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SGLT2 inhibitors and metformin: Dual antihyperglycemic therapy and the risk of metabolic acidosis in type 2 diabetes.
Donnan, K, Segar, L
European journal of pharmacology. 2019;:23-29
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Abstract
The prevalence of type 2 diabetes mellitus (T2D) has risen in the United States and worldwide, with an increase in global prevalence from 4.7% to 8.5% between 1980 and 2014. A variety of antidiabetic drugs are available with different mechanisms of action, and multiple drugs are often used concomitantly to improve glycemic control. One of the newest classes of oral antihyperglycemic agents is the sodium glucose cotransporter-2 (SGLT2) inhibitors or "flozins". Recent clinical guidelines have suggested the use of SGLT2 inhibitors as add-on therapy in patients for whom metformin alone does not achieve glycemic targets, or as initial dual therapy with metformin in patients who present with higher glycated hemoglobin (HbA1c) levels. The FDA has approved fixed-dose combination (FDC) tablets with each of the three available SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) and metformin. Both drug classes are associated with the rare but serious life-threatening complications that result from metabolic acidosis, including lactic acidosis (with metformin) and euglycemic diabetic ketoacidosis (with SGLT2 inhibitors). This review summarizes the current literature on the pharmacokinetics and the molecular targets of metformin and SGLT2 inhibitors. It also addresses the common adverse effects and highlights the molecular mechanisms by which this dual antihyperglycemic therapy contributes to high anion gap metabolic acidosis. In conclusion, while the combination of metformin and SGLT2 inhibitors would be a better option in improving glycemic control with a low risk of hypoglycemia, an increase in the risk of metabolic acidosis during combination therapy may be borne in mind.
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Metabolic Effects of Metformin in Humans.
Adeva-Andany, MM, Rañal-Muíño, E, Fernández-Fernández, C, Pazos-García, C, Vila-Altesor, M
Current diabetes reviews. 2019;(4):328-339
Abstract
BACKGROUND Both insulin deficiency and insulin resistance due to glucagon secretion cause fasting and postprandial hyperglycemia in patients with diabetes. INTRODUCTION Metformin enhances insulin sensitivity, being used to prevent and treat diabetes, although its mechanism of action remains elusive. RESULTS Patients with diabetes fail to store glucose as hepatic glycogen via the direct pathway (glycogen synthesis from dietary glucose during the post-prandial period) and via the indirect pathway (glycogen synthesis from "de novo" synthesized glucose) owing to insulin deficiency and glucagoninduced insulin resistance. Depletion of the hepatic glycogen deposit activates gluconeogenesis to replenish the storage via the indirect pathway. Unlike healthy subjects, patients with diabetes experience glycogen cycling due to enhanced gluconeogenesis and failure to store glucose as glycogen. These defects raise hepatic glucose output causing both fasting and post-prandial hyperglycemia. Metformin reduces post-prandial plasma glucose, suggesting that the drug facilitates glucose storage as hepatic glycogen after meals. Replenishment of glycogen store attenuates the accelerated rate of gluconeogenesis and reduces both glycogen cycling and hepatic glucose output. Metformin also reduces fasting hyperglycemia due to declining hepatic glucose production. In addition, metformin reduces plasma insulin concentration in subjects with impaired glucose tolerance and diabetes and decreases the amount of insulin required for metabolic control in patients with diabetes, reflecting improvement of insulin activity. Accordingly, metformin preserves β-cell function in patients with type 2 diabetes. CONCLUSION Several mechanisms have been proposed to explain the metabolic effects of metformin, but evidence is not conclusive and the molecular basis of metformin action remains unknown.
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Should metformin still be the first-line of treatment in type 2 diabetes mellitus? A comprehensive review and suggested algorithm.
