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Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) are newly approved class of oral anti-diabetic drugs, in the treatment of type 2 diabetes, which reduces blood glucose through glucouresis via the kidney, independent, and irrespective of available pancreatic beta-cells. Studies conducted across their clinical development program found, a modest reduction in glycated hemoglobin ranging from -0.5 to -0.8%, without any significant hypoglycemia. Moreover, head-to-head studies versus active comparators yielded comparable efficacy. Interestingly, weight and blood pressure reduction were additionally observed, which was not only consistent but significantly superior to active comparators, including metformin, sulfonylureas, and dipeptydylpeptide-4 inhibitors. Indeed, these additional properties makes this class a promising oral anti-diabetic drug. Surprisingly, a potentially fatal unwanted side effect of diabetic ketoacidosis has been noted with its widespread use, albeit rarely. Nevertheless, this has created a passé among the clinicians. This review is an attempt to pool those ketosis data emerging with SGLT-2i, and put a perspective on its implicated mechanism.

Background There is a paucity of global data on cardiovascular disease (CVD) prevalence in people with type 2 diabetes (T2D). The primary objective of the CAPTURE study was to estimate the prevalence of established CVD and its management in adults with T2D across 13 countries from five continents. Additional objectives were to further characterize the study sample regarding demographics, clinical parameters and medication usage, with particular reference to blood glucose-lowering agents (GLAs: glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors) with demonstrated cardiovascular benefit in randomized intervention trials. Methods Data were collected from adults with T2D managed in primary or specialist care in Australia, China, Japan, Czech Republic, France, Hungary, Italy, Argentina, Brazil, Mexico, Israel, Kingdom of Saudi Arabia, and Turkey in 2019, using standardized methodology. CVD prevalence, weighted by diabetes prevalence in each country, was estimated for the overall CAPTURE sample and participating countries. Country-specific odds ratios for CVD prevalence were further adjusted for relevant demographic and clinical parameters. Results The overall CAPTURE sample included 9823 adults with T2D (n = 4502 from primary care; n = 5321 from specialist care). The overall CAPTURE sample had median (interquartile range) diabetes duration 10.7 years (5.6–17.9 years) and glycated hemoglobin 7.3% (6.6–8.4%) [56 mmol/mol (49–68 mmol/mol)]. Overall weighted CVD and atherosclerotic CVD prevalence estimates were 34.8% (95% confidence interval [CI] 32.7–36.8) and 31.8% (95% CI 29.7–33.8%), respectively. Age, gender, and clinical parameters accounted for some of the between-country variation in CVD prevalence. GLAs with demonstrated cardiovascular benefit were used by 21.9% of participants, which was similar in participants with and without CVD: 21.5% and 22.2%, respectively. Conclusions In 2019, approximately one in three adults with T2D in CAPTURE had diagnosed CVD. The low use of GLAs with demonstrated cardiovascular benefit even in participants with established CVD suggested that most were not managed according to contemporary diabetes and cardiology guidelines. Study registration NCT03786406 (registered on December 20, 2018), NCT03811288 (registered on January 18, 2019).

Inflammation is implicated in the development and severity of the coronavirus disease 2019 (COVID-19), as well as in the pathophysiology of diabetes. Diabetes, especially when uncontrolled, is also recognized as an important risk factor for COVID-19 morbidity and mortality. Furthermore, certain inflammatory markers [i.e. C-reactive protein (CRP), interleukin-6 (IL-6) and ferritin] were reported as strong predictors of worse outcomes in COVID-19 positive patients. The same biomarkers have been associated with poor glycemic control. Therefore, achieving euglycemia in patients with diabetes is even more important in the era of the COVID-19 pandemic. Based on the above, it is clinically interesting to elucidate whether antidiabetic drugs may reduce inflammation, thus possibly minimizing the risk for COVID-19 development and severity. The present narrative review discusses the potential anti-inflammatory properties of certain antidiabetic drugs (i.e. metformin, pioglitazone, sitagliptin, linagliptin, vildagliptin, alogliptin, saxagliptin, liraglutide, dulaglutide, exenatide, lixisenatide, semaglutide, empagliflozin, dapagliflozin, canagliflozin), with a focus on CRP, IL-6 and ferritin. •Inflammation is implicated in the development and severity of the coronavirus disease 2019 and diabetes.•C-reactive protein, interleukin-6 and ferritin were linked to poor glycemic control and worse COVID-19 outcomes.•There are limited and, in many cases, inconsistent data on the potential anti-inflammatory actions of antidiabetic drugs.•The most suggestive data are those on ferritin for the sodium glucose co-transporter-2 inhibitors.•Multiethnic trials are required to determine whether certain antidiabetic drugs exert inherent anti-inflammatory actions.

