achieving glycemic targets. GLIM as an add-on to metformin and TZD resulted in significant improvement in A1C level (mean [SE]: −1.31% [0.08] vs. −0.33% [0.08], respectively; P < 0.001) from baseline with more patients achieving target A1C ≤ 7% compared with metformin and TZD combination (62.2% vs. 26.0%, P < 0.001).[119] Evidence suggests that GLIM strongly enhances the glucose-lowering effect in triple oral antidiabetic therapy with sitagliptin and metformin for patients with T2DM.[120]

A systematic review and network meta-analysis evaluated the efficacy of triple therapy regimen for T2DM. The study included SUs in all combinations except one (MET + TZD + DPP-4I). For A1C reduction, all triple therapies were statistically superior to MET + SU dual therapy. However, none of the triple therapy combinations demonstrated differences in A1C compared with other triple therapies.[121]

Body weight

In a randomized, double-blind, placebo-controlled, multicentric study at the end of the 1^st year, GLIM with pioglitazone (4.9%) and GLIM with rosiglitazone (6.2%) treatment groups had significant increases from baseline in body mass index (BMI) (P < 0.05).[122] Furthermore, when added to GLIC, pioglitazone resulted in an increment of body weight in comparison to metformin (3.7 vs.−1.7 kg).[89] However, in a 52-week, prospective, single-arm study, sitagliptin and low-dose GLIC or GLIM reduced BMI by −0.38 kg/m² (95% CI:−0.72, –0.04) (P < 0.05) from baseline.[118]

In a prospective observational study, no change in body weight (69.6 ± 3.0–69.1 ± 2.9 kg in the low-dose group and 62.1 ± 2.6–61.9 ± 3.0 kg in the high-dose group; P > 0.05 for both groups) was observed in patients taking combination of 50 mg/day sitagliptin and low-dose GLIM (2 or 3 mg decreased to 1 mg: n = 15) compared to high-dose GLIM (4 or 6 mg decreased to 1 mg).[111]

Safety and tolerability

Evidence suggests that the combination regimens of SU and TZD were well tolerated by the patients with no significant difference in adverse effects with the comparators.[114,115,122,123]

Furthermore, no hypoglycemic episodes were reported by various studies assessing the efficacy of sitagliptin and SU combinations.[111,124] Moreover, several studies reported that the combination treatments with sitagliptin and SU were safe and well tolerated in patients with T2DM.[111,117,118]

In a 30-week, randomized, double-blind, placebo-controlled, parallel-group study, the risk of hypoglycemia (51.2% vs. 8.3%, P < 0.001) was greater with GLIM add-on to metformin-TZD than placebo.[119] Similarly, in EUREXA trial, the ratio of documented symptomatic (blood glucose ≤70 mg/dl [3.9 mmol/L]) hypoglycemic rates for add-on GLIM to add-on TZD was 8.48 (P < 0.0001).[125]

All-cause mortality and macrovascular complications

The increase of lipid risk factors for CV diseases (CVDs) from baseline was more significant in GLIM-rosiglitazone patients compared to GLIM-pioglitazone patients.[122,126] In an Indian RCT, FDC containing GLIM (2 mg), pioglitazone (15 mg), and metformin sustained release (500 mg) significantly reduced the levels of triglyceride, low-density lipoprotein cholesterol, and total cholesterol.[127]

A summary of published RCTs comparing combinations of SUs and other OADs in the management of T2DM is shown in Table 9.

Table 9.

