Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin,type 1 diabetes medication costs 97,diabetes mellitus type 2 recipes ks2 - .


Our New BMJ website does not support IE6 please upgrade your browser to the latest version or use alternative browsers suggested below. An individualised approachThe current approach to management of type 2 diabetes involves individualisation of treatment and is centred on achieving glycaemic control while minimising the risk of hypoglycaemia. Graph shows the adjusted mean change from baseline as a repeated-measures analysis in patients who had a baseline value and at least one post-baseline value.
At the end of the 52-week, short-term phase, patients continued in a 52-week extension study receiving the same double-blind treatment. Data from a Phase IIIb, double-blind, parallel-group study to evaluate efficacy and safety of saxagliptin 5 mg as add-on therapy in 455 patients with Type 2 diabetes with inadequate glycaemic control (HbA1c 7.5–11% ) on insulin alone or combined with metformin. In Type 2 Diabetes Mellitus (T2DM) patients, the evident metabolic abnormalities include obesity, insulin resistance, qualitative and quantitative abnormalities in insulin secretion, dysregulated secretion of other islet hormones such as amylin and glucagon and increased endogenous glucose production. In April 2005, the US Food and Drug Administration (US FDA) approved the first incretin mimetic, Exenatide, a GLP-1 receptor analogue resistant to Dipeptidyl peptidase-4 (DPP-4) degradation, as adjunctive therapy for patients with T2DM, but the use of this drug is limited by its parenteral route of administration.
In 1932, the term a€?incretina€? was used for the first time to refer to a substance derived from the gut presumably a hormone that regulates insulin secretion after eating. Recent improvement in understanding of the incretin effect on pathophysiology of T2DM has led to development of new hypoglycaemic agents.2 Studies have shown that in T2DM, there is deficient insulin as well as GLP-1 secretion after the injection of glucose or a meal, though biological effects of GLP-1 are preserved.
Sitagliptin is a highly selective DPP-4 inhibitor for the treatment of T2DM that was discovered through the optimisation of class of I?-amino acids derived DPP4 inhibitors. DPP-4 inhibitors enhance the levels of active incretin hormones; gut derived peptides that are released into circulation after the ingestion of meal.
The pharmacokinetics of Sitagliptin is similar in healthy individuals and in T2DM patients. Few adverse effects reported with Sitagliptin are nasopharyngitis, upper respiratory tract infections, headache, back pain, osteoarthritis, and pain in extremities. As Sitagliptin is primarily secreted via renal elimination, therefore, the dosage must be adjusted in patients with moderate-to-severe renal impairment or end stage renal disease. Studies have shown that moderate hepatic insufficiency (Child-Pugh classification scores 7 to 9) have no clinical effect on pharmacokinetics of Sitagliptin. DPP-4, the cell surface protease is expressed in various normal tissues and functions as tumour suppressor. There are 13 published double-blind trials ( n = 4780) (age range, 18-80 years) in which Sitagliptin was compared with a DPP-4 inhibitor given as monotherapy, or as add-on therapy to oral hypoglycaemic agents or insulin2, out of which a few have been shown in Table 1. Goldstein et al {2007} demonstrated the effect of Sitagliptin and Metformin as monotherapy and as combination therapies (at different doses) in T2DM patients who had inadequate glycaemic control with diet and exercise.
In another combination study by Cherbonnel et al {2006}, in 701 patients of type T2DM who had inadequate glycaemic control with metformin alone, the addition of Sitagliptin 100 mg once daily was well tolerated and provided effective and sustained improvement in HbA1c, FPG and PPG levels. In a head-to-head comparison, Nauck et al {2007} found that Sitagliptin 100 mg once daily was non-inferior to Glipizide 20 mg once daily as an adjunct to Metformin a‰? 1500 mg once daily.
Comparable results were observed in a study by Rosenstock et al {2006} with similar design with an add-on combination of Sitagliptin to an existing Pioglitazone therapy.
Hermansen et al {2007} found that Sitagliptin 100 mg once daily significantly improved glycaemic control and I?-cell function in patients with T2DM, who had inadequate glycaemic control with Glimepiride or Glimepiride plus Metformin therapy. Most trials of Sitagliptin in combination with oral anti-diabetic drugs (OADs) indicated that DPP-4 inhibitors produce incremental or sometimes additive improvement in glycaemic parameters. Due to a lack of safety and efficacy data, Sitagliptin is not recommended for use in children under 18 years of age and caution is advised in patients > 75 years old. The maximum approved and recommended dose for Sitagliptin is 100 mg daily and this is the most effective dose for various glycaemic parameters. Metformin, a sulphonylurea is widely viewed as the initial drug of choice for treatment of type 2 DM owing to its 30 year track record, efficacy, safety and low cost. The past few years have witnessed considerable progress in pharmacotherapy of T2DM and ease of use, favourable adverse event profile and lack of hypoglycaemia or weight gain are attractive features for the new class of DPP-4 inhibitors exemplified by Sitagliptin, though long term safety of prolonged DPP-4 inhibition in patients with T2DM is unknown. It has been observed from various clinical studies (Table 1) that Sitagliptin is effective, well tolerated and safe in the treatment of T2DM as monotherapy or in the combination with metformin or thiazolidinediones. Sitagliptin and other DPP-4 inhibitors in general present a novel multimodal approach in treatment of T2DM.
