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An emerging new concept for the management of type 2 diabetes with a paradigm shift from the glucose-centric to beta cell-centric concept of diabetes - an Asian perspective.
Saisho, Y
Expert opinion on pharmacotherapy. 2020;(13):1565-1578
Abstract
INTRODUCTION Recent advances in anti-diabetic medications and glucose monitoring have led to a paradigm shift in diabetes care. Newer anti-diabetic medications such as DPP-4 inhibitors, GLP-1 receptor agonists (GLP-1RAs), and SGLT2 inhibitors have enabled optimal glycemic control to be achieved without increasing the risk of hypoglycemia and weight gain. Treatment with GLP-1RAs and SGLT2 inhibitors has been demonstrated to improve cardiorenal outcomes, positioning these agents as the mainstay of treatment for patients with type 2 diabetes (T2DM). The development of these newer agents has also prompted a paradigm shift in the concept of T2DM, highlighting the importance of beta cell dysfunction in the pathophysiology of T2DM. AREAS COVERED Recent advances in pharmacotherapy for diabetes are summarized with a focus on the role of incretin-based drugs and SGLT2 inhibitors. The importance of a paradigm shift from a glucose-centric to a beta cell-centric concept of T2DM is also discussed, given from an Asian perspective. EXPERT OPINION Management of T2DM including lifestyle modification as well as pharmacotherapy should be focused on reducing beta cell workload, to preserve functional beta cell mass. A paradigm shift from a glucose-centric to a beta cell-centric concept of T2DM enhances the implementation of person-centered diabetes care.
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Understanding Metabolic Memory: A Tale of Two Studies.
Miller, RG, Orchard, TJ
Diabetes. 2020;(3):291-299
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The results of the Diabetes Control and Complications Trial (DCCT) have given rise to much encouragement in the battle to stave off the complications of type 1 diabetes, showing dramatic declines in the development of severe retinopathy, nephropathy, and neuropathy in those treated intensively compared with conventional therapy. Particularly encouraging has been the continuing difference between the two groups despite both having similar HbA1c (∼8%) since the end of DCCT, when 96% of participants entered the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. This continuing relative benefit has been termed "metabolic memory," which implies altered metabolic regulation. Based on evidence from both the Epidemiology of Diabetes Complications (EDC) prospective cohort study of childhood-onset type 1 diabetes and DCCT/EDIC, we show that the metabolic memory effect can be largely explained by lower cumulative glycemic exposure in the intensive therapy group, and, on average, the development of complications increases with greater glycemic exposure, irrespective of whether this results from a high exposure for a short time or a lower exposure for a longer time. Thus, there is no need for a concept like "metabolic memory" to explain these observations. Potential mechanisms explaining the cumulative glycemic effect are also briefly discussed.
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Noninsulin Diabetes Therapies in Older Adults.
Tekin, Z, Zimmerman, RS
Clinics in geriatric medicine. 2020;(3):385-394
Abstract
Diabetes risk increases with age due to changes in β-cell function and increased insulin resistance and is one of the most common chronic medical conditions in the elderly. Diabetes management in this population requires a multidisciplinary, patient-centric approach due to wide heterogeneity in patients' health and functional capacities. Meticulous assessment of each patient before formulating a regimen and thorough patient education are keys to success in achieving glycemic goals, which should be individualized. Lifestyle modification is recommended for every patient.
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Osmolar-gap in the setting of metformin-associated lactic acidosis: Case report and a literature review highlighting an apparently unusual association.
Elshafei, MN, Alamin, M, Mohamed, MFH
Medicine. 2020;(41):e22492
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Abstract
RATIONALE Metformin-associated lactic acidosis (MALA) is a rare adverse effect that has significant morbidity and mortality. MALA is a high anion gap (AG), nonosmolar acidosis. Associated osmolar-gap (OG) is rarely reported, so finding an OG may make the diagnosis of MALA challenging. PATIENT CONCERNS Forty-five years' old type II diabetic patient on metformin presented to emergency with a two-day history of vomiting, watery diarrhea, and mild abdominal discomfort. On examinations, he looked dehydrated. Investigation revealed acute kidney injury (AKI) with a high lactic acid (LA) level of 24 mmol/L, pH of 6.8, AG of 40, and an OG of 20 mOsm/kg DIAGNOSES The presence of an OG made the diagnosis challenging; the history was negative for alcohol, osmolar substance, or illicit drug ingestion or use. The toxicology screen was negative. After ruling out plausible causes of AG and OG, MALA was deemed the likely reason for his presentation likely precipitated by dehydration and AKI. INTERVENTIONS He underwent two sessions of hemodialysis, afterward managed with fluid hydration. OUTCOMES On day 3, he was in the polyuric phase suggestive of acute tubular necrosis. His serum creatinine improved afterward with improved acidosis; after 8 days, he was discharged in stable condition. LESSONS MALA is a rare side effect of metformin therapy. Acute kidney injury is a known precipitant of MALA. In our review, we highlight the association of MALA and the presence of an OG. We believe that treating physicians should be aware of this relationship to avoid delaying or overlooking such an important diagnosis.
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Tubular effects of sodium-glucose cotransporter 2 inhibitors: intended and unintended consequences.