Bin Hussain, AK, Abdelgadir, E, Rashid, F, Al Haj, A, Thadani, P, Bashier, AMK
Diabetes & metabolic syndrome. 2019;(3):1935-1942
Abstract
For more than a century, the high occurrences of coronary and peripheral artery diseases in diabetes mellitus patients has been well recognised; despite that, the ability to improve CV event rates by optimizing glycaemic control has remained elusive. Nevertheless, the last decade has seen several cardiovascular outcome clinical trials (CVOTs) of many antihyperglycemic agents that reported promising results for cardiovascular and renal outcomes. This leads to a hot debate on the ideal drug choice for first-line treatment in T2DM. The purpose of this paper is to review the evidence supporting the use of metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors and incretin-based therapies for the management of individuals with T2DM and, discuss the rationale for selection.
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Glucose-lowering therapies in patients with type 2 diabetes and cardiovascular diseases.
Prattichizzo, F, La Sala, L, Rydén, L, Marx, N, Ferrini, M, Valensi, P, Ceriello, A
European journal of preventive cardiology. 2019;(2_suppl):73-80
Abstract
Type 2 diabetes mellitus is a major risk factor for developing cardiovascular disease, and many patients with diabetes have prevalent cardiovascular complications. Recent cardiovascular outcome clinical trials suggest that certain new glucose-lowering drugs are accompanied by additional cardioprotective properties. Indeed, selected glucagon-like peptide-1 receptor agonists have a proved cardiovascular benefit in terms of a reduced incidence of ischaemic events, while sodium/glucose co-transporter-2 inhibitors have also shown significant protection, with a striking effect on heart failure and renal endpoints. These findings have been integrated in recent guidelines which now recommend prescribing (when initial metformin monotherapy fails) a glucagon-like peptide-1 receptor agonist or a sodium/glucose co-transporter-2 inhibitor with clinical trial-confirmed benefit in patients with diabetes and atherosclerotic cardiovascular disease, and a sodium/glucose co-transporter-2 inhibitor in such patients with heart failure or chronic kidney disease at initial stages. Furthermore, the new 2019 European Society of Cardiology guidelines in collaboration with the European Association for the Study of Diabetes recommend a glucagon-like peptide-1 receptor agonist or a sodium/glucose co-transporter-2 inhibitor in treatment-naive patients with type 2 diabetes mellitus with pre-existing cardiovascular disease or at high cardiovascular risk. Future research will disentangle the mechanisms underpinning these beneficial effects and will also establish to what extent these results are generalisable to the whole diabetes population. In the meantime, available evidence should prompt a wide diffusion of these two classes of drugs among patients with diabetes and cardiovascular disease. Here, we briefly summarise recent findings emerging from cardiovascular outcome clinical trials, discuss their impact on treatment algorithms and propose new possible approaches to improve our knowledge further regarding the cardiovascular effect of glucose-lowering medications.
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Neglecting regression to the mean continues to lead to unwarranted conclusions: Letter regarding "The magnitude of weight loss induced by metformin is independently associated with BMI at baseline in newly diagnosed type 2 diabetes: Post-hoc analysis from data of a phase IV open-labeled trial".
Hannon, BA, Thomas, DM, Siu, CO, Allison, DB
Advances in clinical and experimental medicine : official organ Wroclaw Medical University. 2019;(11):1569-1570
Abstract
As the prevalence of type 2 diabetes mellitus and obesity increases worldwide, scientifically rigorous research is needed in this field to determine effective interventions for the prevention and treatment of these chronic diseases. In a recent study published in this journal, Zhou et al. conclude that metformin, a drug used for treatment of type 2 diabetes mellitus, can be used effectively for weight loss, and that this effect is even more pronounced in individuals who weigh more at baseline. Unfortunately, we believe these results to be due to the regression to the mean (RTM) phenomenon, which weakens the causal inference proposed in this study. The conclusions of Zhou et al. that metformin is an effective strategy for weight loss in individuals with type 2 diabetes mellitus are not substantiated due to the lack of a control group and failure to consider other factors that may have confounded these results.
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Fixed-dose combination of ertugliflozin and metformin hydrochloride for the treatment of type 2 diabetes.
