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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 15  |  Issue : 3  |  Page : 169-176

Oral antidiabetic agents: Recently available novel oral antidiabetic agents in India: Aclinical review


1 Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, India; Non communicable Diseases Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia
2 Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, India

Date of Web Publication7-Aug-2017

Correspondence Address:
Nitin Kapoor
Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore - 632 004, Tamil Nadu, India

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_39_17

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  Abstract 


Oral anti-diabetic agents form an important therapeutic strategy in the management of diabetes, after lifestyle modification. There are several new agents available, like dipeptidyl peptidase 4 (DPP4) inhibitors and sodium- glucose cotransporter 2 (SGLT2) inhibitors have been approved for use as monotherapy when diet and exercise are inadequate and when metformin is not tolerated, and can also be utilized as an add on to other glucose-lowering agents, including insulin. The therapeutic, pharmacokinetic and safety profiles of these agents are different from the older agents. Hydroxychloroquine (hcq) and bromocriptine have been recently cleared for use and show beneficial effects in control of blood glucose and HbA1C levels.

Keywords: Dipeptidyl peptidase 4 inhibitors, glibenclamide, gliclazide, oral antidiabetic agents, pioglitazone


How to cite this article:
Kapoor N, Thomas N. Oral antidiabetic agents: Recently available novel oral antidiabetic agents in India: Aclinical review. Curr Med Issues 2017;15:169-76

How to cite this URL:
Kapoor N, Thomas N. Oral antidiabetic agents: Recently available novel oral antidiabetic agents in India: Aclinical review. Curr Med Issues [serial online] 2017 [cited 2017 Sep 25];15:169-76. Available from: http://www.cmijournal.org/text.asp?2017/15/3/169/212367




  Introduction Top


The mainstay of treatment of patients with type2 diabetes includes modifications in lifestyle(diet and exercise), oral antidiabetic agents, and insulin therapy. The major aims are not only to improve glycemic control, reduce weight, and improve the quality of life of these patients but also to reduce the long-term risk of cardiovascular disease by ensuring compliance to their medicines and minimizing adverse effects. The specific medications used in patients with type2 diabetes are determined by clinical judgment about the likely balance between beta cell impairment and insulin resistance. Preventing hypoglycemia and improving compliance through less frequent dosing are the other important targets. The variety of available medications has expanded greatly over the last decade, and even more are in the pipeline, this is especially because there is a greater understanding of the pathogenesis now and of type 2 diabetes mellitus (T2DM) and at least eight organs are implicated in its pathogenesis [Figure 1].[1],[2] In this review, the authors discuss the latest recommendations in initiating oral antidiabetic agents (OADs) in diabetes and have summarized the current understanding and available literature on the recently available novel oral antidiabetic agents in India.
Figure1: Diabetes pathophysiology: Traditional triad to ominous octet.

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  Role Of Oral Antidiabetic Agent Therapy In Type2 Diabetes Mellitus Top


Oral antidiabetic agents follow diet and exercise in the management of an individual with T2DM. While trying to use OADs in the control of diabetes mellitus, one should also attempt to:

  • Conserve islet cell function and thereby delay subsequent use of insulin
  • Decrease the prevalence of hypoglycemic episodes
  • Improve patient compliance with medications(attempting to reduce the frequency of dosing)
  • Consider the cost factor and affordability of the patient
  • To prevent weight gain.


The mechanism of actions of various classes of OADs is summarized in [Figure2], and a comparative summary of the existing oral antidiabetic agents is presented in [Figure3] and [Table1].
Figure2: Mechanism of action of obstructive airway diseases.

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Figure3: Comparison of the oral antidiabetic agents available for diabetes.

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Table 1: Clinical markers to determine the choice of obstructive airway disease's

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  Guidelines for Initiating Oral Antidiabetic Agents in an Individual Diagnosed With Diabetes Top


These guidelines[Figure4] are based on the new American Diabetes Association(ADA 2017) recommendations. Some excerpts from the ADA 2017 guidelines are given below.[3]
Figure4: Guidelines for initiating oral antidiabetic agents in a newly diagnosed patient with diabetes.