A summary of published randomized controlled trials comparing sulfonylureas and other oral antidiabetic drugs in the management of type 2 diabetes mellitus

Sulfonylurea + insulin

Mechanism

SUs when added to insulin increase endogenous insulin secretion and possibly exert some extra pancreatic actions on muscle and liver, thereby improving glycemic control and decreasing daily insulin requirements.[128] A subset of T2DM patients who are mild to moderately obese, have adequate endogenous insulin secretory reserve, and are in poor glycemic regulation (A1C >10%), despite twice-daily insulin administration, may show significant improvement in glycemic regulation and/or decrease in insulin daily dose of insulin-SU therapy.[129] Evidence suggests that addition of SUs to insulin in patients with uncontrolled glycemic levels reduces the insulin dose by 20%–30% and avoids hypoglycemia.[130] Therefore, studies have compared the treatments with a smaller insulin dose with SU and a larger insulin dose without SU. A summary of published RCTs comparing combinations of SUs and insulin in the management of T2DM is shown in Table 10.

Table 10.

A summary of published randomized controlled trials comparing sulfonylureas and insulin in the management of type 2 diabetes mellitus

Glycemic efficacy

In a Cochrane systematic review including nine trials (316 patients), insulin-SU combination therapy compared with insulin monotherapy was associated with a reduction of A1C; MD of −1% (95% CI: −1.6 to −0.5; P < 0.01). However, insulin-metformin (−0.9%), insulin-AGIs (−0.4%), and insulin-DPP4I (−0.4%) combinations had revealed a less significant change in A1C compared to insulin-SU combination therapy.[138] Furthermore, a meta-analysis comprising 17 RCTs reported a significantly lower A1C in SU groups (in combination with insulin) compared with placebo (0.46% lower; 95% CI: 0.24, 0.69, I² = 43.6%).[60] Moreover, another meta-analysis also found favorable outcomes with insulin-SU combination therapy in terms of glycemic control compared to insulin monotherapy (P < 0.0001).[139]

Past studies show that approximately half of the patients attain A1C <7% with dual insulin therapy whereas patients taking insulin alone met goals only one-third of the time.[133,134,140,141,142] Yki-Järvinen et al. determined that a basal insulin regimen containing GLIM decreased total daily insulin requirements by approximately one-third.[143] A combination of once-daily basal insulin with an SU versus monotherapy with premixed insulin has proven to decrease total insulin dose by the same factor.[133,143]

A Korean RCT after 24 weeks of observation period reported a pronounced reduction of A1C with the addition of GLIM to insulin glargine and metformin than insulin glargine plus metformin (0.49% [95% CI: 0.16%–0.82%], P = 0.005).[136]

In “4-T” trial, patients with uncontrolled glycemic level with SUs and metformin were randomized to receive twice-daily biphasic insulin aspart 30 or thrice-daily prandial insulin aspart, or once-daily (twice if required) basal insulin detemir. After 1-year follow-up, the mean reduction in A1C was significantly greater in the biphasic (1.3%) and prandial groups (1.4%) than in the basal group (0.8%).[144] However, after 3 years, basal or prandial insulin-based regimen had better A1C control than biphasic insulin-based regimen.[145]

Safety tolerability and body weight

The combination of insulin and SU results in a reduction of necessary insulin dose per day.[60,138] However, most studies adding SUs to insulin reported milder hypoglycemic episodes versus insulin monotherapy (range: 2.2–6.1 vs. 2.0–2.6 episodes per participant).[138] The addition of SUs into insulin monotherapy resulted in an additional weight gain of 0.4 to 1.9 kg versus −0.8 to 2.1 kg in the insulin monotherapy group.[138] However, no change in body weight was observed by addition of SUs to insulin in several older RCTs.[146,147]

ROLE OF SULFONYLUREAS IN COMBINATION

Cost

Medication cost always plays a significant role in the management of any disease in underdeveloped and developing countries, as it directly affects the drug utilization and patient compliance. Patients without any medical insurance and below the poverty line encounter numerous challenges for the use of expensive medicines in the management of T2DM. A study revealed that the medication cost for diabetes was USD 138 per patient per year which is equivalent to 8.1% of the total budgeted health expenditure for that financial year in sub-Saharan Africa.[148] However, SUs are associated with a significantly lower cost per quality-adjusted-life-years (QALYs) and result in the longest time to insulin dependence.[149] Sensitivity analysis on the medication cost reported the difference in the expected medication cost per QALY from the base-case cost; metformin costs 81.75 USD/month, SU costs 54.85 USD/month, DPP-4I costs 232.84 USD/month, GLP-1 receptor agonist costs 325.97 USD/month, and insulin therapy costs 245.70 USD/month.[149] This cost comparison indicates that SUs should be preferred as an add-on to metformin if the choice of drug is based on cost.[19] Furthermore, FDC users on an average had higher out-of-pocket costs for their prescriptions and had a less restricted heath plan.[150] In summary, lower cost without compromising the glycemic efficacy and tolerability could make SUs the prime choice of treatment of T2DM.

