Newer Anti Diabetic Medications

Introduction

Diabetes mellitus (DM) prevalence has increased rapidly in the 21st century. This is because of obesity, ageing population, lack of exercise and increased migration of susceptible patients. Type 2 diabetes mellitus is more prevalent. Main aim of management includes delaying micro and macro vascular complications along with achieving good glycaemic control. Changes in lifestyle, such as weight loss and exercise and drug therapy play an important role here. Pathophysiology based novel treatments: glucagon-like peptide-1 (GLP-1) mimetics, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), and insulin analogues have gained importance. GLP-1 agonists mimic incretin effect; DPP-4 inhibitors prevent inactivation of the endogenously released hormone. Both novel agents are effective alternative to currently available hypoglycaemic drugs.New insulin analogues, fast-acting, basal release formulations have been a spearhead as basal-bolus regimen for the management of blood glucose. With this there occurs continuous, low basal insulin release between meals with bolus fast-acting insulin to limit hyperglycaemia after meals. Insulin therapy has become a better option in type 2 DM which aids effective glycaemic control. In spite of focus on newer agents in the treatment of diabetes, metformin and the sulphonylureas are mostly used in many patients. Metformin may have novel anti-cancer properties.

Biguanides

The only biguanide used is metformin (dimethyl biguanide). Because of unacceptable risk of lactic acidosis, phenformin was withdrawn in early 1970s. Metformin reduces excessive rates of hepatic glucose production, improves insulin stimulated glucose utilization by extra hepatic tissues. Metformin lowers circulating levels of plasminogen activator inhibitor-1, which may contribute to reduced risk of atherothrombotic events. Metformin is increasingly used in type 2 diabetes in childhood patients. The usual starting dose is 500 mg twice daily with meals. The dosage may be increased by 500 mg increments at weekly intervals. The maximum dose is 2.51 to 3.0 g daily for adults; a lower maximum dose is suggested for children.

Sulphonylureas

Sulphonylureas lowers blood glucose levels by stimulating insulin secretion from β-cells of islets of pancreas. Hypoglycaemia is the most common side effect.Weight gain is the major drawback of sulphonylureas. Concerns persist regarding cardiovascular safety of sulphonylurea. The sulphonylureas are grouped as first generation and second generation; first generation include tolbutamide, tolazamide, chlorpropamide, acetohexamide and second generation sulphonylureas include glipizide, gliclazide, glibenclamide, glimepride. The newer sulphonylureas have lesser incidence of hypoglycaemia. Sustained release preparations of Glipizide and Glyclazide have also reduced incidence of hypoglycaemia.

Vitamin B₁₂ neuropathy

A minority of patients with vitamin B₁₂ deficiency develop a neuropathy due to symmetrical damage to the peripheral nerves, and posterior and lateral columns of the spinal cord. The legs are usually more affected than the arms. Psychiatric abnormalities and visual disturbances may also occur.

Meglitinides

Repaglinide and nateglinide comes under meglitinides category. They are secretagogues that stimulate rapid insulin production by the pancreas and reduce both post-prandial blood glucose and HbA1c by 0.5–2%.This early insulin release rapidly suppresses hepatic glucose production and reduces the need for additional insulin secretion. The meglitinides have a faster onset and shorter duration of action than the sulphonylureas. They are associated with a reduced risk of hypoglycaemia. They cause less weight gain and are metabolized and excreted by the liver, and so can be used in patients with impaired renal function.

α-Glucosidase inhibitors

Alpha-glucosidase inhibitors block the enzyme α-glucosidase in the small intestine. This delays absorption of glucose, thereby decreasing meal-related blood glucose increase. Acarbose is taken before carbohydrate containing meals. They must not be used when meals are missed. They do not cause weight gain or hypoglycaemia. Their use is contraindicated in patients with hepatic or renal impairment, inflammatory bowel disease, or a history of bowel obstruction. Bloating, flatulence, abdominal cramps and diarrhoea are their side-effects which limit their clinical use. The drugs available in this group are Acarbose, Miglitol and Voglibose. These are given with the first bite of food for better effect. Acarbose is most studied in this group. According to some studies its use is associated with a reduction in cardiovascular events and it has a favourable effect on lipid metabolism.