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Recommendations

  • The first choice of management in a person newly diagnosed with diabetes is always calculated diabetic diet and exercise[Table2][3]
  • Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for the treatment of type2 diabetes. Along-term use of metformin may be associated with biochemical Vitamin B12 deficiency, and periodic measurement of Vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy(B)*
  • Consider initiating insulin therapy(with or without additional agents) in patients with newly diagnosed type2 diabetes who are symptomatic and/or have A1C≥10% (86 mmol/mol) and/or blood glucose levels≥300mg/dL (16.7 mmol/L)(E)*
  • If noninsulin monotherapy at maximum tolerated dose does not achieve or maintain the A1C target after 3months, add a second oral agent, a glucagon-like peptide 1(GLP1) receptor agonist, or basal insulin(A)*
  • A patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include efficacy, hypoglycemia risk, impact on weight, potential side effects, cost, and patient preferences(E)*
  • For patients with type2 diabetes who are not achieving glycemic goals, insulin therapy should not be delayed(B)*
  • In patients with long-standing suboptimally controlled type2 diabetes and established atherosclerotic cardiovascular disease, empagliflozin, or liraglutide should be considered as they have been shown to reduce cardiovascular and all-cause mortality when added to standard care. Ongoing studies are investigating the cardiovascular benefits of other agents in these drug classes(B)*.
Table 2: Exercise recommendations in diabetes (American Diabetes Association 2017)

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(*Levels of evidence: A-Clear evidence from well-conducted, generalizable randomized controlled trials[RCTs] that are adequately powered, B-supportive evidence from well-conducted cohort studies, C-supportive evidence from poorly controlled or uncontrolled studies, E-expert consensus or clinical experience).


  Recently Available Novel Oral Antidiabetic Agents in India Top


Dipeptidyl peptidase 4 inhibitors

The currently available dipeptidyl peptidase 4(DPP4) inhibitors in India(sitagliptin, vildagliptin, saxagliptin, linagliptin, and teneligliptin) are approved to be used as monotherapy or combination with other antidiabetic agents.[4] In addition, once-weekly DPP4 inhibitors(omarigliptin and trelagliptin) are licensed in Japan and may reach the Indian market soon.[5],[6]

Mechanism of action

The mechanism of action of DPP4 inhibitors is by elevating the circulating levels of incretin hormones, notably GLP1 and gastric inhibitory polypeptide(GIP). This helps to improve the defective nutrient response in secretion of incretins by the intestine. In addition to its incretin effect, GIP also reduces gastric acid secretion and has a role in adipogenesis and possibly β-cell proliferation.[7] In addition, GLP1 causes a reduction in glucagon secretion and has extrapancreatic actions that enhance satiety and delay gastric emptying.

Commonly available dipeptidyl peptidase 4 inhibitors

Sitagliptin

Sitagliptin, the first approved DPP-IV inhibitor exerts its antihyperglycemic effect by slowing the inactivation of incretin hormones. Concentrations of intact incretin hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones, which ultimately leads to lowering of blood glucose both in fasting and postprandial state. Sitagliptin has been reported to have minimal hypoglycemic events and reduced weight gain when compared to sulfonylureas. Sitagliptin can also be combined with insulin to reduce the dose requirement.

Dosing

Initially as 100mg once daily with or without food. If creatinine clearance is 30–50mL/min/1.73 m [2], reduce dosage to 50mg daily. If creatinine clearance is<30mL/min/1.73 m [2], reduce dosage to 25mg daily.

Adverse effects

Mild gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal pain have been reported, but are not clinically significant. There is a small increased risk of upper respiratory tract infection, urinary tract infection(UTI), and headache but the prevalence of these infections appear to be less according to a recent Cochrane review. Sitagliptin is also rarely associated with skin reactions which may rarely include Stevens–Johnson syndrome.