Bayliss and Starling inferred the existence of gut-derived substances affecting carbohydrate metabolism more than a century ago, but the incretin effect was not described until 1969: the observation that for a given achieved level of plasma glucose, oral glucose produced a higher insulin concentration than intravenous glucose (Fig.
The incretin system is critical in stimulating postprandial insulin secretion in response to nutrients entering the gut; about 50% of secretion is thought to be mediated by incretins and therefore is at least as important as glucose itself. The dominant effect of GLP-1 is therefore on postprandial glucose levels, and two additional mechanisms are important here: (i) decreasing postprandial glucagon secretion (an important factor in type 2 diabetes) and (ii) slowing gastric emptying. GLP-1 analogues, like insulin analogues, are GLP-1 molecules modified in various ways, but primarily to resist degradation by DPP-4. In trials comparing exenatide and insulin (usually basal glargine) added to metformin plus sulphonylurea, changes in glycemia are similar, though some studies have been criticized for not optimizing insulin doses. This unlicensed combination is in widespread use where additional oral agents have failed, and glycemic control and weight are deteriorating despite large daily doses of insulin. These are once- or twice-daily orally active drugs which are weight neutral, with overall similar or slightly less powerful glycemic effect compared with other medications for type 2 diabetes.
Three agents, sitagliptin, vildagliptin and saxagliptin, are currently licensed in the UK, with several more in late-stage development. Vildagliptin and saxagliptin are licensed for use only in dual therapy with metformin, a sulphonylurea or a glitazone.
The practical use of these agents within license, apart from sitagliptin, is currently limited, but the low risk of hypoglycemia (except when combined with insulin) makes them attractive alternative second-line agents either when a sulphonylurea has caused hypoglycemia or in others at high risk of hypoglycemia, for example the elderly. Many bodies have issued guidelines and consensus documents on combination treatment in type 2 diabetes, but there is surprisingly little common ground among them, other than the initial steps of lifestyle intervention and metformin. Since then, countless large-scale RCTs have compared different insulin regimens for short- and medium-term glycemic control. While much of the discussion and all the trials of insulin treatment in type 2 diabetes relate to overweight or obese subjects failing on routine combined oral hypoglycemic agents, the relatively small proportion, but large absolute number, of patients with late-onset type 1 diabetes must be recognized (see Chapter 1). Insulin regimens in these patients should be the same as those in type 1 diabetes with the same intensity and targets. However, there is little contemporary evidence to support this notion, when insulin (usually with metformin) is compared with combination treatment.
While there is still controversy surrounding the indications for insulin treatment in patients with type 2 diabetes, earlier studies progressively supported the use of basal insulin with continuing oral hypoglycemics as the most effective initial insulin regimen. Even when basal insulin treatment has been maximized to achieve good fasting levels, HbA1c remains very poor (e.g.
Sequentially add prandial insulin to one meal at a time, starting with the most carbohydrate-rich meal, and thereafter to the other main meals. Regrettably there are no RCTs to help guide practice in this common, difficult and distressing clinical problem, the frequency of which could appear to the sceptical as undermining the concept of the limitless impact of insulin.
Taking into account the results of the recent glycemia trials, the duration of diabetes and complications, would focusing on more achievable, non-glycemic targets be a better use of time and resources?
Bariatric surgery in the obese or very obese patient on multiple ineffective medications with or without late complications. Roux-en-Y bypass is usually performed laparoscopically, is safe (operative mortality about 0.5%), and NICE suggests considering it in diabetic patients with a BMI of 35–40. While many new drugs are in early development, probably only one novel group of agents will be introduced over the next few years, the type 2 sodium glucose cotransporter (SGLT2) inhibitors.
Diabetes mellitus type 1 The classical symptoms of type 1 diabetes include: polyuria (excessive urination) polydipsia According to the Canadian Diabetes Association 15% of people living wih diabetes have major depression IBS-C Symptoms? Then the patient drinks a sweet liquid which contains Testing can improve your blood sugar results, and help you maintain healthy blood sugar ranges. After adjustment for body mass index and smoking, no significant effect of metformin on folate concentrations was found. This information is not intended as a substitute for medical advice from a qualified health professional. Objectives of the extension study were long-term safety, tolerability and efficacy of saxagliptin + metformin versus glipizide + metformin after 104 weeks of treatment. The objectives of the extension study were long-term safety, tolerability and efficacy of saxagliptin + metformin versus glipizide + metformin after 104 weeks of treatment. Therefore considerable efforts have been devoted for creating an oral hypoglycaemic drug targeting the incretin pathway. Thereafter in 1971, the first incretin GIP and in 1985, second incretin GLP-1 was described.5 GIP and GLP-1 are secreted by enteroendocrine K-cells in the proximal gut and L-cells in the distal gut respectively. In contrast, plasma levels of GIP are normal or slightly increased in T2DM, while its activity is defective or absent.5, 6 This is clear that the incretin effect of GLP-1 in T2DM is better preserved in contrast to that of GIP. DPP4 is complex molecule that exists as membrane spanning cell anchored protein that is expressed on many cell types, and as soluble form in circulation both forms have proteolytic activity. In presence of elevated glucose concentrations, GLP-1 and GIP increase insulin release and GLP-1 in addition, lowers glucagon secretion, thereby decreasing post meal rise in glucose concentration and reducing fasting glucose concentration.
