Introduction
Methods
Results
Glucocrinology: Concept of Interplay and Interlink of Glucose Homeostasis and Endocrine Glands
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Acromegaly
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Cushing syndrome
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Pheochromocytoma
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Hyperthyroidism
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Hyperaldosteronism
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Hyperparathyroidism
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Polycystic ovary syndrome
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Hypothyroidism
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Subclinical Cushing syndrome
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Autoimmune polyglandular syndromes
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Multiple endocrine neoplasia
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Mitochondrial disorders
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Hyperthyroidism
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Cushing syndrome
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Acromegaly
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Adrenal insufficiency
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Hypothyroidism
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Growth hormone deficiency
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Glucocorticoids
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Thyroid hormones
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Inotropes
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Growth hormone
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Estrogen
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Somatostatin analogs
Sulfonylureas: An Established Treatment of DM
Classification of SUs
Mechanism of Action
Indications of SUs
Reduced Risk of Hypoglycemia with Modern SUs
American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) Recommendations for SUs in T2DM Management
Hidden Facets of SUs
Hidden Pleiotropic Effects of Modern SUs
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Human chorionic gonadotropin-induced testosterone secretion by Leydig cells is inversely related to insulin sensitivity among men with varying degrees of glucose tolerance. Thus, the lesions resulting in hypogonadism in obesity and T2DM may occur at several levels of the hypothalamic–pituitary–gonadal axis. However, the absence of an increase in gonadotropin concentrations indicates that the primary defect in T2DM and obesity is at the hypothalamo-hypophyseal level.
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A study evaluated the impact of sulfonylurea as an initial treatment for hypogonadism in T2DM patients. In the study, the initial dose of oral glimepiride was 1 mg/day and the dose was titrated according to blood glucose levels for 16 weeks. Results indicated that as compared with the healthy control group, the middle-aged men with type 2 diabetes had significantly decreased total testosterone levels and a lower testosterone secretion index.
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Another modern SU, gliclazide, has also been associated with reduced risk of hypoglycemic episodes and long-term cardiovascular safety when compared with other OADs in the treatment of DM [12].
Key recommendations | Evidence and/or rationale |
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Modern SUs (such as glimepiride and gliclazide MR) should be preferred to conventional SUs especially in | Low rate of hypoglycemia and weight gain conferred by modern SUs as compared to conventional SUs could be attributed to its lower binding affinity (2–3 fold) and quick association and dissociation with sulfonylurea receptor (SUR proteins). Conventional SUs inhibit the mitochondrial KATP channels in cardiac myocytes, which contributes to impairment of ischemic preconditioning; however, modern SUs do not exert this effect and preserve myocardial ischemic preconditioning [13] |
Overweight/obese T2DM patients | |
Patients at a high risk of hypoglycemia | |
Patients at a high risk of CV diseases | |
Modern SUs (such as glimeperide and gliclazide MR) should be preferred to conventional SUs with the aim to reduce mortality, bring better outcomes, and preserve renal function | A meta-analysis of randomized clinical trials conducted by Varvaki Rados et al. [14] evaluated the association between SU use and all-cause and cardiovascular mortality in patients with T2DM. Sulfonylureas were not associated with all-cause (OR 1.12 [95% CI 0.96–1.30]) or cardiovascular mortality (OR 1.12 [95% CI 0.87–1.42]) Modern SUs exhibit several extra-pancreatic effects, apart from glycemic control, and thereby contribute to better clinical outcomes [1] Modern SUs are mainly excreted as unchanged drug or inactive metabolite. Therefore, they may produce less hypoglycemia in patients with renal impairment. Glimepiride has been reported to be safe and effective in diabetic patients with renal impairment [1] |
