Mania Radfar Pharm.D. Novel oral antidiabetic agents

INTRODUCTION Initial treatment of patients with type 2 diabetes mellitus includes education, with emphasis on lifestyle changes including diet, exercise, and weight reduction when appropriate Monotherapy with metformin is indicated for most patients and insulin may be indicated for initial treatment for some After a successful initial response to oral therapy, patients fail to maintain target A1C levels (<7 percent) at a rate of 5 to 10 percent per year An analysis from the UKPDS found that 50% of patients originally controlled with a single drug required the addition of a second drug after 3 Yrs; by nine years 75% of patients needed multiple therapies to achieve the target HbA1c value

Incretin based therapies The incretin concept was first proposed in the 1920s, based on the clinical observation that endogenous insulin secretion was much more potently stimulated after the ingestion of rather than the intravenous administration of a particular amount of glucose GLP-1 and GIP, two major incretin hormones that are secreted into the circulation by cells of the small intestine

Mechanism insulinotropic effects suppresses glucagon release reduces hepatic gluconeogenesis delays gastric emptying reduces food intake by promoting satiety

Incretin effect in Type 2 diabetes Incretin effect is substantially reduced or even lost in patients with Type 2 diabetes GIP concentrations are normal or slightly decreased but it shows noticeable attenuated insulinotropic action GLP incretin effectiveness is well preserved, but blood levels after oral glucose load are too low to ensure normal incretin effect

Pharmacological approach Since GLP-1 action remains preserved, major efforts at developing incretin-based therapies have focused on GLP-1 rather than on GIP

DPP-4 inhibitors DPP-4 inhibitors are termed incretin enhancers as they prolong the half-life and availability of endogenous GLP-1 by inhibiting DPP-4. Sitagliptin was the first DPP-4 inhibitor approved for clinical use in October 2006 Others: saxagliptin, linagliptin, vildagliptin,alogliptin

Mechanism The DPP-4 inhibitors inhibit the degradation of GIP and GLP-1 on entering the GI vasculature, thus increasing the effects of these endogenous incretins on first -phase insulin secretion and glucagon inhibition In contrast to GLP-agonists, which increase GLP-1 levels by 6- to 10_fold these agents only modestly increase GLP-1 levels (2- to 3-fold), but also increase GIP levels As a result,DPP-4 inhibitors have minimal to no effect on satiety and delaying gastric-emptying.

Adverse effects Because these agents differ significantly in chemical structure from one another, some adverse events may be unique to the individual agent and may not be indicative of a class wide effect The most commonly reported side effects include: increased risk of upper respiratory tract infection, nasopharyngitis, UTI and headache

Adverse effects When used with a TZD, saxagliptin use is associated with increased peripheral edema Case reports of severe hypersensitivity reactions, including anaphylaxis, angioedema, and exfoliative skin reactions- including Stevens-Johnson syndrome These reactions suggest DPP-4 inhibitors may have an effect on the immune system, as lymphocytes express DPP-4

Adverse effects There have been postmarketing case reports of acute pancreatitis in patients using sitagliptin, saxagliptin, and alogliptin It is unclear if exposure to DPP-4 inhibitors or other drugs that act through GLP-1 play a causal role in the development of pancreatitis Pancreatitis should be considered in patients with persistent severe abdominal pain (with or without nausea), and DPP-4 inhibitors should be discontinued in such patients. DPP-4 inhibitors should be used with caution and with careful monitoring in patients with a history of pancreatitis

Adverse effects There have also been reports of an increased risk of subclinical pancreatic inflammation, pancreatic cancer, and neuroendocrine tumors in sitagliptin users A causal relationship has not been established After a review of currently available data, the FDA and the EMA agreed that there was insufficient evidence to confirm an increased risk of pancreatic cancer with use of GLP-1 based therapies Additional clinical experience and postmarketing studies are needed to clearly establish the long term safety of these agent

Efficacy In monotherapy clinical trials versus placebo lowers fasting glucose by mg/dL andA1C by 0.5% to 0.7% compared with baseline and reduce 2-hour postprandial glucose by approximately 45 mg/dL When used as add-on combination therapy, A1C lowering is greater (0.7%-0.9%) The DPP-4 inhibitors appear to have similar glycemic efficacy further studies are needed to more clearly determine the effects of DDP-4 inhibitors on long term preservation of β- cell function