In Laboratory parameters, small increase in white blood cells, serum uric acid and small decrease in alkaline phosphatase is reported. The single 100 mg dose of the Sitagliptin was well tolerated with no meaningful changes observed in liver function tests.
DPP-4 expression is lost in many types of human cancers like non small cell lung carcinoma (NSCLC) and prostate cancer. Nearly half of the patients receiving Sitagliptin 100 mg once daily achieved current American Diabetes Association glycaemic goal of HbA1c < 7% compared with less than one-fifth of placebo treated patients. Sitagliptin has shown reproductive toxicity at high doses and has been detected in high amounts in the milk of lactating animals. Sitagliptin is metabolised by CYP3A4 but it does not appear to induce or inhibit cytochrome P450 isoenzymes and does not show interactions with inducers or inhibitors of cytochromes. Vildagliptin (Glavus- Novartis) has been approved for use in the European Union and is under regulatory review in United states.
There is also no long term data available to inform the patients and physicians about Sitagliptin therapy to prevent progression of T2DM. Sitagliptin when used as monotherapy produces dose-dependent reduction in PPG levels but effect on HbA1C and FPG levels is independent of dose. By preserving stimulated circulating plasma levels of incretin hormones, insulin secretion is stimulated under hyperglycaemic conditions and glucagon secretion is suppressed. Targeting Incretins in Type 2 Diabetes: Role of GLP-1 Receptor agonists and DPP-4 inhibitiors. Differential chemistry (structure), Mechanism of action, and Pharmacology of GLP-1 receptor agonist and DPP-4 inhibitors. Incretin-based therapies: a new potential treatment approach to overcome clinical inertia in type 2 diabetes. Efficacy and safety of the Dipeptidyl Peptidase-4 inhibitor Sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone.
Efficacy and safety of the Dipeptidyl Peptidase-4 inhibitor Sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Effect of Renal insufficiency on the pharmacokinetics of Sitagliptin, a Dipeptidyl Peptidase-4 inhibitor.
Role of Dipeptidyl Peptidase IV in tumor suppression of human non small cell lung carcinoma cells. Dipeptidyl Peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway. DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells.
Effect of the Dipeptidyl Peptidase-4, inhibitor Sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Effect of initial combination therapy with Sitagliptin, a dipeptidyl peptidase-4 inhibitor, and Metformin on Glycaemic control in patients with type 2 diabetes. Efficacy and Safety of the dipeptidyl peptidase-4 inhibitor, Sitagliptin, compared with the Sulfonylures, Glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone : a randomized, double-blind, non-inferiority trial. Efficacy and Safety of Dipeptidyl Peptidase -4 inhibitor Sitagliptin added to ongoing Pioglitazone therapy in patients with Type 2 Diabetes: A 24-week, multicentric, randomized double-blind, placebo-controlled, parallel-group study.
Efficacy and Safety of the dipeptidyl peptidase-4 inhibitor, Sitagliptin, in patients with type 2 diabetes inadequately controlled on glimepiride alone or on glimepiride and Metformin.
Saxagliptin: a dipeptidyl peptidase 4 inhibitor for the treatment of type 2 diabetes mellitus.


In type 2 diabetes, the incretin effect is reduced, through a combination of GLP-1 deficiency and defective GLP-1 signalling, and possibly reduced islet responsiveness to GIP (Fig. Exendin-4 occurs in the saliva and venom of the rare binge-eating gila lizard (Heloderma suspectum) and beaded lizard (H. Prospective studies are needed, but in a retrospective 2-year study in patients taking a mean total daily insulin dose of 100 units, adding exenatide reduced Hb1c by 0.5%.
It gained a European licence in 2009, and was approved in the USA in 2010, but with a caution relating to a possible increased risk of medullary thyroid cancer in non-human studies.
Nausea with liraglutide occurred for a shorter time, 2–4% of patients reporting nausea by 16 weeks compared with 14% at onset of treatment. Like the injectable GLP-1 analogues, they are glucose-sensitive and do not cause hypoglycemia when used as monotherapy or with agents that themselves do not cause hypoglycemia. Indeed, until the 1950s, it was the only treatment available and, until the mid-1990s, the only combination treatment available in the USA was insulin with a sulphonylurea.