Vildagliptin

This agent has to be administered at a dosage of 50mg twice a day. It has not been approved by the Food and Drug Administration(FDA) for usage in renal failure. However, it has been approved by FDA for use as a combination with insulin. It reduces postprandial lipemia and has a favorable effect on the blood pressure. It is not recommended for use in moderate renal failure.

Saxagliptin

The usual dose of saxagliptin is 2.5mg or 5mg once daily, with the 2.5mg dose recommended for patients with moderate to severe chronic kidney disease(glomerular filtration rate [GFR] ≤50mL/min) and for patients taking strong cytochrome P4503A4/5 inhibitors(e.g., ketoconazole).

Linagliptin

The usual dose of linagliptin is 5mg once daily. No dose adjustment is needed in patients with renal or hepatic impairment. Inducers of CYP3A4(e.g., rifampicin) may decrease the efficacy of linagliptin. Therefore, patients requiring such drugs should receive an alternative to linagliptin.

Teneligliptin

The usual dose of teneligliptin is 20mg once daily. It is a cheaper DPP4 inhibitor available in Japan, Korea and India. Its pharmacological profile is similar to other DPP4 inhibitors. No dose adjustment is required in patients with renal dysfunction. However, caution needs to be exercised when prescribing teneligliptin to patients who are prone to QT prolongation.

Cardiovascular safety and adverse effects

DPP4 inhibitors are usually well tolerated, and the incidence of adverse effects is often similar to placebo and much lower than other glucose-lowering agents.[8] The incidence of gastrointestinal symptoms, which is the most common side effect, is lower with DPP4 inhibitors than with metformin or a GLP1RA.[8] The chance of hypoglycemia in subjects receiving DPP4 inhibitor is very low except when used in combination with sulfonylureas or insulin.[9]

Several meta-analyses and pooled analyses have shown that DPP4 inhibitors (individually and as a class) are associated with reductions in cardiovascular events.[10] However, most of these studies were retrospective and not specifically designed to examine the effect of DPP4 inhibitors on the incidence of cardiovascular disease. The results of three RCTs(SAVOR–TIMI, EXAMINE, and TECOS) demonstrated that saxagliptin, alogliptin, and sitagliptin are not associated with an increased risk of adverse cardiovascular outcomes.[11],[12],[13]

The individual results of the SAVOR–TIMI, EXAMINE, and TECOS trials did not show any increased risk of pancreatitis or pancreatic cancer, but a meta-analysis of these RCTs did demonstrate a significantly increased risk of acute pancreatitis in patients using DPP4 inhibitors compared with those receiving standard care(odds ratio: 1.82, 95% confidence interval[CI]: 1.17–2.82, P=0.008).[11],[12],[13]

Comparisons of existing dipeptidyl peptidase 4 inhibitors

Sitagliptin has been compared to saxagliptin and vildagliptin in two randomized control trials. Though in both comparisons, the drugs performed almost at par with each other, sitagliptin resulted in slightly lower fasting blood glucose than saxagliptin (treatment difference 5mg/dl, 95% CI: 1.3–8.8mgl/dl).[14],[15] An ongoing study(CAROLINA80) has been designed to examine the effect of linagliptin on cardiovascular outcomes with an active comparator(glimepiride) rather than placebo.


  Sodium glucose Cotransporter2 Inhibitors Top


The currently available sodium-glucose cotransporter 2(SGLT2) inhibitors include dapagliflozin, canagliflozin, and empagliflozin. They have been approved for use as monotherapy when diet and exercise are inadequate and when metformin is not tolerated, and can also be utilized as an add-on to other glucose-lowering agents, including insulin.[16]

Mechanism of action

The concept behind the action of these drugs is based on the fact that each day, approximately 180g of glucose is filtered daily from the glomeruli of a normal adult individual, and almost all of it is reabsorbed from the glomerular filtrate and returned to the circulation. This co-transport of glucose along with sodium is brought about by the active transport of sodium out of the basolateral cells by the Na/K-ATPase pump. Glucose is also shifted out of the cell with the concentration gradient and subsequently returned to the bloodstream by glucose transporters.