Adherence

Medication compliance is directly related to the cost, availability, dosage regimen, and complications associated with the treatment.[151,152] In the current scenario, FDCs increase the patient compliance by reducing the frequency of drug administration and cost of the medication. Pan F et al. reported that the FDC of metformin-glyburide resulted in 13% increase in patient adherence (P < 0.001) compared to the 2-pill regimen.[150] Similarly, a meta-analysis also reported that FDC decreases the risk of medication noncompliance, improves clinical outcomes, and should be considered in patients with chronic conditions.[153]

Fixed-dose combinations

Combining two or three antihyperglycemic agents with complementary mechanisms of action is a cornerstone of T2DM management.[154] Apart from that, low-dose combination therapy compared to high-dose monotherapy might exhibit lesser side effects and can achieve similar or better glycemic control.[155] Furthermore, FDCs reduce number, frequency, and flexibility of dosage administration and minimize the treatment complexity, thereby improving patient adherence.[156] In a meta-analysis, use of FDCs with antihyperglycemic agents was associated with lower A1C and higher mean possession ratio values compared to dual therapies in patients with T2DM.[157] Furthermore, a systematic review suggested that T2DM patients treated with FDC therapy may have better adherence, improved satisfaction, and lower direct medical costs, compared to those treated with loose pill combination therapy.[158] A list of available SUs either individually or in FDCs with their strength, dose, and required dose titration is summarized in Table 11.

Table 11.

A list of sulfonylurea monotherapy and fixed-dose combinations of sulfonylureas with available strength, recommended dose, and dose titration

SPECIAL SITUATIONS

Elderly

SUs are usually well tolerated; however, mild hypoglycemia has been reported with long-acting SUs (e.g., CHOL, glyburide,).[128] For older patients who have persistent hyperglycemia with lifestyle intervention and metformin, the addition of a short-acting SU such as GLIP is a preferred option. A double-blind randomized and open-label comparative study after 2 years of treatment concluded that GLIC MR in combination with other OADs significantly improved glycemic control in the elderly and renal-impaired T2DM patients with a very good safety profile.[159] A recent review evaluated the comparative safety and efficacy of commonly available SUs (GLIB, GLIC, GLIM, and GLIP) for the management of T2DM in older patients.[160] The study reported that GLIC can be used in older patients due to its low risk of hypoglycemia; however, it is suggested to restrict the use of GLIB in such populations. Furthermore, several guidelines including IDF and Canadian guidelines also recommend modern SUs (GLIC MR and GLIM) as a drug of choice for elder T2DM patients.[161,162] In GENERATION trial, a similar proportion of patients achieved the primary end point of A1C <7.0% at week 52 without confirmed/severe hypoglycemia with saxagliptin compared to GLIM when added to metformin (37.9% vs. 38.2%; OR: 0.99, 95% CI: 0.73, 1.34; P = 0.9415). However, it is noteworthy that saxagliptin was numerically (but not significantly) inferior for patients aged ≥75 years (35.9% vs. 45.5%).[110]