The panel suggests that the patients/family members should be educated on the appropriate use (dose, time, route, and adherence) of modern SUs | Self-management plan on a day-to-day basis is very important in management of diabetes mellitus. Diabetic education enables the patients to effectively manage the disease without any complications. 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 in the safe use of fixed-dose combination (FDC) containing SUs and should be able to detect the hypoglycemic complications. Therefore, patients along with their family members should be educated about the usage of SMBG systems [1] |
The expert group addressed the safety issues of conventional SUs. Conventional SUs may cause hypoglycemia and weight gain in most patients with T2DM. Additionally, older SUs are believed to increase β-cell apoptosis, risk of ischemic complications, and thereby result in non-fatal CV outcomes and all-cause mortality | A prospective study conducted by Lee and Chou [15] determined the impact of administration of different SUs on cardioprotective effects in T2DM patients undergoing coronary angioplasty. Nondiabetic patients treated with glimepiride had a significantly lowered ischemic burden (assessed by an ST-segment shift, chest pain score [3.4 ± 0.9 vs. 5.5 ± 1.5; p = 0.02], and myocardial lactate extraction ratios [− 59 ± 21% vs. − 26 ± 16% in non-diabetics; p = 0.007]) compared with glibenclamide-treated patients, demonstrating that acute administration of glimepiride does not abolish cardioprotection |
The pleiotropic effects of modern SUs, including beneficial effects on the pancreas, extra-pancreatic effects, immunomodulatory effects, and other effects on endocrine functions, were reinforced in the meeting | Sulfonylureas (SUs) exhibit several extra-pancreatic effects, apart from glycemic control, including inhibition of metabolic clearance rate of insulin, inhibition of glucagon secretion from pancreatic α-cells, insulin sensitization, increases adiponectin levels, exerts antioxidative and anti-angiogenetic effects, and preserves ischemic preconditioning [1] |
Cardiovascular Effects of SUs
Cardiovascular Phenotype
Definition of Cardiovascular Phenotype
Cardiovascular Phenotype in Diabetes
The Clinical Expert Group Endorsed Newer SUs Because of CV Safety
Influence of Cardiovascular Phenotype on OAD Choice
OAD Choice and (Risk of) Heart Failure
Effect of Metformin Therapy on Prognosis of Patients with HF and New-Onset DM
Increase in Risk of Hospitalizations for HF in Patients Treated with Saxagliptin: Reports from the SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes) Trial
Addition of Sitagliptin to Usual Care is Not Associated with an Increased Risk of Hospitalization for HF: Data from the (Trial Evaluating Cardiovascular Outcome with Sitagliptin) TECOS Study
Reduction in Hospitalization for HF with Empagliflozin: Reports from the (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial) EMPA-REG OUTCOME Trial
Increased Incidence of HF in DM Patients Treated with Pioglitazone: PROactive Study
Reduction in Risk of Cardiovascular Death or Hospitalized HF in DM Patients Treated with Canagliflozin: Results from the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program
Efficacy and Safety of Dapagliflozin in Patients with T2DM and Concomitant HF
OAD Choice and Risk of Myocardial Infarction
Non-statistical Trend in Reduction of Non-fatal Myocardial Infarction: Results from CV Safety Outcome Trials (CVSOTs)
Glimepiride Was Associated with Reduced Mortality Rates in DM Patients with CAD
OAD Choice and Risk of Stroke
OADs with Neutral Outcome on Non-fatal Stroke: Evidence from CVSOTs
Pioglitazone Reduces Stroke in DM Patients
Cardiovascular Safety of Modern SU Gliclazide: ADVANCE Study
Ongoing CVOTs for SUs: The CAROLINA Trial
Key recommendations | Evidence and/or rationale |
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Modern SUs (such as glimepiride) are found to maintain myocardial ischemic preconditioning with fewer CV side effects as compared to conventional SUs | A preclinical trial conducted by Mocanu et al. [10] compared the effect of glimepiride vs. glibenclamide on ischemic preconditioning (IP) protection and the protection afforded by diazoxide, an opener of mitochondrial KATP channels. The protective actions of IP or diazoxide were not eliminated by glimepiride; however, glibenclamide eliminated the infarct-limiting effects of IP and diazoxide |
Use of OADs in HF patients should be considered on the basis of the stages of HF | Patients with diabetes mellitus are at increased risk of developing heart failure because of the abnormal cardiac handling of glucose and free fatty acids (FFAs), and also due to the effect of the metabolic derangements of diabetes on the cardiovascular system. The metabolic risk of diabetes in heart failure is increased by the effect of most OADs, as the use of certain antidiabetic agents increases the risk of mortality and hospitalization for heart failure both in patients with and without heart failure. Therefore it is important to use OADs on the basis of the stage of HF [31] |
Strong suggestion for avoidance of metformin use in patients with acute stroke was proposed. However, it was decided that metformin could be considered for use in patients with stable HF | Experimental studies suggest that neuronal AMP-activated protein kinase (AMPK) activation induced by metformin during the acute phase of stroke has adverse clinical implications, while glial AMPK activation plays a beneficial role. The experimental evidence also suggests that cerebral AMPK activation by metformin is detrimental to stroke outcomes, while peripheral AMPK activation by metformin reduces stoke-enhanced serum glucose levels [32] A study conducted by Romero et al. [19] suggested that metformin therapy was associated with a decreased mortality and hospitalization rate in patients with HF and new-onset DM |