Many have explored insulin as an early intervention in type 2 diabetes, concluded that it is effective, safe and associated with no detrimental effects on quality-of-life measures, and in many instances seems to have improved it, and have increasingly recommended it in clinical practice. While insulin deficiency is rarely complete, and ketonuria therefore uncommon, the persistent presence of urinary ketones should be a warning that insulin treatment may be needed; occasionally patients will be ketonuric during an intercurrent illness that uncovers insulin deficiency. Statements like this are common, and continue to be made even after the recent trials implicating hypoglycemia as a serious adverse prognostic factor, and suggesting that HbA1c levels below 7.0% do not meaningfully improve the vascular prognosis in many patients.
The rationale behind its early use is that it preserves beta-cell function better than other agents, but there are no long-term data to support this.
The most recent study is the long-term follow-up of the 4-T, in typical overweight patients (e.g. Several possible strategies are therefore valuable after establishing an optimum basal insulin regimen with oral hypoglycemic agents (Fig. Some patients may not eat breakfast, and long-acting analogue bedtime insulin may maintain satisfactory control until lunch, thereby limiting the number of prandial insulin injections. Humulin M3, NovoMix 30, Insuman Comb 25); in some short-term studies, this is more effective than basal insulin. However, the durability of these regimens is not assured, and results of long-term outcome studies are badly needed, for example the 2-year DURABLE study.
Give a trial of modified-release metformin in patients previously intolerant of immediate-release metformin.
Add pioglitazone 15 mg daily, increasing very gradually up to 45 mg if beneficial and tolerated. Inhibition of glucose reabsorption in the proximal renal tubules by the prototype clinical compound dapagliflozin is insulin independent and causes mild glycosuria and diuresis without hypoglycemia. Explain What Causes Diabetes Cheese Cream Diet Diabetic are you suddenly feeling much thirstier hungrier and losing weight without trying? Doctors in India note that Gymnema Sylvestre is used in the treatment of diabetes mellitus and in food Cinnamon has been shown to help regulate blood glucose levels and several studies indicate that it may be helpful against diabetes particularly type II Learn how to prevent foot problems caused by diabetes with this Howcast video about foot care. Health professionals should rely on their own expertise and enquiries when providing medical advice or treatment.
Reported HbA1c reduction may be impacted by medicine class, dose, duration of diabetes and baseline glycaemia.
Objectives of the extension were long-term safety, tolerability and efficacy of saxagliptin + metformin versus glipizide + metformin after 104 weeks of treatment. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a new therapeutic approach for type 2 diabetes.
Inhibition of the enzyme DPP-4 extends the half life of native incretins, thereby prolonging their physiological effects. Both GIP and GLP-1 are secreted into the circulation as active hormones within minutes in response to food consumption and are rapidly inactivated by the enzyme DPP- 4, an ubiquitous serine protease.
In human beings, the protein binding of Sitagliptin, as determined by ultracentrifugation is 34-46%. Therefore, no dosage adjustments of Sitagliptin are required in patients with mild to moderate hepatic insufficiency.12 There are no clinical studies on humans in literature to demonstrate the effects of Sitagliptin in severe hepatic insufficiency patients.
The FDA has granted an approval letter for Vildagliptin but require additional safety data prior to final approval.4 Saxagliptin (Onglyza-BMS and Astra Zeneca) is approved and recently marketed in India for the treatment of T2DM. Sulphonylureas and glitinides are inexpensive but are associated with weight gain and hypoglycaemia, which can be problematic in elderly. Sitagliptin when used in combination of Metformin or any other oral hypoglycaemic drug produces additive effect in reducing glycaemic parameters. In non-diabetic individuals, plasma GLP-1 levels increase within 10–15 min of starting to eat, and remain elevated for several hours, due to different populations of L cells being sequentially stimulated [15]. Vomiting is described in 17% of patients; rarely it is severe and recurrent, and very rarely it can destabilize diabetes control sufficiently to require admission. Although a rare complication, and a causal link has not been confirmed, patients with a past history of pancreatitis, or risk factors for it (e.g. Prandial insulin doses fell by more than 50%, although there was no change in basal insulin doses. The molecule is linked to a fatty acid–albumin complex, similar to the long-acting insulin analogue detemir, adding to its DPP-4 resistance and conferring 24-hour duration of action (Box 6.3). Although it is assumed they act by increasing endogenous GLP-1 levels by inhibiting its breakdown, GLP-1 levels rise only modestly with DPP-4 treatment, and other mechanisms may be relevant, for example improved GLP-1 signalling and insulin processing, and effects on other neuropeptides. They are generally well tolerated, with no specific side-effects, other than occasional mild nausea. Vildagliptin has been rarely associated with liver dysfunction, and baseline alanine aminotransferase should be less than three times the upper limit of normal; 3-monthly liver function tests are suggested during the first year of treatment, annually thereafter. Since it is derived from the pancreas and not the gut, it is not a true incretin, and has no significant direct pancreatic effects. The number of combinations might therefore be considered conservative, DPP-4 inhibitors are not included, and exenatide appears in only one combination. In these simple historical facts lie the problems of objectively assessing insulin treatment in type 2 diabetes, which naturally has not been subjected to the same comparative large-scale RCTs as more recently introduced agents (Box 6.4). Most RCT protocols require frequent and intensive patient contact and education with algorithmically driven titration regimens and treat-to-target objectives; the result can be long-term glycemic stability, in contrast with, for example, the near-continual upward glycemic drift seen in all treatment arms of the UKPDS, which probably more closely resembles what happens in real life. The remaining discussion relates to the much more contentious question of insulin treatment in overweight or obese patients. Nevertheless, it is still widely believed that insulin is a more potent and more effective treatment than other agents. This phenomenon is of no long-term importance, but the very rapid fall in glucose levels often seen in the early stages of insulin treatment may be one factor contributing to an impression that insulin treatment is more effective (compare sulphonylurea treatment in newly diagnosed symptomatic patients). Most patients (80% in 4-T) required additional insulin, effectively converting them to MDI, 60% of the total insulin dose being prandial.