Children and adolescents

The evidence on the use of SUs in children is limited.[163] A 26-week, single-blind, active-controlled study, conducted in 285 pediatric patients with T2DM, found that GLIM was as effective as metformin in A1C reduction (−0.54%, P = 0.001 and −0.71%, P = 0.0002, respectively) with similar rates of hypoglycemia (4.9% vs. 4.2%, respectively).[164] Furthermore, a prospective trial evaluated the effect of SUs (mainly CHOL) in patients with Maturity-Onset Diabetes of the Young (MODY) patients with 9–29 years of age and found that long-term administration of SUs significantly enhanced glucose-induced insulin concentrations by approximately 68%.[165] Evidence and guidelines suggested that SUs are the drug of choice for the treatment of MODY.[166,167,168] Neonatal diabetes mellitus (NDM) is generally caused by several genetic abnormalities and might be either permanent or transient. In patients with NDM, SUs facilitate insulin secretion through the hormone GLP-1 pathway in response to food present in the gut. Evidence suggests that patients with permanent or transient NDM due to mutations in KCNJ11 or ABCC8 gene were successfully treated with SU (GLIB) therapy rather than insulin.[169,170,171,172] An observational case study reported that young children with neonatal diabetes even with blood glucose level of 350 mg/dL also responded to a usual dose of SU.[173]

Pregnancy and lactation

Second-generation SUs such as GLIB despite low molecular weight do not cross the placenta in significant amounts.[174] This phenomenon may be attributed either to its high protein-binding capacity (99.8%) or reverting the total GLIB content into the maternal system by an unidentified placental transport system. Furthermore, the absence of fetal adverse effects such as malformations and hypoglycemia makes GLIB an acceptable treatment option for patients with T2DM during pregnancy.[174,175] In a meta-analysis including one RCT from India, the outcomes of GLIB, metformin, and insulin were assessed. The study reported similar rate of cesarean delivery (range: 23%–52%) and infant birth weights (MD: −93 g, 95% CI: −191 to 5 g), with no significant difference in maternal glycemic control between the treatments.[176] Furthermore, a systemic review and meta-analysis reported no significant difference in terms of glycemic control or pregnancy outcomes between GLIB and insulin when used during pregnancy.[177] Moreover, in a meta-analysis, no significant difference was observed in the rate of neonatal major abnormality or neonatal death among women treated with GLIB-metformin compared with nonexposed women during first trimester; however, the study was limited by heterogeneity.[178] Nonetheless, long-term efficacy studies of GLIB during pregnancy and lactation are limited.[175] GLIB compared to metformin was more effective in lowering blood glucose in women with gestational diabetes with a lower treatment failure rate.[175] Moreover, there are some contradicting results from other studies and the paucity of data regarding the usage of SU combination therapy available during pregnancy and lactation.

Patients with comorbidity

Patients with diabetes are always at an increased risk of developing CVD. The risk of stroke, heart disease, and death due to heart disease is 2 folds high in patients with diabetes than in those without diabetes. Newer-generation SUs such as GLIM and GLIC MR reduce CV risk and may prevent protective ischemic cardiac preconditioning after MI.[179] In the ADVANCE trial, intensive glucose control with a GLIC-containing regimen has been shown to reduce the incidence of combined major macro- and microvascular events (18.1% vs. 20.0% with standard control; HR: 0.90; 95% CI: 0.82–0.98; P = 0.01), as well as that of major microvascular events (9.4% vs. 10.9%; HR: 0.86; 95% CI: 0.77–0.97; P = 0.01).[17] Similarly, the Veterans Affairs Diabetes Trial including 1791 military veterans (median follow-up: 5.6 years) reported that GLIM-based intensive regimen was associated with a 17% relative risk reduction in the rate of CV events compared to standard therapy.[13] Moreover, a recent meta-analysis demonstrates that SUs are not associated with increased risk for all-cause mortality, CV mortality, MI, or stroke.[38]

