Clifford J. Bailey

Use of Metformin in the Setting of Mild-to-Moderate Renal Insufficiency

A common clinical conundrum faces all U.S. practitioners treating patients with type 2 diabetes. Today’s U.S. Food and Drug Administration prescribing guidelines for metformin contraindicate its use in men and women with serum creatinine concentrations ≥1.5 and ≥1.4 mg/dL (≥132 and ≥123 µmol/L), respectively. In a patient tolerating and controlled with this medication, should it automatically be discontinued as the creatinine rises beyond these cut points over time? Stopping metformin often results in poorly controlled glycemia and/or the need for other agents with their own adverse-effect profiles. Moreover, is the now widespread use of estimated glomerular filtration rate (eGFR) in lieu of serum creatinine levels creating even more confusion, especially in those with abnormalities in one but not the other indirect measure of renal function? Indeed, more than a decade and a half after metformin became available in the U.S., debate continues over the best approach in these settings (1–3). How many patients are unable to receive this medication on the basis of guidelines which, although well intentioned, are somewhat arbitrary and outdated based on modern assessments of renal status? There is some evidence that early treatment with metformin is associated with reduced cardiovascular morbidity and total mortality in newly diagnosed type 2 diabetic patients (4). However, the data come from a small subgroup of a much larger trial. In contrast, despite multiple trials of intensive glucose control using a variety of glucose-lowering strategies, there is a paucity of data to support specific advantages with other agents on cardiovascular outcomes (5–7). In the original UK Prospective Diabetes Study (UKPDS), 342 overweight patients with newly diagnosed diabetes were randomly assigned to metformin therapy (8). After a median period of 10 years, this subgroup experienced a 39% ( P = 0.010) risk reduction for myocardial infarction and a …

Oral Antidiabetic Agents

Type 2 diabetes mellitus is a progressive and complex disorder that is difficult to treat effectively in the long term. The majority of patients are overweight or obese at diagnosis and will be unable to achieve or sustain near normoglycaemia without oral antidiabetic agents; a sizeable proportion of patients will eventually require insulin therapy to maintain long-term glycaemic control, either as monotherapy or in conjunction with oral antidiabetic therapy. The frequent need for escalating therapy is held to reflect progressive loss of islet β-cell function, usually in the presence of obesity-related insulin resistance.Today’s clinicians are presented with an extensive range of oral antidiabetic drugs for type 2 diabetes. The main classes are heterogeneous in their modes of action, safety profiles and tolerability. These main classes include agents that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (α-glucosidase inhibitors) or improve insulin action (thiazolidinediones).The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated the benefits of intensified glycaemic control on microvascular complications in newly diagnosed patients with type 2 diabetes. However, the picture was less clearcut with regard to macrovascular disease, with neither sulphonylureas nor insulin significantly reducing cardiovascular events. The impact of oral antidiabetic agents on atherosclerosis — beyond expected effects on glycaemic control — is an increasingly important consideration. In the UKPDS, overweight and obese patients randomised to initial monotherapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with type 2 diabetes. Concern about cardiovascular safety of sulphonylureas has largely dissipated with generally reassuring results from clinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Study showed that intensive target-driven, multifactorial approach to management, based around a sulphonylurea, reduced the risk of both micro- and macrovascular complications in high-risk patients. Theoretical advantages of selectively targeting postprandial hyperglycaemia require confirmation in clinical trials of drugs with preferential effects on this facet of hyperglycaemia are currently in progress. The insulin-sensitising thiazolidinedione class of antidiabetic agents has potentially advantageous effects on multiple components of the metabolic syndrome; the results of clinical trials with cardiovascular endpoints are awaited.The selection of initial monotherapy is based on a clinical and biochemical assessment of the patient, safety considerations being paramount. In some circumstances, for example pregnancy or severe hepatic or renal impairment, insulin may be the treatment of choice when nonpharmacological measures prove inadequate. Insulin is also required for metabolic decompensation, that is, incipient or actual diabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certain comorbidities, for example presentation with myocardial infarction during other acute intercurrent illness, may make insulin the best option.Oral antidiabetic agents should be initiated at a low dose and titrated up according to glycaemic response, as judged by measurement of glycosylated haemoglobin (HbA1c) concentration, supplemented in some patients by self monitoring of capillary blood glucose. The average glucose-lowering effect of the major classes of oral antidiabetic agents is broadly similar (averaging a 1–2% reduction in HbA1c), α-glucosidase inhibitors being rather less effective. Tailoring the treatment to the individual patient is an important principle. Doses are gradually titrated up according to response. However, the maximal glucose-lowering action for sulphonylureas is usually attained at appreciably lower doses (approximately 50%) than the manufacturers’ recommended daily maximum. Combinations of certain agents, for example a secretagogue plus a biguanide or a thiazolidinedione, are logical and widely used, and combination preparations are now available in some countries. While the benefits of metformin added to a sulphonylurea were initially less favourable in the UKPDS, longer-term data have allayed concern. When considering long-term therapy, issues such as tolerability and convenience are important additional considerations.Neither sulphonylureas nor biguanides are able to appreciably alter the rate of progression of hyperglycaemia in patients with type 2 diabetes. Preliminary data suggesting that thiazolidinediones may provide better long-term glycaemic stability are currently being tested in clinical trials; current evidence, while encouraging,is not conclusive.Delayed progression from glucose intolerance to type 2 diabetes in high-risk individuals with glucose intolerance has been demonstrated with troglitazone, metformin and acarbose. However, intensive lifestyle intervention can be more effective than drug therapy, at least in the setting of interventional clinical trials. No antidiabetic drugs are presently licensed for use in prediabetic individuals.