Humalog Mix 25) if more intermediate-acting insulin is needed to achieve good fasting levels.
Ten years after surgery, the Swedish Obesity Study reported a 30% reduction in mortality, with substantial reductions in myocardial infarction and cancers [26], but as yet there are no systematic studies on microvascular complications. While some severe cases (10-15% of all cases) may require daily injections of insulin most gestational diabetes can be controlled by diet and exercise with Benefits of Storing Cord Blood.
Diabetes mellitus type 1 (Type 1 diabetes, T1DM, IDDM, or, formerly, juvenile diabetes) Diabetes is often detected when a person suffers a problem that may be caused by diabetes, such as a heart attack, stroke, neuropathy, poor wound healing or a foot "Type 1 diabetes mellitus in pediatrics". There was no imbalance in CV deaths due to heart failure (0.5% in each group according to 2-year Kaplan-Meier estimates). Sitagliptin is highly selective DPP-4 inhibitor that has been approved for type 2 diabetes therapy. On October 17 2006, the US FDA approved the first oral incretin enhancer, Sitagliptin, a selective DPP-4 inhibitor, for use as monotherapy or in combination with metformin or thiazolidinediones.2 In India, Sitagliptin (MK-O431) is approved and available for use as monotherapy under the brand name Januvia-Merck. Both GIP and GLP-1 bind to specific G-protein coupled receptors present on I?-cells and other target tissues. In healthy volunteers and in patients with T2DM of different ethnic background, the tolerability of different doses as once or twice daily is good.
Clinical trials have demonstrated that Saxagliptin (in doses 2.5, 5, 10, 20, 40 mg once daily) is non inferior to Sitagliptin in monotherapy and in combination therapy with metformin. The I±-glycosidase inhibitors are effective and safe but frequently associated with gastrointestinal side effects that limit their tolerability.
Sitagliptin is weight neutral and does not increase the incidence of hypoglycaemic episodes or the occurrence of adverse events. GIP (now named glucose-dependent insulinotropic hormone) was the first incretin to be sequenced in 1970, and the main therapeutic target in diabetes, GLP-1, in 1983…. However, there is currently nothing to suggest that abnormalities of incretins themselves contribute to type 2 diabetes [14]. Native GLP-1, which has a circulating half-life of only 1–2 min, cannot be used clinically, though continuous intravenous infusions have been used to beneficial effect in pilot studies in myocardial infarction and heart failure, where GLP-1 may increase myocardial glucose uptake and be anti-apoptotic for cardiomyocytes. In its modified synthetic form, exenatide, it was introduced therapeutically in the USA in 2005. The two agents are therefore similar in clinical practice, though the clinical impression is that liraglutide is somewhat better tolerated. For such an abundant hormone, little is known of amylin’s true physiological functions, but pramlintide has been licensed in the USA for use in type 1 and insulin-treated type 2 diabetes. The first comparison of insulin treatment against other therapies (other than the fraught University Group Diabetes Program in the early 1960s) was UKPDS, but this aspect of the trial was somewhat overlooked in comparison with the novel intensive versus conventional treatment strategy and its effect on complications. From this admittedly non-random selection of studies, it is difficult to conclude that insulin treatment, however intensive, gives consistently better glycemic control than judiciously chosen regimens using other agents (Box 6.5). The rationale for using it later is that it is the logical agent in patients with depleted beta-cell function, though if this were the only mechanism operating it should be simple to achieve the kind of glycemia we target in type 1 diabetes. In general, the more intensive the insulin regimen, the greater the weight gain and risk of significant hypoglycemia. No standard regimen can be stipulated, but consider the following, and individualize the approach. The most commonly used and most effective routine bariatric procedure, the Roux-en-Y gastric bypass (Fig.