Modern SUs (such as gliclazide MR and glimepiride) are associated with a lower risk of all-cause and CV-related mortality compared to conventional SUs in T2DM patients. The clinical expert group suggests that the modern SUs can be safely used in T2DM patients with CV risk, myocardial infarction, or stroke | Simpson et al. [33] conducted a network meta-analysis to compare the relative risk of mortality and adverse CV events among SUs. Network meta-analysis using both direct and indirect evidence showed that gliclazide and glimepiride were associated with a lower risk of all-cause and CV-related mortality compared with glibenclamide, whereas glipizide use had a similar risk. No significant differences were observed among SUs, neither on traditional nor on network meta-analysis on the incidence of MI |
The expert group listed out all the conditions and the OADs that could be considered safe or unsafe in each of the following conditions
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Recommendations on use of various OADs in patients with stable CAD | |
Preferred choice: Metformin, modern SU | Preferred choice Metformin reduces CV events significantly and reduces blood pressure and low-density lipoprotein levels (LDL). The United Kingdom Prospective Diabetes Study (UKPDS), a subpopulation study that included overweight patients with diabetes, found that metformin, when initiated early in the disease, is associated with significant risk reductions of 32% for any diabetes-related endpoint (sudden death, fatal or non-fatal myocardial infarction [MI], angina, heart failure, stroke, and amputation), 42% for diabetes-related death (death from MI, stroke, peripheral vascular disease), and 36% for all-cause mortality [34] Modern SUs: A nationwide registry comprising 1310 DM patients with acute myocardial infarction revealed that the mortality was lower in patients previously treated with modern SUs when compared to those treated with other oral medications or insulin [1, 17] Use with caution Conventional SU: According to South Asia Consensus Statements, modern SUs should be preferred over conventional SUs in patients with CAD [1] |
May use: Dipeptidyl peptidase-4 inhibitor (DPP4i), alpha-glucosidase inhibitors (AGI) | |
Use with caution, only if necessary: Conventional SUs | |
Recommendations on use of various OADs in patients with unstable CAD | |
Preferred choice: Pioglitazone | Preferred choice Pioglitazone is associated with reduced CV risk, all-cause mortality, non-fatal MI, and stroke and therefore is preferred OAD in patients with unstable CAD. A meta-analysis conducted by Lee et al. [28] on three randomized controlled studies reported that use of pioglitazone in stroke patients with insulin resistance, prediabetes, and DM was associated with a lower risk of recurrent stroke and future major vascular events Use with caution Metformin should be avoided in patients with unstable CAD [35] EMPA-REG OUTCOME Study: In the study, although beneficial effect of empagliflozin was reported on mortality and hospitalization for heart failure, it failed to reduce hospitalization from unstable angina [22] |
May use: Modern SU, DPP4i, AGI | |
Use with caution, only if necessary: Metformin, SGLT2i | |
Recommendations on use of various OADs in patients with HF EF preserved | |
Preferred choice: Metformin, SGLT2i | Preferred choice Metformin: In failing hearts, metformin improves myocardial energy metabolic status through the activation of AMP (adenosine monophosphate)-activated protein kinase (AMPK) and the regulation of lipid and glucose metabolism. By increasing nitric oxide (NO) bioavailability, limiting interstitial fibrosis, reducing the deposition of advanced glycation end-products (AGEs), and inhibiting myocardial cell apoptosis, metformin reduces cardiac remodeling and hypertrophy, and thereby preserves left ventricular systolic and diastolic functions [36]. A study conducted by Romero et al. [19] suggested that metformin therapy was associated with a decreased mortality and hospitalization rate in patients with HF and new-onset DM SGLT2 inhibition promotes natriuresis and osmotic diuresis, leading to plasma volume contraction and reduced preload, as well as decreases in blood pressure, arterial stiffness, and afterload, thereby improving subendocardial blood flow in patients with HF. SGLT2 inhibition is also associated with preservation of renal function [37] Absolute contraindication Pioglitazone: The pioglitAzone Clinical Trial In macroVascular Events (PROactive Study) conducted by Erdmann et al. [23] proved that a larger number of patients treated with pioglitazone were reported to have serious HF compared to those treated with placebo |
May use: Modern SU, DPP4i, AGI | |
Use with caution, only if necessary: Conventional SU | |
Absolute contraindication: Pioglitazone | |
Recommendations on use of various OADs in patients with HF low EF | |