Frias, JP
Expert review of endocrinology & metabolism. 2019;(2):75-83
Abstract
Combining antihyperglycemic agents in order to rapidly and safely achieve the best possible glycemic control is the standard of care today for the management of type 2 diabetes. Agents should ideally have mechanisms of actions that are complementary and that improve glycemic control without unacceptable gain in body weight or hypoglycemia. Areas covered: Ertugliflozin and metformin hydrochloride (ertugliflozin/metformin, SEGLUROMET) is a recently approved fixed-dose combination tablet containing the sodium-glucose co-transporter 2 (SGLT-2) inhibitor ertugliflozin and metformin. This review summarizes key characteristics of ertugliflozin and metformin, as well as the efficacy and safety results of co-administration of these agents in the ertugliflozin clinical development program. This information comes from the ertugliflozin/metformin prescribing information as well as published clinical trials obtained through a PubMed search. Expert commentary: SGLT-2 inhibitors are an important class of antihyperglycemic agents that are efficacious as monotherapy and in combination with other antihyperglycemic agents. Given their favorable effects on glycemia control as well as 'extra-glycemic' parameters such as body weight and blood pressure, they are ideal agents for appropriate patients with type 2 diabetes. The fixed-dose combination of ertugliflozin with metformin is an effective combination that is conveniently administered and may improve medication adherence and persistence.
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Abilities of berberine and chemically modified berberines to interact with metformin and inhibit proliferation of pancreatic cancer cells.
Akula, SM, Candido, S, Libra, M, Abrams, SL, Steelman, LS, Lertpiriyapong, K, Ramazzotti, G, Ratti, S, Follo, MY, Martelli, AM, et al
Advances in biological regulation. 2019;:100633
Abstract
Pancreatic cancer is devastating cancer worldwide with few if any truly effective therapies. Pancreatic cancer has an increasing incidence and may become the second leading cause of death from cancer. Novel, more effective therapeutic approaches are needed as pancreatic cancer patients usually survive for less than a year after being diagnosed. Control of blood sugar levels by the prescription drug metformin in diseases such as diabetes mellitus has been examined in association with pancreatic cancer. While the clinical trials remain inconclusive, there is hope that certain diets and medications may affect positively the outcomes of patients with pancreatic and other cancers. Other natural compounds may share some of the effects of metformin. One "medicinal" fruit consumed by millions worldwide is berberine (BBR). Metformin and BBR both activate AMP-activated protein kinase (AMPK) which is a key mediator of glucose metabolism. Glucose metabolism has been shown to be very important in cancer and its significance is increasing. In the following studies, we have examined the effects of metformin, BBR and a panel of modified BBRs (NAX compounds) and chemotherapeutic drugs on the growth of four different human pancreatic adenocarcinoma cell lines (PDAC). Interestingly, the effects of metformin could be enhanced by BBR and certain modified BBRs. Upon restoration of WT-TP53 activity in MIA-PaCa-2 cells, an altered sensitivity to the combination of certain NAX compounds and metformin was observed compared to the parental cells which normally lack WT-TP53. Certain NAX compounds may interact with WT-TP53 and metformin treatment to alter the expression of key molecules involved in cell growth. These results suggest a therapeutic approach by combining certain pharmaceutical drugs and nutraceuticals to suppress the growth of cancer cells.
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The Changing Landscape of Pharmacotherapy for Diabetes Mellitus: A Review of Cardiovascular Outcomes.
Wu, L, Gunton, JE
International journal of molecular sciences. 2019;(23)
Abstract
The prevention of cardiovascular morbidity and mortality has always been a primary concern in patients with type 2 diabetes. Modern trials of glucose-lowering therapies now assess major adverse cardiac events as an endpoint in addition to the effects on glycaemic control. Whilst the data on the efficacy of intensive glucose lowering on reducing cardiovascular risk are limited, there are now increasing numbers of glucose-lowering therapies that have proven cardiovascular benefit independent of glucose lowering. This review will summarise the available literature on cardiovascular outcomes in relation to metformin, sulphonylureas, di-peptidyl peptidase-4 inhibitors, glucagon-like peptide receptor agonists, sodium-glucose co-transporter 2 inhibitors, thiazolidinediones, acarbose and insulin. In addition, new paradigms in diabetes management and the importance of treatment selection based on considerations including but not limited to glycaemic control will be discussed.