Aims: Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors play a key role in the treatment of type 2 diabetes mellitus. This meta-analysis aims to evaluate the efficacy and safety of their combination, emphatically focusing on the effects of treatment duration and add-on drugs. Methods: Seven databases were searched until June 2021 for randomized controlled trials with a duration of at least 12 weeks, evaluating the effects of combination therapy with glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors. Results: A total of eight eligible articles were included, pooling data retrieved from 1895 patients with type 2 diabetes mellitus. Compared to monotherapy, combination therapy resulted in a greater reduction in glycated haemoglobin (HbA1c), body weight, fasting plasma glucose (FPG), 2 h postprandial glucose (2 h PG), systolic blood pressure (SBP), body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C). The decrease in HbA1c, body weight and FPG was maintained for more than 1 year, but these effects gradually regressed over time. The risk for hypoglycaemia was significantly increased with combination therapy. In addition, drug discontinuation, diarrhoea, injection-site-related events, nausea, vomiting and genital infections were more likely to occur in combination therapy. Conclusion: Glucagon-like peptide-1 receptor agonist and sodium-glucose co-transporter-2 inhibitor combination therapy showed superior effects on reducing HbA1c, body weight, FPG, 2 h PG, SBP, BMI and LDL-C, without major safety issues, when compared with monotherapy in patients with type 2 diabetes mellitus.

Purpose of ReviewThis review offers a critical narrative evaluation of emerging evidence that sodium-glucose co-transporter-2 (SGLT2) inhibitors exert nephroprotective effects in people with type 2 diabetes.Recent FindingsThe SGLT2 inhibitor class of glucose-lowering agents has recently shown beneficial effects to reduce the onset and progression of renal complications in people with and without diabetes. Randomised clinical trials and ‘real world’ observational studies, mostly involving type 2 diabetes patients, have noted that use of an SGLT2 inhibitor can slow the decline in glomerular filtration rate (GFR), reduce the onset of microalbuminuria and slow or reverse the progression of proteinuria.SummaryThe nephroprotective effects of SGLT2 inhibitors are class effects observed with each of the approved agents in people with a normal or impaired GFR. These effects are also observed in non-diabetic, lean and normotensive individuals suggesting that the mechanisms extend beyond the glucose-lowering, weight-lowering and blood pressure-lowering effects that accompany their glucosuric action in diabetes patients. A key mechanism is tubuloglomerular feedback in which SGLT2 inhibitors cause more sodium to pass along the nephron: the sodium is sensed by macula cells which act via adenosine to constrict afferent glomerular arterioles, thereby protecting glomeruli by reducing intraglomerular pressure. Other effects of SGLT2 inhibitors improve tubular oxygenation and metabolism and reduce renal inflammation and fibrosis. SGLT2 inhibitors have not increased the risk of urinary tract infections or the risk of acute kidney injury. However, introduction of an SGLT2 inhibitor in patients with a very low GFR is not encouraged due to an initial dip in GFR, and it is prudent to discontinue therapy if there is an acute renal event, hypovolaemia or hypotension.