Preferred choice: SGLT2i | Preferred choice SGLT2i: The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) conducted by Rådholm et al. [24] on 10,142 patients with T2DM and high cardiovascular risk proved that the treatment with canagliflozin resulted in reduced risk of cardiovascular death or hospitalized HF across a broad range of different patient subgroups. Benefits were found to be greater in those patients with a history of HF at baseline Absolute contraindication Pioglitazone: The pioglitAzone Clinical Trial In macroVascular Events (PROactive Study) conducted by Erdmann et al. [23] proved that a larger number of patients treated with pioglitazone were reported to have serious HF compared to those treated with placebo Conventional SUs: Conventional SUs do not preserve ischemic preconditioning and therefore should be used with caution in patients with HF only if necessary [1] |
May use: Modern SU, metformin, AGI | |
Use with caution, only if necessary: DPP4i | |
Absolute contraindication: Pioglitazone, conventional SU | |
Recommendations on use of various OADs in patients with stroke | |
Preferred choice: Modern SU, metformin, pioglitazone | Preferred choice Modern SU: Meta-analysis of 47 RCTs by Varvaki Rados et al. [14] reported that SUs are not associated with increased risk for all-cause mortality, CV mortality, myocardial infarction, or stroke Metformin: The United Kingdom Prospective Diabetes Study (UKPDS), a subpopulation study that included overweight patients with diabetes, found that metformin, when initiated early in the disease, is associated with significant risk reductions of 32% for any diabetes-related endpoint (sudden death, fatal or non-fatal myocardial infarction [MI], angina, heart failure, stroke, and amputation), 42% for diabetes-related death (death from MI, stroke, peripheral vascular disease), and 36% for all-cause mortality [34] Pioglitazone: A meta-analysis conducted by Lee et al. [28] on three randomized controlled studies reported that use of pioglitazone in stroke patients with insulin resistance, prediabetes, and DM was associated with a lower risk of recurrent stroke and future major vascular events |
May use: DPP4i, AGI | |
Use with caution, only if necessary: SGLT2i, conventional SU | |
Recommendations on use of various OADs in patients with peripheral artery disease | |
Preferred choice: Modern SU, metformin, DPP4i | Preferred choice Modern SUs: Evidence from a randomized controlled study suggests that glimepiride exerts an inhibitory effect on the initiation and development of atherosclerosis [38] Metformin and DPP4i delay the progression of atherosclerosis by improving endothelial dysfunction and are thereby preferred in patients with peripheral arterial disease [39] Use with caution SGLT2i and conventional SU increase the atherosclerotic plaque and therefore should be used with caution [39] |
May use: Pioglitazone, AGI | |
Use with caution, only if necessary: SGLT2i, conventional SU | |
Recommendations on use of various OADs in patients with dyslipidemia uncontrolled | |
Preferred choice: Modern SU, metformin, DPP4i, SGLT2i, pioglitazone | Preferred choice Modern SU: Glimepiride increases high-density lipoprotein cholesterol by increasing adiponectin levels [40] Metformin: Metformin reduces LDL cholesterol and triglycerides and increases HDL cholesterol [41] DPP4i, SGLT2i, and pioglitazone: Increase HDL cholesterol [41] Use with caution Conventional SU: Increases LDL [41] |
May use: AGI | |
Use with caution, only if necessary: conventional SU | |
Recommendations on use of various OADs in patients with arrhythmias | |
Preferred choice: Metformin | Preferred choice Metformin: In a population-based cohort study, metformin use was associated with a decreased risk of atrial fibrillation in patients with T2DM who were not using other antidiabetic medication. Reduced atrial fibrillation risk could be attributed to attenuation of atrial cell tachycardia-induced myolysis and oxidative stress [42] Use with caution Conventional SU: glibenclamide interferes with the beneficial action of KATP channel opening during acute ischemia–reperfusion events and therefore should be cautiously used in patients with arrhythmias [1] |
May use: Modern SU, DPP4i, SGLT2i, AGI | |
Use with caution, only if necessary: Conventional SU, pioglitazone |
Modern SUs Enhance Adherence and Are the Preferred Management Option
Importance of Medication Adherence in Achieving Glycemic Control
Patient Adherence
Physicians’ Communication
Affordability and Improved Adherence with Modern SUs
Key recommendations | Evidence and/or rationale |
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Treatment with modern SUs is associated with a lower economic burden and better patient adherence, and hence can be considered as an effective alternative to other newer antidiabetic drugs | South Asia consensus statement recommends modern SUs as an effective alternative to other antidiabetic medications; SU-containing dual or triple fixed dose combinations, if available, (with drugs that have complementary modes of action) reduce cost, offer convenience, and improve patient adherence [1] |
The panel also highlighted the role of physicians in proper communication about the illness and the risks and benefits of treatment. Support, empathy, understanding, collaborative partnerships, and patient-centered interviewing are essential for improving effective communication and enhancing adherence [34] | In a meta-analysis conducted by Haskard Zolnierek et al. of across 106 studies, a strong relationship was identified between patient adherence and physicians’ communication [49] |