Dominguez Rieg, JA, Xue, J, Rieg, T
Current opinion in nephrology and hypertension. 2020;(5):523-530
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PURPOSE OF REVIEW Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antihyperglycemic drugs that act by inhibiting renal sodium-glucose cotransport. Here we present new insights into 'off target', or indirect, effects of SGLT2 inhibitors. RECENT FINDINGS SGLT2 inhibition causes an acute increase in urinary glucose excretion. In addition to lowering blood glucose, there are several other effects that contribute to the overall beneficial renal and cardiovascular effects. Reabsorption of about 66% of sodium is accomplished in the proximal tubule and dependent on the sodium-hydrogen exchanger isoform 3 (NHE3). SGLT2 colocalizes with NHE3, and high glucose levels reduce NHE3 activity. The proximal tubule is also responsible for the majority of phosphate (Pi) reabsorption. SGLT2 inhibition is associated with increases in plasma Pi, fibroblast growth factor 23 and parathyroid hormone levels in nondiabetics and type 2 diabetes mellitus. Studies in humans identified a urate-lowering effect by SGLT2 inhibition which is possibly mediated by urate transporter 1 (URAT1) and/or glucose transporter member 9 in the proximal tubule. Of note, magnesium levels were also found to increase under SGLT2 inhibition, an effect that was preserved in nondiabetic patients with hypomagnesemia. SUMMARY Cardiorenal effects of SGLT2 inhibition might involve, in addition to direct effects on glucose homeostasis, effects on NHE3, phosphate, urate, and magnesium homeostasis.
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Diabetic ketoacidosis with SGLT2 inhibitors.
Musso, G, Saba, F, Cassader, M, Gambino, R
BMJ (Clinical research ed.). 2020;:m4147
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[New pharmacological treatment options for nonalcoholic fatty liver disease].
Stefan, N
Der Internist. 2020;(7):759-765
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) continues to increase worldwide, presently affecting 25% of the adult population, and is associated with an elevated risk of total and liver-specific mortality. NAFLD is a chronic disease and results from a combination of genetic, environmental and predominantly lifestyle-related causes. Therefore, NAFLD, similarly to cardiovascular disease, type 2 diabetes and many different types of cancer, can be considered a noncommunicable disease. Consequently, lifestyle intervention, particularly if associated with a large amount of weight loss, is considered highly effective and safe to treat NAFLD. For patients with advanced-stage NAFLD or that cannot lose weight, metabolically-based pharmacotherapy is effective to improve liver histology and cardiometabolic risk profile. If a moderate or advanced stage of liver fibrosis is present, additional antifibrotic therapy is necessary to halt the progression of the disease.
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Anti-inflammatory properties of antidiabetic drugs: A "promised land" in the COVID-19 era?
Katsiki, N, Ferrannini, E
Journal of diabetes and its complications. 2020;(12):107723
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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.
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Incretin-based therapies and renin-angiotensin system: Looking for new therapeutic potentials in the diabetic milieu.
Yaribeygi, H, Maleki, M, Sathyapalan, T, Jamialahmadi, T, Sahebkar, A
Life sciences. 2020;:117916
Abstract
Incretin-based therapies include pharmacologic agents such as glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors which exert potent anti-hyperglycemic effects in the diabetic milieu. They are also shown to have extra-pancreatic effects. Renin-angiotensin system is part of the endocrine system which is widely distributed in the body and is closely involved in water and electrolyte homeostasis as well as renal and cardiovascular functions. Hence the renin-angiotensin system is the main target for treating patients with various renal and cardiovascular disorders. There is growing evidence that incretins have modulatory effects on renin-angiotensin system activity; thereby, can be promising therapeutic agents for the management of renal and cardiovascular disorders. But the exact molecular interactions between incretins and renin-angiotensin system are not clearly understood. In this current study, we have reviewed the possible molecular mechanisms by which incretins modulate renin-angiotensin system activity.
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Translating the statistical benefits of SGLT-2 inhibitors on cardio-renal outcomes into clinical practice.
Ghosal, S, Sinha, B
Expert review of clinical pharmacology. 2020;(5):545-551
Abstract
BACKGROUND/OBJECTIVES This study aims to analyze the positive outcomes observed in cardiovascular outcomes trials conducted with sodium-glucose co-transporter inhibitors and determine their statistical and clinical significance. METHODS A literature search conducted using the Cochrane library resulted in five citations - randomized controlled trials (RCTs), identified for analysis. Positive cardio-renal outcomes from the five RCTs were analyzed in accordance with a pre-defined strategy which included the hierarchical flow chart, presence of a persuasive p-value (p < 0.001), and number needed to treat (NNT) estimation calculated from the absolute risk reduction (ARR) reported. RESULTS Only four instances fulfilled these stringent criteria - reduction of cardiovascular (CV) death with empagliflozin in T2DM patients with established atherosclerotic cardiovascular disease (eASCVD) (p < 0.001; NNT 45), reduction in cardiorenal outcomes with canagliflozin in a pooled T2DM population with macroalbuminuria (p < 0.00001; NNT 22), as well as reduction in the composite of CV death or hospitalization for heart failure (hHF) (p < 0.001; NNT 30) and also reduction in hHF or CV death with dapagliflozin in T2DM with heart failure with reduced ejection fraction (HFrEF) (p < 0.001; NNT 21). CONCLUSIONS Statistically positive outcome results must be interpreted in the context of associated clinical benefits and not in isolation.