Synthetic amylin analogues

Amylin is a peptide neuro hormone. It is synthesized and secreted by the β-cells of the pancreas with insulin. Patients with type 1 DM or advanced type 2 DM are deficient in both insulin and amylin. Amylin secretion is stimulated by the presence of food in the gut and its 24 h profile resembles that of insulin with low baseline values and a rapid increase in response to meals. GLP-1 and amylin have similar physiological effects but amylin is not an incretin hormone. Along with suppression of glucagon secretion, amylin delays gastric-emptying. Acts centrally in area postrema of brain to induce satiety. It slows the passage of glucose into the circulation while insulin stimulates cellular uptake of glucose to reduce glucose concentrations.

Pramlintide

Pramlintide, synthetic analogue of amylin is a stable bioactive analogue that differs from human amylin by three amino acid substitutions. It is given as a subcutaneous injection two to three times daily and is administered before meals. It has a rapid onset of action and duration of action of 2–4 h. It is currently used in patients with type 1 DM and in type 2 diabetics using meal time insulin or insulin in combination with a sulphonylurea or metformin. Common side-effect is nausea. In the first 4 weeks of treatment hypoglycaemia can occur. To avoid this problem decrease the dose of pre-meal insulin by 50% when starting therapy. Pramlintide also causes some weight loss, reduces HbA1c by 0.3–0.6%. It also lowers postprandial glucose.The role of pramlintide in the treatment of type 2 DM is unclear but it may be of some benefit to those patients already on insulin regimens.

Sodium Glucose Co-transporter 2 (SGLT2) inhibitor

Sodium–glucose transporters (SGLT) are specialized in the co-transport of sodium and glucose across different cell types. SGLT-2 is expressed in the brush-border membrane of proximal renal tubular cells. They contribute to renal glucose reabsorption. During hyperglycaemia glucose is excreted in urine due to saturation of transport channels. SGLT2 Inhibitors enhance renal glucose excretion and consequently lower plasma glucose levels in case of hyperglycaemia.Hence these agents are shown to play a significant rolein the management of Type II diabetes. Dapagliflozin, Remogliflozin, Sergliflozin and Canagliflozin belong to this class.

Dapagliflozin

Dapagliflozin, an SGLT2 inhibitor is a newer agent, which has been recently approved for type 2 DM. Dapagliflozinbinding inhibits renal glucose reabsorption and promotes urinary glucose excretion. Studies involving use of Dapagliflozin in patients with inadequate glycemia control with metformin alone, found that addition of dapagliflozin reduces HbA1c and FPG, with no increased risk in hypoglycaemia. The only drawback isan increased incidence of genital infections. According to investigators addition of dapagliflozin to metformin provides a new therapeutic option.

Dual PPAR Agonist

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors. They belong to nuclear receptor superfamily. They act on pharmacologic targets for combating obesity and diabetes. PPARs play a central role in insulin sensitivity, lipid metabolism and inflammation. It consists of three isoforms i.e. PPAR-α, PPAR-β and PPAR-Ƴ. PPAR-α activating drugs produces significant improvements in deranged lipid profile and decrease atherosclerotic lesions. They do not show any effect on plasma glucose levels. PPAR-γ improves glycaemic control by increasing peripheral insulin sensitivity and reducing hepatic gluconeogenesis. Thus it preserves the β-cell function. There is a need for development of new anti-diabetic drugs combining the insulin-sensitizing effects of PPAR-γ activation with the additional lipid-modifying activity of the PPAR-α.

Glitazars are a new generation of dual PPAR α / Ƴ agonists. The dual activation of PPAR Ƴ and PPAR α enhances the action of adiponectin which in turn increases the expression of its receptor in white adipose tissue

Saroglitazar

Saroglitazor is the only Glitazor approved. It is a dual regulator that corrects both the lipid profile and the glycemic indices. It is is available as an oral tablet containing 4 mg of Saroglitazar. The chemical name for Saroglitazar is Benzenepropanoic acid, α-ethoxy-4[2-[2-methyl-5-[4-(methylthio)phenyl]-1H-pyrrol-1yl]ethoxy]-magnesiumsalt(2:1),(αS). Saroglitazar is indicated for the treatment of diabetic dyslipidemia with and hypertriglyceridemia with Type 2 diabetes mellitus not controlled by statin therapy. In clinical studies, Saroglitazar has demonstrated reduction of triglycerides (TG), Low Density Lipoprotein (LDL) cholesterol, Very Low Density Lipoprotein (VLDL) cholesterol, non-High Density Lipoprotein (non-HDL) cholesterol and an increase in HDL cholesterol. It has also shown favourable glycemic indices by reducing the fasting plasma glucose and glycosylated haemoglobin in diabetic patients. The recommended dose of Saroglitazar is one tablet of 4 mg once a day.