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Review of Biguanide (Metformin) Toxicity.
Wang, GS, Hoyte, C
Journal of intensive care medicine. 2019;(11-12):863-876
Abstract
In the 1920s, guanidine, the active component of Galega officinalis, was shown to lower glucose levels and used to synthesize several antidiabetic compounds. Metformin (1,1 dimethylbiguanide) is the most well-known and currently the only marketed biguanide in the United States, United Kingdom, Canada, and Australia for the treatment of non-insulin-dependent diabetes mellitus. Although phenformin was removed from the US market in the 1970s, it is still available around the world and can be found in unregulated herbal supplements. Adverse events associated with therapeutic use of biguanides include gastrointestinal upset, vitamin B12 deficiency, and hemolytic anemia. Although the incidence is low, metformin toxicity can lead to hyperlactatemia and metabolic acidosis. Since metformin is predominantly eliminated from the body by the kidneys, toxicity can occur when metformin accumulates due to poor clearance from renal insufficiency or in the overdose setting. The dominant source of metabolic acidosis associated with hyperlactatemia in metformin toxicity is the rapid cytosolic adenosine triphosphate (ATP) turnover when complex I is inhibited and oxidative phosphorylation cannot adequately recycle the vast quantity of H+ from ATP hydrolysis. Although metabolic acidosis and hyperlactatemia are markers of metformin toxicity, the degree of hyperlactatemia and severity of acidemia have not been shown to be of prognostic value. Regardless of the etiology of toxicity, treatment should include supportive care and consideration for adjunct therapies such as gastrointestinal decontamination, glucose and insulin, alkalinization, extracorporeal techniques to reduce metformin body burden, and metabolic rescue.
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Efficacy and safety of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as monotherapy or add-on to metformin in patients with type 2 diabetes mellitus: A systematic review and meta-analysis.
Wang, Z, Sun, J, Han, R, Fan, D, Dong, X, Luan, Z, Xiang, R, Zhao, M, Yang, J
Diabetes, obesity & metabolism. 2018;(1):113-120
Abstract
AIMS: To compare the efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) as monotherapy or add-on to metformin (Met) in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS PubMed, Embase and ClinicalTrials.gov sites were systematically searched for randomized controlled trials to assess the efficacy and safety of DPP-4is and SGLT-2is in patients with T2DM. Risk ratio (RR) and weighted mean difference (WMD) were used to evaluate outcomes. RESULTS In the analysis of 25 randomized trials, which involved 14 619 patients, SGLT-2is were associated with a significantly stronger reduction in haemoglobin A1c (HbA1c) (WMD 0.13%, 95% credible interval [CI], 0.04%-0.22%, P = .005) and fasting plasma glucose (FPG) (WMD 0.80 mmol/L, 95% CI, 0.58-1.01 mmol/L, P < .00001) than were DPP-4is. However, no significant difference between the 2 drug categories was found in the risk of hypoglycaemic events (RR, 0.99; 95% CI, 0.78-1.26, P = .92). SGLT-2is plus Met was associated with a more significant decrease in FPG (WMD 0.71 mmol/L, 95% CI, 0.43-1.00 mmol/L, P < .00001) than was DPP-4is plus Met. However, no differences were found in the reduction of HbA1c (WMD 0.11%, 95% CI, -0.03%-0.25%, P = .12) or the risk of hypoglycaemic events (RR, 1.02; 95% CI, 0.80-1.31, P = .86). CONCLUSIONS This review revealed that, compared to DPP-4is, SGLT-2is significantly reduced HbA1c, FPG and body weight without increasing the risk of hypoglycaemia in diabetes treatment.