BackgroundIn the UK, approximately half of patients with heart failure and a reduced ejection fraction (HeFREF) are discharged from hospital on triple therapy (angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), beta-blockers (BB), and mineralocorticoid receptor antagonists (MRA). It is unknown what proportion of patients would be eligible for uptitration of medicines prior to discharge, nor how many might be eligible for initiation of sacubitril-valsartan or sodium-glucose co-transporter-2 inhibitors (SGLT2I).MethodsBetween 2012 and 2017, 1,277 patients admitted with suspected heart failure were enrolled at a single hospital serving a local community around Kingston-Upon-Hull, UK. Eligibility for sacubitril-valsartan or SGLT2I was based on entry criteria for the PIONEER-HF, DAPA-HF and EMPEROR-Reduced trials.Results455 patients had HeFREF with complete data on renal function, heart rate and systolic blood pressure (SBP) on discharge. 83% were taking an ACEI/ARB, 85% a BB and 63% MRA on discharge (figure 1). More than 60% were eligible for sacubitril-valsartan and more than 70% for SGLT2i (figure 2). Among those not already receiving a each drug, 37%, 28%, and 49% were eligible to start ACEI/ARB, BB, or MRA respectively (tables 1 and 2). Low SBP (<105 mmHg) was the most common reason for failure to initiate or up-titrate (table 2).Abstract 117 Table 1 Class Drug N (%)† Low Dose High dose Step 1 Step 2 Step 3 ACEI Enalapril 74 (19) 2.5mg BD 5mg BD 10-20mg BD Ramipril 253 (66) 1.25mg BD 2.5mg BD 5mg BD Perindopril 10 (3) 2.5mg OD 5mg OD 10mg OD Lisinopril 10 (3) 5mg OD 10mg OD 20-35mg OD ARB Candesartan 15 (4) 4-8mg OD 16mg OD 32mg OD Losartan 15 (4) 50mg OD 100mg OD 150mg OD Valsartan 2 (1) 40mg BD 80mg BD 160mg BD Beta-blocker Bisoprolol 116 (30) 2.5mg OD 5mg OD 10mg OD Carvedilol 262 (68) 3.125-6.25 mg BD 12.5mg BD 25-50mg BD Nebivolol 5 (1) 1.25 – 2.50 mg OD 5mg OD 10mg BD Timolol 2 (1) 5mg BD 10mg BD Atenolol 1 (0) 25mg OD 50mg OD MRA Spironolactone 169 (59) 25mg OD 50mg OD Eplerenone 170 (41) 25mg OD 50mg OD † - Percentage of those taking that class of medicationAbstract 117 Table 2Reasons for non-prescription or non-uptitration of medications Reason ACEI or ARB Β-blocker MRA S0 → S1 N=76 S1 → S2 N=175 S2 → S3 N=154 S0 → S1 N=69 S1 → S2 N=211 S2 → S3 N=121 S0 → S1 N=169 S1 → S2 N=282 SBP <90 mmHg – N (%)a 3 (4) 13 (7) 8 (5) 6 (9) 9 (4) 7 (6) 9 (5) 14 (5) SBP <105 mmHg – N (%)b 25 (33) 70 (40) 56 (36) 23 (33) 74 (35) 51 (42) 60 (36) 100 (36) eGFR <30 ml/min/1.73m2 or Cr >221 µmmol/La/b 10 (12) 15 (9) 13 (8) NA NA NA 25 (15) 14 (5) Potassium >5.0 mmol/La/b 7 (9) 18 (10) 9 (6) NA NA NA 14 (8) 18 (6) Heart rate <50 bpma NA NA NA 0 2 (1) 1 (1) NA NA Heart rate <70 in SR or <80 in AF – N (%)b NA NA NA 37 (54) 109 (52) 64 (53) NA NA Severe valvular heart disease 7 (9) 8 (5) 2 (1) 3 (4) 10 (5) 4 (3) 6 (4) 11 (4) Palliative 8 (11) NA NA 7 (10) NA NA 6 (4) NA Documented intolerance or allergy in the medical notes – N (%) 20 (26) 14 (20) 5 (3) Hyperkalaemia - N 1 NA 0 Hypotension - N 1 0 0 Renal dysfunction – N 3 NA 4 Cough – N 1 NA NA Angio-oedema – N 0 NA NA Bradycardia - N NA 4 NA Lung disease – N NA 3 NA Gynaecomastia - N NA NA 1 Non-specified allergy – N 13 7 0 Eligible to start or titrate treatment by criteria A – N (%) 36 (47) 131 (75) 123 (80) 55 (80) 190 (90) 109 (90) 115 (68) 230 (82) Eligibile to start or titrate treatment by criteria B – N (%) 28 (37) 82 (47) 83 (54) 19 (28) 52 (25) 26 (22) 82 (49) 156 (55) a – criteria derived from ESC HF guidelines; b – criteria based on higher SBP and HR cut-offs. S0 – not taking the treatment; S1-3 - steps of titration as per supplementary table 1 derived from ESC HF guidelines. Abbreviations used: ESC – European Society of Cardiology; HF – heart failure; ACEI – angiotensin converting enzyme inhibitor; ARB – angiotensin receptor blocker; MRA – mineralocorticoid receptor antagonist; SBP – systolic blood pressure; eGFR – estimated glomerular filtration rateAbstract 117 Figure 1Abstract 117 Figure 2ConclusionMost patients admitted for heart failure are eligible for initiation of life prolonging medications prior to discharge. A hospital admission may be a common missed opportunity to improve treatment for HeFREF.Conflict of Interestnone

•Cardiovascular outcome trials for sodium glucose co-transporter-2 inhibitors (SGLT2i) showed promise in secondary kidney outcomes.•Trials in individuals with chronic kidney disease (CKD) proved beneficial in slowing CKD progression and reducing cardiovascular risk.•SGLT2i should be added to ACEI or ARB therapy for patients with CKD.•Guidelines are being updated with recommendations for using SGLT2i early in CKD to provide these benefits. One in seven Americans is at risk for chronic kidney disease (CKD). For decades, the only treatment proven to slow progression of CKD was the use of renin-angiotensin-aldosterone system inhibitors. Based on promising secondary kidney outcomes in the cardiovascular outcome trials with sodium-glucose co-transporter-2 inhibitors, kidney outcome trials in patients with CKD were published for canagliflozin, dapagliflozin, and empagliflozin. A literature search was conducted of PubMed using the MeSH terms “Sodium-Glucose Transporter 2 Inhibitors” and “Renal Insufficiency, Chronic” and looking for clinical trials, meta-analyses, or randomized controlled trials in humans between 2015 and 2023. Primary and secondary outcomes from CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), and EMPA-KIDNEY (Empagliflozin in Patients with Chronic Kidney Disease) are described along with complete descriptions of the patient populations studied. This review describes the role of sodium-glucose co-transporter-2 inhibitors in slowing the progression of CKD, describes guideline changes that have occurred because of these data, and provides information on how these agents may be used clinically.