SUs such as GLIP and GLIC are mainly excreted as unchanged drug or inactive metabolite. Therefore, they may produce less hypoglycemia in patients with renal impairment. GLIM has been reported to be safe and effective in diabetic patients with renal impairment.[180,181] However, GLIB may aggravate the risk of hypoglycemia in such populations.[182] Short-acting SUs such as GLIC and GLIP can be used with proper dose adjustment and monitoring in patients with renal insufficiency.[5] An RCT reported that in patients with chronic renal insufficiency, sitagliptin and GLIP provided similar A1C-lowering efficacy, and GLIP produced more hypoglycemia and weight gain than sitagliptin.[183] Furthermore, SUs should be cautiously used in patients with liver diseases, as most of the SUs are inactivated in the liver, they might accumulate in the body during liver dysfunction, and ultimately cause hypoglycemia. Moreover, in hypoalbuminemia, the concentration of free drug will increase and may produce hypoglycemia.[5,184] SUs with a short half-life such as GLIP or GLIB are preferred in liver disease patients. Patients with decompensated cirrhosis, i.e., encephalopathy, ascites, or coagulopathy, may have a reduced ability to counteract hypoglycemia, and thus, the response to therapy should be monitored closely.[185]

Diabetes and Ramadan

Patients who are continuing antidiabetic medications and undergoing fasting during Ramadan may encounter several difficulties such as hypoglycemia and other health-related complications.[5] Due to the increased risk of hypoglycemia, individuals with SUs should be careful during fasting period; however, some modern SUs (GLIC, GLIM, and GLIP) are associated with lower risk of hypoglycemia compared to GLIB.[96] The recent IDF-DAR practical guideline advocates that patients continuing second-generation SUs can fast safely during Ramadan.[186] The Glimepiride in Ramadan study reported that the efficacy and safety of GLIM have remained unchanged during the period of Ramadan in patients with T2DM.[187] In the STEADFAST study, there was no significant difference reported in hypoglycemic episodes between vildagliptin and GLIC (both add-ons to metformin) (P = 0.039).[188] Similarly, in Treat 4 Ramadan Trial, liraglutide compared to SUs (both add-ons to metformin) did not reveal any episodes of severe hypoglycemia in either group.[189] Table 12 summarizes the efficacy and safety of SU combination therapy during Ramadan. Incretin-based therapies such as DPP-4I and GLP-1 receptor agonist work by increasing insulin secretion in a glucose-dependent manner; therefore, they may not produce any risk of hypoglycemia. However, they may amplify the hypoglycemic effect of SUs when used in combination.[193] Studies conducted during Ramadan found higher hypoglycemic episodes with SUs compared to DPP-4I; however, subgroup analysis found GLIC having least hypoglycemic episodes among all SUs, almost similar to DPP-4I.[36,192]

Table 12.

Summary of randomized controlled trials comparing sulfonylureas versus other drugs as add on to metformin during Ramadan

Diabetes and other fasting

Fasting is a universal religiocultural tradition observed in varying forms, in different religions across the world. Hindus observe fasting during Navaratri, Karva Chauth, and Guru Purnima; Buddhists observe during Lent; Jains observe in the occasion of Paryushana.[194,195,196] In the diabeto-centric viewpoint, patients taking antidiabetic agents should be monitored regularly for the event of hypoglycemia and other associated complications. Furthermore, the antidiabetic dose should be modified or omitted during the fasting period in order to prevent future complications. The dose modification or omission should be tailored according to the type of medication, food plan, and patient characteristics. Long-acting SUs such as GLIB should not be used; however, modern SUs with low tendency of hypoglycemia such as GLIM and GLIC MR can be considered with dose reduction.[194,195,196] In addition, patients with diabetes and who are undergoing fasting should be educated properly for the daily blood glucose monitoring and about hypoglycemic symptoms in order to maintain a safe fasting during rituals.