Sodium glucose transporters(SGLTs) in the gut and kidneys transfer glucose into enterocytes or ductal epithelial cells across the luminal membrane. The main types of SGLTs are SGLT1 and SGLT2, which are essentially responsible for intestinal glucose absorption and for reabsorption of the filtered glucose in the renal tubules, respectively.[17],[18] SGLT2 has a low-affinity but a high-capacity for glucose transport in the S1 segment of the proximal tubules, which is suited for reabsorption of a large load of filtered glucose that enter the tubules. SGLT1, which is also present in the kidneys, has a high-affinity but low-capacity of glucose transport that is best suited to reabsorb of glucose at lower concentrations in the S3 segment of proximal tubules.[18],[19]

In T2DM, renal glucose handling and transport is increased, likely due to the upregulation of SGLT2. Inhibition of this reduces reabsorption of filtered glucose and therefore lowers the blood glucose concentration by enhancing glucose excretion.

Competitively inhibition of SGLT2 can potentially eliminate 60–90g of glucose per day.[20] The effects of SGLT2 inhibition is self-limiting, dependent on renal functions and noninsulin-dependent.[20] SGLT2 inhibition and the resultant glycosuria results in mild diuresis and calorie loss with corresponding reductions in blood pressure and weight.[21]

Commonly available sodium glucose transporter 2inhibitors

Dapagliflozin

When used in doses of 5 or 10mg per day, dapagliflozin has been showed to reduce glycated hemoglobin(HbA1c) by 0.8%–0.9% and also has shown to reduce body weight by 2.8–3.2kg.[22] It has also improved glycemic control and achieved weight reduction when used as an add-on therapy with other oral glucose lowering agents.[23] It is available as 5mg/10mg tablets and is prescribed as a once-daily dose.

Canagliflozin

Canagliflozin showed similar effects in weight and HbA1c reduction when used as monotherapy(HbA1c-1.08%) or as add-on treatment to other oral antidiabetic agents(0.73%)[24] The addition of canagliflozin to insulin treatment has also shown to result in a significant reduction in HbA1c up to a duration of 52weeks.[25] Canagliflozin became the first SGLT2 inhibitor to be approved by the FDA in 2013. It is currently indicated as an adjunct to diet and exercise in adults with T2DM. Canagliflozin is available as 100mg/300mg tablets and is prescribed as a once-daily dose.

In light of the recently published CANVAS trial in June 2017, it suggested that canaglifozin significantly reduced composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke than placebo(occurring in 26.9vs. 31.5 participants per 1000patient-years; hazard ratio, 0.86; 95% CI: 0.75–0.97; P<0.001 for noninferiority; P=0.02 for superiority). However, it was also associated with an increased risk of amputation(6.3vs. 3.4 participants per 1000patient-years; hazard ratio, 1.97; 95% CI: 1.41–2.75); amputations were primarily at the level of the toe or metatarsal. It is not yet clear if this risk is a class effect or specific to this drug.

Empagliflozin

The reductions in HbA1c, body weight, and systolic blood pressure using empaglifozin were to the scale of 0.7%–0.8%, 1.5–2.5kg, and 2.9–4.1mmHg respectively, and this has been shown to be maintained in trial extensions up to 76weeks.[26],[27],[28],[29] Empagliflozin has also been well tolerated and efficacious in patients with estimated GFR 30–60ml/min/1.73 m [2] over a 24-week trial.[30]

All the three drugs have also shown modest reductions in blood pressure as well.