In two controlled phase III clinical studies of 12 to 24 weeks treatment duration with saroglitazar, the most common adverse events (AEs > 2%) reported were gastritis, asthenia and pyrexia. Most of the AEs were mild to moderate in nature and did not result in discontinuation of the study. Because clinical studies are conducted under widely varying conditions, AE rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Glucagon Like Peptide (GLP)-1 Mimetic

Incretins are gut-derived peptides which are secreted in response to meals. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are major incretins. GLP-1 is produced by the neuroendocrine L cells of the ileum and colon; GIP is produced by K cells of the duodenum and jejunum. Both are released rapidly after meals and their secretion appears to be under neural control. GLP-1 and GIP stimulate insulin output from pancreatic cells in a glucose-dependent fashion. GLP-1, but not GIP, decreases pancreatic α-cell secretion of glucagon and thus prevent hepatic gluconeogenesis. GLP-1 retards gastric emptying and hence has a direct suppressive effect on central appetite centres. Incretins are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). Exenatide and Liraglutide are GLP-1 analogues belonging to this class.

Exenatide

Exenatide is homologous to human GLP-1. It activates human GLP- 1 receptors, administered as a subcutaneous injection twice daily in the dose of 5 to 10 μg. It is efficacious at lowering glucose in patients with T2DM in combination with metformin and/or sulfonylurea’s. In some trials, Exenatide showed HbA1c reduction of 1.0% compared with placebo treatment. The major effect was seen on lowering postprandial glucose with less on fasting glucose. Exenatide shows impact on gastric emptying and appetite and helps in weight loss.Progressive islet dysfunction results in decrease of β-cell mass. Any agent that alters this balance may delay or prevent the decline in insulin secretory capacity.This effect of GLP-1 mimetics has not been yet demonstrated in long-term clinical trials.
Nausea and vomiting are side effects. Some post marketing reports have shown incidence of pancreatitis in exenatide-treated patients. Most patients have at least one risk factor for this condition. The association with exenatide is yet not clear. Exenatide does not increase the risk of hypoglycaemia. Exenatide is approved for use in combination with metformin, a sulfonylurea, a thiazolidinedione,the combination of metformin and a sulfonylurea, or the combination of metformin with a thiazolidinedione. Exenatide is also effective as monotherapy.

Liraglutide

Liraglutide is a GLP-1 analogue which is 97% identical to human native GLP-1. It is safe and efficacious as glucose lowering drug in type 2 diabetes mellitus. It is effective in reducing body weight, decreasing visceral fat, lowering systolic blood pressure, and improving lipid profile as well as other cardiovascular risks factors. Reduction in triglyceride levels have been seen with Liraglutide. Some studies have also shown a cardio-protective effect of liraglutide.

Liraglutide reaches maximum concentration after 9–12 hrs. It has a half-life of approximately 13 hrs (11–15hs). It is administered once daily to provide optimal glycaemic control for 24-hrs. The recommended initial dose is of 0.6 mg, progressing to 1.2 mg or up to 1.8 mg, if required.Liraglutide is generally well tolerated. Nausea, vomiting, and diarrhoea are most common adverse events. No major hypoglycaemic events have been reportedwith liraglutide monotherapy (LEAD-3), liraglutide + metformin (LEAD-2), and liraglutide + metformin + rosiglitazone (LEAD-4). It was also observed (in LEAD-6) that Liraglutide once a day significantly improved the glycaemic control than exenatide twice a day. Liraglutide could be a better treatment option especially when weight loss and risk of hypoglycaemia are major concerns. Liraglutide is effective and safe drug for long-term administration in patients with type 2 diabetes. On January 25, 2010, US FDA approved liraglutide, as a single daily dose to improve glycaemic control in adults with type 2 DM.

