Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to
Galega officinalis
(also known as goat’s rue), ...a traditional herbal medicine in Europe, found to be rich in guanidine, which, in 1918, was shown to lower blood glucose. Guanidine derivatives, including metformin, were synthesised and some (not metformin) were used to treat diabetes in the 1920s and 1930s but were discontinued due to toxicity and the increased availability of insulin. Metformin was rediscovered in the search for antimalarial agents in the 1940s and, during clinical tests, proved useful to treat influenza when it sometimes lowered blood glucose. This property was pursued by the French physician Jean Sterne, who first reported the use of metformin to treat diabetes in 1957. However, metformin received limited attention as it was less potent than other glucose-lowering biguanides (phenformin and buformin), which were generally discontinued in the late 1970s due to high risk of lactic acidosis. Metformin’s future was precarious, its reputation tarnished by association with other biguanides despite evident differences. The ability of metformin to counter insulin resistance and address adult-onset hyperglycaemia without weight gain or increased risk of hypoglycaemia gradually gathered credence in Europe, and after intensive scrutiny metformin was introduced into the USA in 1995. Long-term cardiovascular benefits of metformin were identified by the UK Prospective Diabetes Study (UKPDS) in 1998, providing a new rationale to adopt metformin as initial therapy to manage hyperglycaemia in type 2 diabetes. Sixty years after its introduction in diabetes treatment, metformin has become the most prescribed glucose-lowering medicine worldwide with the potential for further therapeutic applications.
Sodium/glucose co‐transporter‐2 (SGLT2) inhibitors, which lower blood glucose by increasing renal glucose elimination, have been shown to reduce the risk of adverse cardiovascular (CV) and renal ...events in type 2 diabetes. This has been ascribed, in part, to haemodynamic changes, body weight reduction and several possible effects on myocardial, endothelial and tubulo‐glomerular functions, as well as to reduced glucotoxicity. This review evaluates evidence that an effect of SGLT2 inhibitors to lower uric acid may also contribute to reduced cardio‐renal risk.
Chronically elevated circulating uric acid concentrations are associated with increased risk of hypertension, CV disease and chronic kidney disease (CKD). The extent to which uric acid contributes to these conditions, either as a cause or an aggravating factor, remains unclear, but interventions that reduce urate production or increase urate excretion in hyperuricaemic patients have consistently improved cardio‐renal prognoses. Uric acid concentrations are often elevated in type 2 diabetes, contributing to the “metabolic syndrome” of CV risk. Treating type 2 diabetes with an SGLT2 inhibitor increases uric acid excretion, reduces circulating uric acid and improves parameters of CV and renal function. This raises the possibility that the lowering of uric acid by SGLT2 inhibition may assist in reducing adverse CV events and slowing progression of CKD in type 2 diabetes. SGLT2 inhibition might also be useful in the treatment of gout and gouty arthritis, especially when co‐existent with diabetes.
Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits ...long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.
•Analogues of glucose-dependent insulinotropic polypeptide (GIP) with agonist or antagonist effects at the GIP receptor have been developed.•Studies in rodents have noted that both reduced and ...enhanced activity of GIP can prevent or reverse obese non-insulin dependent forms of diabetes.•Species differences in GIP receptor responsiveness have complicated the extrapolation of evidence from rodents to humans.•Clinical studies have shown potential of GIP receptor agonists combined with other glucose-lowering peptides to treat obese type 2 diabetes.
The potential application of glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide, GIP) in the management of obesity and type 2 diabetes has been controversial. Initial interest in the therapeutic use of GIP was dampened by evidence that its insulinotropic activity was reduced in type 2 diabetes and by reports that it increased glucagon secretion and adipose deposition in non-diabetic individuals. Also, attention was diverted away from GIP by the successful development of glucagon-like peptide-1 (GLP-1) receptor agonists, and a therapeutic strategy for GIP became uncertain when evidence emerged that both inhibition and enhancement of GIP action could prevent or reverse obese non-insulin dependent forms of diabetes in rodents. Species differences in GIP receptor responsiveness complicated the extrapolation of evidence from rodents to humans, but initial clinical studies are investigating the effect of a GIP antagonist in non-diabetic individuals. A therapeutic role for GIP agonists was reconsidered when clinical studies noted that the insulinotropic effect of GIP was increased if near-normal glycaemia was re-established, and GIP was found to have little effect on glucagon secretion or adipose deposition in obese type 2 diabetes patients. This encouraged the development of designer peptides that act as GIP receptor agonists, including chimeric peptides that mimic the incretin partnership of GIP with GLP-1, where the two agents exert complementary and often additive effects to improve glycaemic control and facilitate weight loss. Polyagonist peptides that exert agonism at GIP, GLP-1 and glucagon receptors are also under investigation as potential treatments for obese type 2 diabetes.