It would be surprising if there were no effects, even if the impact of near-normoglycemia might not be as dramatic as on resolution of hypertension and its associated features (e.g. Dapagliflozin is effective in poorly controlled patients taking combination insulin and oral hypoglycemic treatments. Sitagliptin is used clinically in India as combination therapy with Metformin and is marketed as Janumet-Merck.
Activation of the incretin receptors on I?-cells acutely enhances glucose dependent exocytosis of insulin and long term effects like stimulation of insulin synthesis, enhancement of I?- cell proliferation and promotion of resistance to apoptosis. It has also been observed that when saxagliptin is used as an add on combination therapy with thiazolidinedione, the incidence of peripheral oedema is increased.24,25 Alogliptin, a highly selective DPP-4 inhibitor, being developed by Takeda Pharmaceutical Company is currently in phase three clinical trials.
Thiazolidinediones improve insulin action with low risk of hypoglycaemia and have appealing long durability but side effects like fluid retention and weight gain might be a problem for many patients. GIP itself does not appear to be deficient, does not lower glucose levels and may even augment postprandial glucose excursions. Exenatide is detectable in plasma up to 10 hours after injection, and therefore requires twice-daily administration (Box 6.2).
In trials, about 5% of patients discontinue treatment because of gastrointestinal side-effects. However, the benefits of GLP-1 treatment over insulin (weight loss, reduced clinic time because of less intensive education and simple dosage titration, and lower risk of hypoglycemia) mean that outside the RCT setting, in the overweight or obese patient failing on dual oral therapy, a trial of GLP-1 treatment with careful clinical supervision should often be considered, with insulin a pre-discussed alternative if unsuccessful.
Another option in this situation, addition of pioglitazone to insulin, gives similar glycemic results but weight increases. Like the GLP-1 analogues, it slows gastric emptying, suppresses postprandial glucagon and glucose levels and increases satiety, but has no effects on peripheral insulin action.
Some studies show improved quality of life with insulin therapy (usually together with metformin) compared with multiple non-insulin agents, but outside the clinical trial setting, individualization of treatment, often involving changes of therapy where necessary, is the best option. Exercise benefits in patients suffering Type 2 lower blood sugar after eating risks during baby pregnancy dabetes?
Diabetes mellitus is a diseased state by which the body suffers from either an absolute Early signs.
Sitagliptin has been shown to be effective, well tolerated and safe in the treatment of type 2 diabetes in monotherapy or in combination with metformin or thiozolidinediones with minimal side effects.


Steady state plasma concentration of Sitagliptin is reached after 3 days with terminal half-life of 10-12 hours at doses of 25-100 mg. Alogliptin in dose range of 25-400 mg causes significant reduction in HbA1c, when used alone or in combination with other oral agents in patients with T2DM similar to Sitagliptin.
However, its therapeutic potential continues to be studied, particularly in obesity, for example, using GIP receptor antagonists. HbA1c reductions of about 1%, sustained up to 3 years, are reported, but in practice individual glycemic changes are highly variable. Avoid in patients with known gastroparesis, and use with great care in patients with advanced peripheral neuropathy (e.g. Local practice is likely to vary on this difficult question; expertise of the team, close monitoring, and intensive support and education are probably as important as the specific pharmacological approach adopted. Insulin does not improve microvascular or macrovascular outcomes compared with other regimens of approximately similar glycemic effectiveness, whether used early (e.g.
Roux-en-Y bypass causes greater weight loss than restrictive procedures (around 60% of excess weight, 10–15 BMI units, or 30–50 kg). Surgical techniques are continually being refined; for example, laparoscopic sleeve (subtotal) gastrectomy, which leaves a small tubular gastric remnant, is a relatively new restrictive procedure (with removal of the appetite-regulating ghrelin produced in the gastric fundus being a possible endocrine mechanism for weight loss). Food and diabetic medication intake causes and treatment of gestational diabetes 2 is mellitus curable type should be scheduled around when exercise is performed to ensure a safe blood glucose level. Day to day routines feeding (type of food frequency) activity and bod weight should be kept as constant as possible as Interventional The Wisconsin Epidemiologic Study of Diabetic Retinopathy Lift Chair * wheelchair lifts *Walk In Tubs * Scooters *Oxygen Concentrators *walkers canes crutches. Metformin does, however, induce vitamin B-12 malabsorption, which may increase the risk of developing vitamin B-12 deficiency5 6 7—a clinically important and treatable condition.
A small number of drugs such as rifampin, phenytoin and ritonavir are identified as inducers of CYP3A4. Weight loss in trials is progressive and meaningful (about 2 kg at 6 months increasing to about 5 kg at 3 years), but like glycemic improvement is highly variable in practice, and there is a weak relationship between weight loss and change in HbA1c.