Euglycemic ketoacidosis is an acute, life-threatening emergency that is characterized by euglycemia, metabolic acidosis, and ketonemia. It is a well-recognized adverse event in diabetic patients taking sodium-glucose cotransporter-2 inhibitor (SGLT-2 inhibitor). However, there is limited data on SGLT-2 inhibitor-related euglycemic ketoacidosis in non-diabetic patients. The mechanism behind SGLT-2 inhibitor-associated euglycemic ketoacidosis involves a general state of starvation or relative insulin deficiency, which exacerbates the mild baseline ketonemia caused by this class of medications while normoglycemia is maintained. The incidence of euglycemic ketoacidosis will likely increase with the increasing use of SGLT-2 inhibitors for various indications in addition to diabetes mellitus type 2, predominantly for congestive heart failure (CHF). Recognizing the signs and symptoms of this life-threatening condition is essential to treat it effectively. Our objective is to comprehensively revisit the pathophysiology of euglycemic ketoacidosis associated with SGLT-2 inhibitors and the risk factors for the condition, review the available data, and summarize the reported cases of euglycemic ketoacidosis in non-diabetic patients on SGLT-2 inhibitors. Our literature search identified five articles with six cases of euglycemic ketoacidosis in non-diabetic patients who were on SGLT-2 inhibitors for heart failure with reduced ejection fraction. The common risk factor in five out of the six cases was decreased oral intake due to acute illness, fasting, or a perioperative state.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a newly developed class of oral anti-diabetic drugs (OADs) with a unique mechanism of action. This review describes the biochemistry and physiology underlying the use of SGLT2 inhibitors, and their clinical pharmacology, including mechanism of action and posology. The pragmatic placement of these molecules in the existing OAD arena is also discussed.

Background As indications for sodium-glucose co-transporter-2 inhibitors (SGLT2i) are expanding, a growing number of older adults have become candidates for treatment. We studied the safety profile of SGLT2i among older adults. Methods A retrospective, pharmacovigilance study of the FDA’s global database of safety reports. To assess reporting of pre-specified adverse events following SGLT2i among adults (< 75 years) and older adults (≥ 75), we performed a disproportionality analysis using the sex-adjusted reporting odds ratio (adj.ROR). Results We identified safety reports of 129,795 patients who received non-insulin anti-diabetic drugs (NIAD), including 24,253 who were treated with SGLT2i (median age 60 [IQR: 51–68] years, 2,339 [9.6%] aged ≥ 75 years). Compared to other NIAD, SGLT2i were significantly associated with amputations (adj.ROR = 355.1 [95%CI: 258.8 − 487.3] vs adj.ROR = 250.2 [79.3 − 789.5]), Fournier gangrene (adj.ROR = 45.0 [34.5 − 58.8] vs adj.ROR = 88.0 [27.0 − 286.6]), diabetic ketoacidosis (adj.ROR = 32.3 [30.0 − 34.8] vs adj.ROR = 23.3 [19.2 − 28.3]), genitourinary infections (adj.ROR = 10.3 [9.4 − 11.2] vs adj.ROR = 8.6 [7.2 − 10.3]), nocturia (adj.ROR = 5.5 [3.7 − 8.2] vs adj.ROR = 6.7 [2.8 − 15.7]), dehydration (adj.ROR = 2.5 [2.3 − 2.8] vs adj.ROR = 2.6 [2.1 − 3.3]), and fractures (adj.ROR = 1.7 [1.4 − 2.1] vs adj.ROR = 1.5 [1.02 − 2.1]) in both adults and older adults, respectively. None of these safety signals was significantly greater in older adults (P interaction threshold of 0.05). Acute kidney injury was associated with SGLT2i in adults (adj.ROR = 1.97 [1.85 − 2.09]) but not in older adults (adj.ROR = 0.71 [0.59 − 0.84]). Falls, hypotension, and syncope were not associated with SGLT2i among either adults or older adults. Conclusion In this global post-marketing study, none of the adverse events was reported more frequently among older adults. Our findings provide reassurance regarding SGLT2i treatment in older adults, although careful monitoring is warranted.