Dipeptidyl- Peptidase-IV (DPP-4) Inhibitors

GLP1 and GIP, which are the major gut hormones are degraded by DPP4 enzyme. GLP1 and GIP stimulate insulin secretion in response to raised plasma glucose concentration.Thus DPP4 inhibitor indirectly lowers the plasma glucose concentration by enhancing the levels of incretins. DPP-4 inhibitors effectively increase incretin levels into a more physiological range. By inhibiting incretin metabolism, these agents stimulate insulin release and reduce the glucagon secretion and thereby lowering the HbA1C and fasting as well as postprandial hyperglycaemia.Sitagliptin, Vildagliptin, Saxagliptin and linagliptin are the major drugs used in this class.

Sitagliptin

Sitagliptin, a selective inhibitor of DPP4 enhances glucose-dependent insulin secretion from the pancreas and decreases hepatic gluconeogenesis. Sitagliptin can be administered as a single daily dose as it inhibits the DPP4 activity for the duration of 24 hours.Bioavailability of Sitagliptin is 87% and plasma half-life is 8-14 hours. It is 38% bound to plasma proteins. It undergoes CYP3A4 and CYP2C8 mediated metabolism, excreted mainly in urine. U.S. FDA approved Sitagliptin in October 2006, as monotherapy and as add-on therapy to either metformin or thiazolidinediones to improve glycaemic control in patients with type 2 diabetes when diet and exercise failed to achieve the desired goals. Later on April 2007, US FDA approved the combination product of Sitagliptin with Metformin for the patients who are not adequately controlled on either Metformin or Sitagliptin monotherapy. This combination should be administered orally twice daily with meals.

Common adverse effects with Sitagliptin are upper respiratory tract infections, urinary tract infections, headache, arthralgias, fatigue, dizziness and diarrhoea. Safety and efficacy of Sitagliptin is controversial in pregnant patients for its use in pregnancy due to lack of adequate data. As it is secreted in breast milk, it should be used cautiously. Patients with renal function impairment require dose adjustments. It is also contraindicated in diabetic ketoacidosis. Hypersensitivity reactions such as anaphylaxis, angioedema and Stevens Johnson Syndrome have been reported rarely

Vildagliptin

Vildagliptin has high affinity for DPP 4 thereby improves glycaemic control. Vildagliptin administration results in rapid inhibition of DPP 4 enzyme activity for period of 24 hours and henceit reduces the fasting and postprandial plasma glucose. Vildagliptin enhances the sensitivity of α- cells to glucose by increasing endogenous GLP 1 levels, resulting in reduced glucagon secretion.Vildagliptin has oral bioavailability of 85% with peak plasma concentrations observed at 1.75 hours. The rate of absorption of vildagliptin slightly decreases on co-administration with food. The plasma protein binding of vildagliptin is low (9.3%). Vildagliptin distributes equally between plasma and red blood cells. Unlike Sitagliptin, Vildagliptin is not metabolized by cytochrome P450 enzymes. Elimination half-life is approximately 2 hours after intravenous administration and 3 hours after oral administration, independent of the dose. Common adverse effects are dizziness, headache, constipation and peripheral oedema. It is contraindicated in renal, hepatic impairment or hypersensitivity to either vildagliptin or any of the excipients.

Saxagliptin

Saxagliptin is approved by the US FDA in July 2009.Primarily Saxagliptin was indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type II diabetes. The recommended dose for Saxagliptin is 5 mg once-daily. Saxagliptin is majorly absorbed after oral administration. Saxagliptin is metabolized primarily by hepatic cytochrome P450 isoenzyme CYP3A4/5. It is cleared by both metabolismand renal excretions.

Linagliptin

Linagliptin is the fourth drug in this class, approved for diabetes management. As there is no renal metabolism of this drug it can be given safely in patients with CKD without any dose adjustment. The recommended therapeutic dose is 5 mg daily. It is also available in combination with metformin.

Bromocriptine

Bromocriptine is a centrally acting dopamine D2 receptor agonist. Itwas approved by the US FDA in May 2012 as an adjunct to diet and exercise to maintain euglycemia in patients with type 2 DM. Dopamine is known to be the most abundant found adrenergic neurotransmitter in the central nervous system. Adrenergic nervous system plays an important role in regulation of glucose levels. Therefore a dopamine agonist may prove beneficial in maintaining euglycemia.