TRANSFORMING EVIDENCE INTO CLINICAL PRACTICE

Patient selection

Selection of patient plays a vital role in optimizing the SU combination therapy. Combination therapies should be introduced early in all patients with T2DM for preserving β-cell functions. The initiation of combination therapy depends on the individual patients’ A1C at entry level. Modern SUs can be used in both obese and lean patients owing to the low risk of weight gain.[5] SUs should be cautiously used in the elderly patients and in patients at high risk of hypoglycemia.[32,34] In addition, patients with T2DM using SU combination therapy who wish to go for fasting should be closely monitored during this period to avoid further complications.[5]

Drug selection

All SUs are not similar in terms of their efficacies, adverse effects, and tolerability. Clinical factors such as levels of fasting, postprandial hyperglycemia, comorbid hypertension or other CVDs, and hepatic or renal dysfunction determine the selection of SU combination therapy.[5] Shortacting SUs should be preferred in the case of postprandial hyperglycemia; however, twice-daily SU in combination with metformin should be preferred in fasting hyperglycemia.[197,198,199] Combining two different SUs is not logical as they have a similar mechanism of action but SUs may be combined with other OADs such as metformin and TZD (with the complementary mechanism of actions), and even with insulin.[5] Patients taking a combination of SUs with incretin-based therapy should be under vigilant monitoring due to the risk of hypoglycemia.[193] FDCs containing SUs should be preferred over combination regimens.

Dose selection

Dose adjustment or modification is inevitable in T2DM patients with the comorbid conditions. Dose selection for FDCs containing SUs should be done as per individual patient characteristics and properties of SUs.[5] The South Asian Federation of Endocrine Societies consensus recommends initiation of SUs at low doses and uptitrating them gradually based on the glycemic responses to prevent hypoglycemia, but when hypoglycemic episodes are confirmed, reduction of dose should be considered.[113] The consensus also recommends educating the patients and family members about the signs and symptoms of hypoglycemia.[5] When using combination therapy containing SUs and incretin-based therapies, the dose of SUs should be reduced in the elderly and/or patients with renal insufficiency.

Diabetes education and patient and physician empowerment

Due to chronic nature of the disease, diabetes necessitates self-management plan in day-to-day basis.[200] Diabetic education enables the patients to make informed decisions and effectively manage the disease without any complications. Diabetic education, which gives information on physical activity, glucose monitoring, diet, hypoglycemia, dosage and timing of medications, and identification of the symptoms of complications, should be provided to patients and their families. Patients should be encouraged and supported to become active partners in the decision-making process, to set realistic goals, select appropriate management strategies, enhance adherence, and improve treatment outcomes.[5] Self-monitoring of blood glucose (SMBG) at home and self-down titration of doses in case of hypoglycemia by patients are recommended. The patient should be trained for the safe use of FDC containing SUs and should be able to detect the hypoglycemic complications. Furthermore, patients along with their family members should be educated about the usage of SMBG system. When FDCs containing SUs are prescribed, physicians should consider the clinical profile of the patient and implement strategies that will not only help to minimize patient's concerns over SUs treatment but also empower them for self-management. At each visit, physicians should look into symptoms suggestive of hypoglycemia and adjust doses accordingly when risks outweigh glycemic benefits.

CONCLUSION

Intensification of diabetic therapy with a proactive approach is crucial to achieve target glycemic levels. SUs are an important component of pharmacological armamentarium in the treatment of T2DM. Owing to their well-established efficacy and safety profile, they are the most commonly recommended class of agents when glycemic targets are not achieved with metformin alone. Owing to their disparity in pharmacokinetic and pharmacodynamic profile, which results in variability in safety and tolerability, the selection of SUs should be highly individualized with careful monitoring in high-risk patients. Due to their unique characteristics such as increased efficacy, CV safety, fewer episodes of hypoglycemia, and weight-neutralizing effects, modern SUs should be used over conventional SUs in the management of T2DM. Lower treatment cost without compromising the glycemic efficacy and tolerability together with good compliance rate positions SUs as the front-line agent in the management of T2DM. In addition, the complementary mechanisms of action of GLIM and metformin contribute to their enhanced glycemic effects. Appropriate patient selection, suitable drug and dose, along with proper patient and physician education may help in the effective and vigilant use of SUs in the management of T2DM.

Financial support and sponsorship

This study was funded by Sanofi Diabetes India.

Conflicts of interest

There are no conflicts of interest.