The past 50 years have seen a growing ageing population with an increasing prevalence of type 2 diabetes mellitus (T2DM); now, nearly half of all individuals with diabetes mellitus are older adults ...(aged ≥65 years). Older adults with T2DM present particularly difficult challenges. For example, the accentuated heterogeneity of these patients, the potential presence of multiple comorbidities, the increased susceptibility to hypoglycaemia, the increased dependence on care and the effect of frailty all add to the complexity of managing diabetes mellitus in this age group. In this Review, we offer an update on the key pathophysiological mechanisms associated with T2DM in older people. We then evaluate new evidence relating particularly to the effects of frailty and sarcopenia, the clinical difficulties of age-associated comorbidities, and the implications for existing guidelines and therapeutic options. Our conclusions will focus on the effect of T2DM on an ageing society.
Metformin (dimethyl‐biguanide) can claim its origins in the use of Galega officinalis as a plant treatment for symptoms ascribed to diabetes. Since the first clinical use of metformin as a ...glucose‐lowering agent in 1957, this medicine has emerged as a first‐line pharmacological option to support lifestyle interventions in the management of type 2 diabetes (T2D). It acts through multiple cellular pathways, principally in the gut, liver and muscle, to counter insulin resistance and lower blood glucose without weight gain or risk of overt hypoglycaemia. Other effects include improvements in lipid metabolism, decreased inflammation and lower long‐term cardiovascular risk. Metformin is conveniently combined with other diabetes medications, can be prescribed in prediabetes to reduce the risk of progression to T2D, and is used in some regions to assist glycaemic control in pregnancy. Consistent with its diversity of actions, established safety profile and cost‐effectiveness, metformin is being assessed for further possible clinical applications. The use of metformin requires adequate renal function for drug elimination, and may cause initial gastrointestinal side effects, which can be moderated by taking with meals or using an extended‐release formulation. Thus, metformin serves as a valuable therapeutic resource for use throughout the natural history of T2D.
Metformin and the gastrointestinal tract McCreight, Laura J.; Bailey, Clifford J.; Pearson, Ewan R.
Diabetologia,
03/2016, Letnik:
59, Številka:
3
Journal Article, Book Review
Recenzirano
Odprti dostop
Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and variability in terms of efficacy and ...side effects remain poorly understood. Although the liver is recognised as a major site of metformin pharmacodynamics, recent evidence also implicates the gut as an important site of action. Metformin has a number of actions within the gut. It increases intestinal glucose uptake and lactate production, increases GLP-1 concentrations and the bile acid pool within the intestine, and alters the microbiome. A novel delayed-release preparation of metformin has recently been shown to improve glycaemic control to a similar extent to immediate-release metformin, but with less systemic exposure. We believe that metformin response and tolerance is intrinsically linked with the gut. This review examines the passage of metformin through the gut, and how this can affect the efficacy of metformin treatment in the individual, and contribute to the side effects associated with metformin intolerance.
Metformin has been in clinical use for the management of type 2 diabetes for more than 60 years and is supported by a vast database of clinical experience: this includes evidence for cardioprotection ...from randomised trials and real-world studies. Recently, the position of metformin as first choice glucose-lowering agent has been supplanted to some extent by the emergence of newer classes of antidiabetic therapy, namely the sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. These agents have benefitted through support from large cardiovascular outcomes trials with more modern trial designs than earlier studies conducted to assess metformin. Nevertheless, clinical research on metformin continues to further assess its many potentially advantageous effects. Here, we review the evidence for improved cardiovascular outcomes with metformin in the context of the current era of diabetes outcomes trials. Focus is directed towards the potentially cardioprotective actions of metformin in patients with type 2 diabetes and heart failure (HF), now recognised as the most common complication of diabetes.
•Metformin has been in clinical use for the management of type 2 diabetes for >60 y.•Randomised and real-world studies have shown cardioprotection with metformin.•Trials with modern designs showed CV protection with SGLT2i & GLP-1 agonists.•There are no head-to-head comparisons of metformin with these newer agents.•The place of metformin in the current era of diabetes outcomes trials is considered with special reference to effects in patients with type 2 diabetes and heart failure.
Current therapies to reduce hyperglycaemia in type 2 diabetes mellitus (T2DM) mostly involve insulin-dependent mechanisms and lose their effectiveness as pancreatic β-cell function declines. In the ...kidney, filtered glucose is reabsorbed mainly via the high-capacity, low-affinity sodium glucose cotransporter-2 (SGLT2) at the luminal surface of cells lining the first segment of the proximal tubules. Selective inhibitors of SGLT2 reduce glucose reabsorption, causing excess glucose to be eliminated in the urine; this decreases plasma glucose. In T2DM, the glucosuria produced by SGLT2 inhibitors is associated with weight loss, and mild osmotic diuresis might assist a reduction in blood pressure. The mechanism is independent of insulin and carries a low risk of hypoglycaemia. This review examines the potential of SGLT2 inhibitors as a novel approach to the treatment of hyperglycaemia in T2DM.
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