Traditional Plant Medicines as Treatments for Diabetes

More than 400 traditional plant treatments for diabetes mellitus have been recorded, but only a small number of these have received scientific and medical evaluation to assess their efficacy. Traditional treatments have mostly disappeared in occidental societies, but some are prescribed by practitioners of alternative medicine or taken by patients as supplements to conventional therapy. However, plant remedies are the mainstay of treatment in underdeveloped regions. A hypoglycemic action from some treatments has been confirmed in animal models and non-insulin-dependent diabetic patients, and various hypoglycemic compounds have been identified. A botanical substitute for insulin seems unlikely, but traditional treatments may provide valuable clues for the development of new oral hypoglycemic agents and simple dietary adjuncts.

Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial

BACKGROUND Correction of hyperglycaemia and prevention of glucotoxicity are important objectives in the management of type 2 diabetes. Dapagliflozin, a selective sodium-glucose cotransporter-2 inhibitor, reduces renal glucose reabsorption in an insulin-independent manner. We assessed the efficacy and safety of dapagliflozin in patients who have inadequate glycaemic control with metformin. METHODS In this phase 3, multicentre, double-blind, parallel-group, placebo-controlled trial, 546 adults with type 2 diabetes who were receiving daily metformin (>/=1500 mg per day) and had inadequate glycaemic control were randomly assigned to receive one of three doses of dapagliflozin (2.5 mg, n=137; 5 mg, n=137; or 10 mg, n=135) or placebo (n=137) orally once daily. Randomisation was computer generated and stratified by site, implemented with a central, telephone-based interactive voice response system. Patients continued to receive their pre-study metformin dosing. The primary outcome was change from baseline in haemoglobin A(1c)(HbA(1c)) at 24 weeks. All randomised patients who received at least one dose of double-blind study medication and who had both a baseline and at least one post-baseline measurement (last observation carried forward) were included in the analysis. Data were analysed by use of ANCOVA models. This trial is registered with ClinicalTrials.gov, number NCT00528879. FINDINGS 534 patients were included in analysis of the primary endpoint (dapagliflozin 2.5 mg, n=135; dapagliflozin 5 mg, n=133; dapagliflozin 10 mg, n=132; placebo, n=134). At week 24, mean HbA(1c) had decreased by -0.30% (95% CI -0.44 to -0.16) in the placebo group, compared with -0.67% (-0.81 to -0.53, p=0.0002) in the dapagliflozin 2.5 mg group, -0.70% (-0.85 to -0.56, p<0.0001) in the dapagliflozin 5 mg group, and -0.84% (-0.98 to -0.70, p<0.0001) in the dapagliflozin 10 mg group. Symptoms of hypoglycaemia occurred in similar proportions of patients in the dapagliflozin (2-4%) and placebo groups (3%). Signs, symptoms, and other reports suggestive of genital infections were more frequent in the dapagliflozin groups (2.5 mg, 11 patients [8%]; 5 mg, 18 [13%]; 10 mg, 12 [9%]) than in the placebo group (seven [5%]). 17 patients had serious adverse events (four in each of the dapagliflozin groups and five in the placebo group). INTERPRETATION Addition of dapagliflozin to metformin provides a new therapeutic option for treatment of type 2 diabetes in patients who have inadequate glycaemic control with metformin alone. FUNDING Bristol-Myers Squibb and AstraZeneca.