Following any procedure there is some rebound weight gain over the years, but this is minor in relation to the overall weight loss. Although its place in the bariatric repertoire is not yet clear, it can be used as a single procedure in the moderately obese or as a bridging procedure in the high-risk severely obese patient, converting it later, after initial weight loss, to a Roux-en-Y bypass or a biliopancreatic diversion with duodenal switch.
Further down the line are G protein-coupled receptor 119 (GPR119) agonists, which seem to have a dual action on intestinal L cells to promote GLP-1 secretion and on the beta-cell. The current intensity and type of exercise should be modified for obvious safety issues (e.g. In phase I drug interaction studies, Sitagliptin did not meaningfully alter the pharmacokinetics of other oral hypoglycaemic agents, including metformin, rosiglitazone or glyburide. Hypoglycemia, sometimes severe, can be avoided by reducing prandial insulin doses by 30–50%. Experimentally, combination with DPP-4 inhibitor treatment increases their therapeutic effect. In RCTs, HbA1c reaches a nadir at about 12 weeks, while weight loss continues for much longer. In type 2 diabetes, it is as effective in reducing HbA1c as titrated prandial rapid-acting insulin, and is weight neutral.
Definition and Complications Gestational diabetes mellitus is defined diabetic neuropathy gi tract 2 care nursing plan type as glucose intolerance that begins or is first recognized during pregnancy.4 A wide 15. Consequently, in individual patients tolerating exenatide treatment, a clinical trial of about 4 months should be offered before discontinuation. Uncover the truth about commercial orange juice and find out why you should avoid other Aside from being versatile in creating a number of different flavors including orange cherry pineapple which is not only an underlying factor of type 2 diabetes and heart Serve with fresh fruit salad and a dinner roll.
Patients were randomly assigned by a computer program to receive either 850 mg of metformin three times a day or 850 mg of placebo thrice daily, which were provided in identical looking boxes. However, this decision can be difficult; some patients report consistently decreased satiety, while objectively showing minor changes in both weight and glycemic control. The diabetes is more likely to resolve in patients on tablets, as opposed to insulin, and those with a shorter duration of diabetes. Minor improvements in blood pressure, lipids (especially HDL- cholesterol) and liver function tests have been seen, probably mostly due to weight loss. Diabetes resolves within days of bypass procedures, well before weight loss occurs, but takes months to occur after restrictive surgery. GLP-1 levels substantially increase, and remain elevated for years after bypass, but other hormones influencing satiety and appetite (e.g. During these visits, a physical examination was carried out, a medical history was taken, and laboratory investigations were performed. Australian Medicines Handbook, 2015, [Online] (accessed 9 March 2015).Royal Australian College of General Practitioners. At baseline, and after 10 and 52 months, dietary counselling was given to all patients.Laboratory investigationsBlood samples for this study were drawn at baseline and after 4, 17, 30, 43, and 52 months, and stored at ?80°C until analysis.
Vitamin B-12 and folate concentrations were determined by an electrochemiluminescence immunoassay (ECLIA) using the competition principle. We log transformed data on vitamin B-12, folate, and homocysteine concentrations before analysis because their distribution was skewed. Head-to-head comparison of dipeptidyl peptidase-IV inhibitors and sulfonylureas a€“ a meta-analysis from randomized clinical trials.
Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. The end point of interest was the percentage change of each variable from baseline at 4, 17, 30, 43, and 52 months, which was calculated from baseline values and the summary mean. The differences between the metformin and the placebo group were tested by a central t test on log transformed values. To test whether results obtained were robust, we also used mixed models analysis to impute missing data. We also investigated whether metformin associated changes in homocysteine concentrations, if any, could be explained by changes in the concentrations of folate, vitamin B-12, or both, and, if so, whether the changes were independent of age, gender, duration of diabetes, smoking, body mass index, insulin dose, serum creatinine, high density lipoprotein cholesterol, or glycated haemoglobin.
GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. The goodness of fit between alternative models was compared using the maximum likelihood technique.ResultsPatientsWe screened the medical files of all three participating outpatient clinics and identified 745 eligible patients. All were approached to enrol into the trial and 390 individuals gave written informed consent.
Systematic review and meta-analysis of the efficacy and hypoglycemic safety of gliclazide versus other insulinotropic agents.
Out of the 390 included patients, 277 individuals (72%) were still receiving metformin or placebo at the end of the trial (fig 2?). A total of 46 patients (30 metformin, 16 placebo) discontinued because of adverse effects, which have been described more extensively elsewhere.3 Only two participants were lost to follow-up (at 33 and 26 months, respectively), both of whom were in the metformin group. Safety and efficacy of gliclazide as treatment for type 2 diabetes: a systematic review and meta-analysis of randomized trials.
At the final visit, laboratory samples were available for 256 patients (127 metformin, 129 placebo). The main outcomes of this trial have been reported previously.3Table 1? shows baseline characteristics of all patients analysed. Five randomised patients were excluded from the analysis because of poor correlations between old and newly measured vitamin B-12 values (see Methods).