Bromocriptine is the first drug for treatment of diabetes to be approved under the FDA’s new guidelines. It still requires clinical trials to demonstrate no increased cardiovascular risk. The recommended initial dose is 0.8 mg daily, increased by 0.8 mg weekly until the target range (1.6 – 4.8 mg) or till maximal tolerance is reached.It should be administered as a single daily dose within two hours of waking in the morning and preferably with food to minimize nausea. Common side effects seen with bromocriptine are nausea, fatigue, dizziness, vomiting and headache. It can be used as monotherapy or as adjunctive therapy to currently available antidiabetic medications like metformin/sulfonylurea. Its use is not recommended for the treatment of type-1 diabetes or diabetic ketoacidosis. There is scarcity of data in regards to its efficacy when used in combination with either insulin or thiazolidinediones.

Insulin therapy

Type 1 DM is caused by autoimmune destruction of the pancreas and patients require insulin for management. In type 2 DM with progressive β-cell failure, individuals may require insulin therapy as the disease progresses. Increasingly, insulin is no longer seen as a ‘last resort’ after long-term oral agent combinations have failed, but as a therapeutic tool for earlier use. Initiating insulin therapy with low doses in combination with oral agents is effective in achieving glycaemic targets and maintaining HbA1c values.Insulin use can improve insulin resistanceand may provide cardiovascular benefits. The aim of insulin therapy is to mimic the physiological pattern of insulin secretion seen in non-diabeticpatients. Normal insulin secretion in response to a meal consists of a first- and second-phase response. Insulin therapy needs to cover both basal and post-prandial insulin requirements, called as the basal-bolus concept.This includes basal insulin which suppress glucose production between meals and overnight and bolus insulin, which limits postprandial hyperglycaemia. Bolus insulin can comprise up to 10–20% of total daily insulin at each meal. Bolus insulin must demonstrate an immediate increase and a sharp peak to effectively control glucose. This pattern has been made feasible by the development of newer fast-acting analogues, such as insulin lispro, insulin aspart, and insulin glulisine.

Rapid acting formulations

They have a rapid onset of action (typically 5–15 min), peak activity seen 2 h after injection, and their effect lasts for upto 4 h. This matches normal mealtime peaks of plasma insulin more closely than regular human insulin. This results in less immediate post-prandial hyperglycaemia and less late post-prandial hypoglycaemia.

Long acting formulations

Long-acting insulin formulations such as glargine, detemir and degludec provide good glycaemic control between meals without the risk of hypoglycaemia. Unique feature of insulin glargine is its amino acid sequence. Asparagine at A21 position is replaced by glycine, which provides stability. Addition of 2 arginines at C terminus of B chain, which makes it soluble at slightly acidic pH, forms precipitate. It is released slowly from the injection site and its duration of action is prolonged up to 24 hrs.

Insulin Degludec

Insulin degludec (IDeg) is a basal insulin for once-daily subcutaneous administration, to improve glycaemic control in adults with diabetes mellitus. IDeg was developed to cover basal insulin needs in patients with diabetes mellitus, either alone or in combination with bolus insulin and/or oral antidiabetic drugs. Also there is a new combination for insulin degludec/insulin aspart (IDegAsp), a soluble co-formulation of 70% IDeg and 30% of the rapid-acting insulin analogue, insulin aspart for once- or twice-daily s.c. administration to improve glycaemic control in adults with diabetes mellitus.

Summary

Continuously there have many advancements in the management of type II DM in the past few years. Choice of anti-diabetic medications always confuses practitioners as the anti-glycaemic therapy for diabetes mellitus is individualized. The newer anti-diabetic medications further add to the dilemma. The newer agents have been frequently started to be used in combinations to the currently used oral anti-diabetic drugs. The treatment of DM is always tailored to the individual patient, depending upon the diabetic profile and other associated co-morbid conditions. The need of further studies for evaluating the risk benefit and cost benefit analysis of these newer drugs cannot be overemphasized.

References

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4. Insulin Degludec and Insulin Degludec/Insulin Aspart Treatment to Improve Glycaemic Control in Patients with Diabetes Mellitus Novo Nordisk Insulin Degludec NDA 203314Insulin Degludec/Insulin Aspart NDA 203313Endocrinologic and Metabolic Drug Advisory Committee, November 8, 2012