Biguanides and NIDDM

The main biguanides, metformin and phenformin, were introduced in 1957 as oral glucose-lowering agents to treat non-insulin-dependent diabetes mellitus (NIDDM). Phenformin was withdrawn in many countries because of an association with lactic acidosis, but metformin does not have the same risk if appropriately prescribed. Metformin is now widely used as a monotherapy and in combination with a sulfonylurea. Unlike sulfonylureas, metformin is not bound to plasma proteins, is not metabolized, and is eliminated rapidly by the kidney. The glucose-lowering effect occurs without stimulation of insulin secretion and results mainly from increased glucose utilization. The presence of insulin is required, and enhancement of insulin action at the postreceptor level occurs in peripheral tissues such as muscle. In peripheral tissues metformin increases insulin-mediated glucose uptake and oxidative metabolism. Metformin also increases glucose utilization by the intestine, primarily via nonoxidative metabolism. The extra lactate produced is largely extracted by the liver and serves as a substrate to sustain gluconeogenesis. This limits the extent to which metformin reduces hepatic glucose production but provides a safeguard against excessive glucose lowering. Because metformin does not cause clinical hypoglycemia, it is actually an antihyperglycemic drug. It does not cause weight gain, it helps combat hypertriglyceridemia, and it has been ascribed some vasoprotective properties. Metformin offers a useful treatment for insulin-resistant overweight NIDDM patients.

Management of type 2 diabetes: new and future developments in treatment

The increasing prevalence, variable pathogenesis, progressive natural history, and complications of type 2 diabetes emphasise the urgent need for new treatment strategies. Longacting (eg, once weekly) agonists of the glucagon-like-peptide-1 receptor are advanced in development, and they improve prandial insulin secretion, reduce excess glucagon production, and promote satiety. Trials of inhibitors of dipeptidyl peptidase 4, which enhance the effect of endogenous incretin hormones, are also nearing completion. Novel approaches to glycaemic regulation include use of inhibitors of the sodium-glucose cotransporter 2, which increase renal glucose elimination, and inhibitors of 11β-hydroxysteroid dehydrogenase 1, which reduce the glucocorticoid effects in liver and fat. Insulin-releasing glucokinase activators and pancreatic-G-protein-coupled fatty-acid-receptor agonists, glucagon-receptor antagonists, and metabolic inhibitors of hepatic glucose output are being assessed. Early proof of principle has been shown for compounds that enhance and partly mimic insulin action and replicate some effects of bariatric surgery.

Abnormal plasma glucose and insulin responses in heterozygous lean (ob/+) mice

SummaryTo investigate the effect of the ob gene in the heterozygous condition, plasma glucose and insulin responses of adult heterozygous lean (ob/+) mice were compared with mice of the homozygous lean (+/+) and homozygous obese (ob/ob) genotypes. The ob/+ mice consumed 24% more food than +/+ mice although body weights were similar. Plasma glucose and insulin concentrations were respectively 16% and 176% higher in ob/+ mice than +/+ mice in the freely fed state, and 44% and 88% higher during glucose tolerance tests. In 24 hour fasted ob/+ mice, plasma glucose concentrations were 23% higher than +/+ mice but plasma insulin concentrations were not significantly different. Arginine produced a greater insulin response (172%) and a greater fall in glycaemia (200%) in ob/ + mice. A significant difference in the hypoglycaemic effect of insulin in ob/+ and +/+ mice was not observed. These results demonstrate an effect of the ob gene on glucose homeostasis in heterozygous lean (ob/+) mice. The abnormalities were qualitatively similar but considerably less severe than those in ob/ob mice, suggesting that ob/+ mice might prove useful to study factors predisposing to inappropriate hyperglycaemia.

Traditional plant treatments for diabetes. Studies in normal and streptozotocin diabetic mice