Patients randomised to metformin were older than those randomised to placebo (64±10 years v 59±11 years), and were more likely to have a history of cardiovascular disease and less likely to be a smoker (30 (19%) v 59 (30%)). Secondary sulfonylurea failure: comparison of period until insulin treatment between diabetic patients treated with gliclazide and glibenclamide.
Fig 3 Concentrations of vitamin B-12, folate, and homocysteine with 95% confidence intervals.
Five patients were excluded from the analysis because of poor correlations between old and newly measured vitamin B-12 values (see Methods). The effects of metformin on concentrations of vitamin B-12, folate, and homocysteine were re-analysed following adjustment for age, previous metformin treatment, duration of diabetes, gender, insulin dose, and smoking habits. None of these variables materially changed the results for vitamin B-12 and homocysteine (data not shown), but they did have an effect on the results for folate.
The number of patients in each treatment group is indicatedLinear mixed modelThe interaction between treatment and time was a significant determinant of vitamin B-12 concentration (P=0.023)—that is, the lowering effect of metformin on vitamin B-12 concentrations increased with time. General mixed model analysis yielded similar results to analysis using last observation carried forward (data not shown). DiscussionOur study on the long term effects of metformin treatment on serum concentrations of vitamin B-12, folate, and homocysteine in patients with type 2 diabetes treated with insulin had three main findings.
Firstly, metformin significantly reduced concentrations of vitamin B-12, in accordance with findings from previous studies.13 18 19 Importantly, our study shows that this decrease is not a transitory phenomenon, but persists and grows over time. Secondly, a small, significant decrease in folate concentrations was found in the metformin group compared with the placebo group; however, this reduction was not statistically significant after adjustments for body mass index and smoking. Thirdly, the decrease in vitamin B-12 concentrations was associated with an increase in homocysteine levels, which was not statistically significant. Furthermore, concentrations in some patients drop to the level at which most authorities agree vitamin substitution is required. We note that there is no consensus on the issue of whether “asymptomatic” vitamin B-12 deficiency should be treated.20 However, studies show that some symptoms of vitamin B-12 deficiency are difficult to diagnose and can be irreversible, and treatment of vitamin B-12 deficiency is relatively easy, cheap, safe, and effective,21 22 23 24 in effect arguing in favour of treatment. In addition, although the necessity of treating “spontaneous” vitamin B-12 deficiency may be debated, one should be more easily inclined to treat drug induced vitamin B-12 deficiency, as a key principle of drug prescription is to do no harm. On the other hand, our study shows that it is reasonable to assume harm will eventually occur in some patients with metformin induced low concentrations of vitamin B-12.Folate concentration increased in both the metformin group and the placebo group, possibly as a result of dietary counselling received by all patients throughout the trial. Our short term interim analysis showed a significantly larger increase in folate concentration in the placebo group,12 a finding that was initially replicated in the current analysis but that disappeared after adjustment for body mass index and smoking.
Previous studies have shown either no or small effects of metformin treatment on concentrations of homocysteine.13 14 25 26 We clearly show that homocysteine concentrations do increase with decreasing levels of vitamin B-12 (fig 4).
The finding that metformin treatment significantly lowered concentrations of vitamin B-12 but did not significantly alter levels of homocysteine probably reflects the relatively low incidence of vitamin B-12 deficiency in the entire study population. Furthermore, the study was conducted in a non-academic setting and, therefore, the findings have high value in a community setting. Another strength is that we used last observation carried forward in this analysis because this method is considered more conservative than general mixed model analysis, “freezing” any observed divergence between two groups by retaining the last observation made.
In a mixed model analysis with missing data, estimations of future observations are made on the basis of observations made earlier in the trial, thereby reflecting a divergence more accurately but less conservatively.Limitations of our study include the fact that we measured only total vitamin B-12 levels and not levels of holotranscobalamin II or methylmalonic acid, which may have been more precise indicators of vitamin B-12 status. Finally, it is likely that, if anything, we underestimated the impact of metformin treatment on the risk of clinically important vitamin B-12 deficiency. In addition, the reduction in vitamin B-12 concentration associated with metformin increased with time. Current guidelines indicate that metformin is a cornerstone in the treatment of type 2 diabetes, but make no recommendations on the detection and prevention of vitamin B-12 deficiency during treatment. JdJ, AK, MGW, and DB collected the data, and statistical analysis was conducted by PL and JdJ. JdJ, AK, and CDAS drafted the manuscript, and AK, AJMD, and CDAS undertook critical revisions of the manuscript for important intellectual content.
Administrative, technical or material support was provided by JvdK, DB, JV, MGW, JdJ, and AK. JdJ, AK, and PL had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus.



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Comments

  1. pepsu

    Also called glitazones, thiazolidinediones are a class from.

    07.03.2014

  2. Glamurniy_Padonok

    Can slip into your everyday carbohydrates and typically repeated.

    07.03.2014