Clinical use DPP-4 inhibitors are not considered as initial therapy for the majority of patients with type 2 diabetes DPP-4 inhibitors are mainly used as add-on therapy in combination with sulfonylureas, biguanides, TZDs, and insulin When either of these agents are added to a patient also on a sulfonylurea or glinide or insulin, the insulin secretagogue or insulin dose may need to be lowered to reduce the risk of hypoglycemia monotherapy

COLESEVELAM In January 2008, the FDA approved a new indication for colesevelam, a bile acid sequestrant, to be used as add-on therapy in type 2 diabetes. The mechanism by which colesevelam reduces glucose is not known. One possibility is that bile acid sequestrants act in the GI tract to reduce glucose absorption. The primary side effects of colesevelam are GI (constipation and dyspepsia)

COLESEVELAM Because of its constipating effects, it should not used in patients with gastroparesis, other GI motility disorders, or in those who have had major GI tract surgery and may be at risk for bowel obstruction It should be used with caution in patients with triglycerides in excess of 300 mg/dL Drug interactions are an important consideration

Efficacy AIC reductions associated with colesevelam are 0.3% to 0.4% compared with baseline Colesevelam is approved for use as combination therapy with metformin, a sulfonylurea, and insulin It has not been studied as monotherapy or in combination with a DPP-4 inhibitor or TZD

Colesvelam Given the modest glucose lowering effectiveness, expense, and limited clinical experience, we typically do not recommend colesevelam to improve glycemic control in patients with type 2 diabetes Since its approval, its use for treatment of type 2 diabetes remains quite limited

BROMOCRIPTINE Bromocriptine mesylate, an ergot derivative, is a dopamine-2 receptor agonist that is a quick-release formulation. It was FDA approved in May 2009 for use in type 2 diabetes The mechanism by which bromocriptine improves glycemic control is not known. A normal circadian peak in the central dopaminergic tone occurs in the early morning and has been linked to induction of normal insulin sensitivity and glucose metabolism

BROMOCRIPTINE It is theorized that taking bromocriptine in the morning will increase central dopaminergic tone and reset the normal circadian rhythm to that of leaner people. The recommended dose of bromocriptine in diabetes is 1.6 mg to 4.8 mg administered once daily within 2 hours after waking in the morning It should be taken with food to help reduce GI side effects such as nausea

Efficacy Its effect on AIC lowering is very mild As monotherapy AIC is lowered by 0.1% compared with baseline (0.4% versus placebo), and as add-on therapy to a sulfonylurea or metformin, AIC is reduced 0.15 to 0.5%. Given its modest glucose lowering effect, very frequent GI side effects, and the availability of more effective drugs, we do not recommend bromocriptine for the treatment of type 2 diabetes

SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS SGLT2 inhibitors that reduce renal reabsorption of glucose. SGLT2 is almost exclusively found in the kidney proximal tubules and reabsorbs most of the glucose that is filtered through the glomeruli (~180 g) daily These agents are highly selective, reversible inhibitors of SGLT2

SGLT2 inhibitors The ability to lower blood glucose and A1C levels is limited by the filtered load of glucose and the osmotic diuresis that is caused by this therapy. The glucose lowering effect is independent of insulin (beta cell function and insulin sensitivity). Dapagliflozin and canagliflozin are available in Europe and the US

SGLT2 inhibitors Dapagliflozin inhibits up to one-half of the filtered glucose from being reabsorbed by the kidneys By increasing urinary glucose excretion, these drugs can lower plasma glucose levels. There are no long-term safety data with regard to the effects of chronic glucosuria on the urinary tract. In addition, there are no data on microvascular or cardiovascular outcomes A drawback is that patients have reported increased urinary tract and genital infections.

SGLT2 inhibitors Given the absence of long-term efficacy and safety data, we do not recommend SGLT2 inhibitors for routine use in patients with type 2 diabetes SGLT2 inhibitors may play a role as a third-line agent in patients with inadequate glycemic control on two oral agents, if for some reason combination metformin and insulin is not a therapeutic option In meta-analyses of clinical trials, SGLT2 inhibitors reduced A1C by approximately 0.5 to 0.7 percentage points, making them relatively weak glucose-lowering agents, similar in potency to the DPP-4 inhibitors

SGLT2 inhibitors Cardiometabolic benefits included a reduction in systolic blood pressure, reduction in triglycerides, and weight loss of up to 3 kg and a low incidence of hypoglycemia

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