SummaryThe effects on glucose homeostasis of eleven plants used as traditional treatments for diabetes mellitus were evaluated in normal and streptozotocin diabetic mice. Dried leaves of agrimony (Agrimonia eupatoria), alfalfa (Medicago saliva), blackberry (Rubus fructicosus), celandine (Chelidonium majus), eucalyptus (Eucalyptus globulus), ladys mantle (Alchemilla vulgaris), and lily of the valley (Convallaria majalis); seeds of coriander (Coriandrum sativum); dried berries of juniper (Juniperus communis); bulbs of garlic (Allium sativum) and roots of liquorice (Glycyrhizza glabra) were studied. Each plant material was supplied in the diet (6.25% by weight) and some plants were additionally supplied as decoctions or infusions (1 g/400 ml) in place of drinking water to coincide with the traditional method of preparation. Food and fluid intake, body weight gain, plasma glucose and insulin concentrations in normal mice were not altered by 12 days of treatment with any of the plants. After administration of streptozotocin (200 mg/kg i.p.) on day 12 the development of hyperphagia, polydipsia, body weight loss, hyperglycaemia and hypoinsulinaemia were not affected by blackberry, celandine, ladys mantle or lily of the valley. Garlic and liquorice reduced the hyperphagia and polydipsia but did not significantly alter the hyperglycaemia or hypoinsulinaemia. Treatment with agrimony, alfalfa, coriander, eucalyptus and juniper reduced the level of hyperglycaemia during the development of streptozotocin diabetes. This was associated with reduced polydipsia (except coriander) and a reduced rate of body weight loss (except agrimony). Alfalfa initially countered the hypoinsulinaemic effect of streptozotocin, but the other treatments did not affect the fall in plasma insulin. The results suggest that certain traditional plant treatments for diabetes, namely agrimony, alfalfa, coriander, eucalyptus and juniper, can retard the development of streptozotocin diabetes in mice.

Accumulation of metformin by tissues of the normal and diabetic mouse

1. Tissue accumulation of the antihyperglycaemic agent metformin (dimethylbiguanide) was examined after oral administration to the normal and streptozotocin (STZ) diabetic mouse. 2. Metformin (50 mg/kg body weight containing 14C-metformin 25 microCi/kg body weight), which is stable and not metabolized, resulted in maximum plasma concentrations at 0.5 h which declined to < 5% of maximum by 24 h. Maximum plasma concentrations (mumol/l, mean +/- SE) in the hepatic portal vein (normal 51.7 +/- 5.4, STZ 61.5 +/- 8.0) were higher than in the inferior vena cava (normal 29.0 +/- 2.8, STZ 35.4 +/- 5.9). 3. The greatest accumulation of metformin occurred in tissues of the small intestine, where maximum concentrations were > 1000 mumol/kg wet weight at 0.5-2 h, but declined to < 2% of maximum by 24 h. 4. Stomach, colon, salivary gland, kidney and liver accumulated metformin more than two-fold, and concentrations of the drug in heart and skeletal (gastrocnemius) muscle were greater than plasma concentrations on some occasions up to 8 h. 5. In a separate study, i.v.-administered metformin was selectively accumulated by tissues of the small intestine. Thus, retention of metformin by tissues of the small intestine may represent a deep compartment for the drug.

The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms.

Metformin is regarded as an antihyperglycaemic agent because it lowers blood glucose concentrations in type 2 (non-insulin-dependent) diabetes without causing overt hypoglycaemia. Its clinical efficacy requires the presence of insulin and involves several therapeutic effects. Of these effects, some are mediated via increased insulin action, and some are not directly insulin dependent.Metformin acts on the liver to suppress gluconeogenesis mainly by potentiating the effect of insulin, reducing hepatic extraction of certain substrates (e.g. lactate) and opposing the effects of glucagon. In addition, metformin can reduce the overall rate of glycogenolysis and decrease the activity of hepatic glucose-6-phosphatase. Insulin-stimulated glucose uptake into skeletal muscle is enhanced by metformin. This has been attributed in part to increased movement of insulin-sensitive glucose transporters into the cell membrane. Metformin also appears to increase the functional properties of insulin- and glucose-sensitive transporters. The increased cellular uptake of glucose is associated with increased glycogen synthase activity and glycogen storage. Other effects involved in the blood glucose-lowering effect of metformin include an insulin-independent suppression of fatty acid oxidation and a reduction in hypertriglyceridaemia. These effects reduce the energy supply for gluconeogenesis and serve to balance the glucose-fatty acid (Randle) cycle. Increased glucose turnover, particularly in the splanchnic bed, may also contribute to the blood glucose-lowering capability of metformin.Metformin improves insulin sensitivity by increasing insulin-mediated insulin receptor tyrosine kinase activity, which activates post-receptor insulin signalling pathways. Some other effects of metformin may result from changes in membrane fluidity in hyperglycaemic states.Metformin therefore improves hepatic and peripheral sensitivity to insulin, with both direct and indirect effects on liver and muscle. It also exerts effects that are independent of insulin but cannot substitute for this hormone. These effects collectively reduce insulin resistance and glucotoxicity in type 2 diabetes.