Safety and adverse effects

SGLT2 inhibitors are usually associated with a low risk of hypoglycemia except when used in combination with insulin or sulfonylureas.[16] SGLT2 inhibitors have also been associated with an increased risk of genitourinary tract infections, but this increase in UTI has not been consistently reported.[16] The risk is shown to be greater in women than men, and none of the reported infections was severe.[24]

SGLT2 inhibitors are also associated with small increases in low-density lipoprotein(LDL) and high-density lipoprotein (HDL) cholesterol, these effects are more than what was observed with canagliflozin, and long-term consequences of these are yet to be determined.[24]

SGLT2 inhibitors, particularly canagliflozin, might have adverse effects on the risk of developing osteoporotic fractures. Asubset analysis of the results from the CANVAS trial (n=4,327) showed a significant increase in fractures with canagliflozin(4.0%) compared with placebo(2.6%; heart rate[HR]: 1.51, 95% CI: 1.04–2.19).[31]

Several case reports of euglycemic and hyperglycemic diabetic ketoacidosis have been reported in patients who received SGLT2 inhibitors.[32],[33] However, many of the reported patients had ketosis either due to a breach in insulin therapy, intercurrent illness, or off-label usage of these drugs. Patients treated with insulin should, therefore, be educated not to discontinue insulin when they observe a reduction in blood glucose levels after the introduction of an SGLT2 inhibitor. These drugs are currently not approved in patients with type1 diabetes mellitus.

There has also been a recent interest in the cardiovascular protection offered by these drugs the mechanisms behind which are still to be elucidated. In a study of 7020patients with high-risk T2DM, the occurrence of a composite end point of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular causes was lower with empagliflozin than placebo, in addition to standard therapy(HR: 0.86, 95% CI: 0.74–0.99, P=0.04 for superiority).[34] Empagliflozin treatment also significantly reduced the risk of cardiovascular death, death from any cause, and hospitalization from heart failure.[34] Subgroup analyses revealed that the benefits of empagliflozin were more evident in the Asian population, in patients with body mass index<30kg/m2 and HbA1c<8.5%, in those not on insulin treatment and in those with diabetic nephropathy.

Hydroxychloroquine in diabetes

Antimalarial drugs are well-tolerated and safely used therapeutic agents that are commonly utilized for disorders such as rheumatoid arthritis and systemic lupus erythematosis. Their benefit for glycemic control has been observed in patients on these drugs for immunological disorders. Hypoglycemia is one of the unusual adverse effects of these groups of drugs. Hydroxychloroquine(HCQ), in particular, was shown to be effective in lowering the HbA1c in sulfonylurea refractory patients. The addition HCQ to insulin therapy causes a significant decrease in the insulin requirements.[35]

The predominant mechanism that is involved is a reduction in insulin metabolism mediated through direct interaction with the insulin receptor, a reduced rate of dissociation of insulin from the insulin receptor, prolongation of the half-life of the insulin-receptor complex and thereby a prolonged insulin action. Other mechanisms of action include an increase in insulin production through islet cell stimulation and a reduction in hepatic gluconeogenesis.

HCQ has a beneficial effect on lipid metabolism acting by reducing triglycerides, LDL-cholesterol, apo-B, and increasing the HDL-cholesterol. Moreover, a recently published study from India showed a favorable effect of HCQ at a dose of 400mg/day on both glycemic and lipid profile in type2 diabetes patients who were inadequately controlled with a combination of sulfonylureas and metformin.

Besides, its glucose-lowering effect in patients with diabetes, interestingly, HCQ has been found to be effective in lowering the incidence of new onset diabetes mellitus. Aprospective randomized study on 4905patients with RA showed that patients with HCQ had 77% reduction in the risk of developing diabetes mellitus in those who had taken HCQ for more than 4years.

Ocular toxicity is one of the less common adverse effects of long-term HCQ therapy. All Patients with HCQ should be routinely screened for retinal toxicity, depending on the cumulative dose, and duration of therapy. It may be judicious not to use it in patients with even mild diabetic retinopathy.

Bromocriptine

The US-FDA had approved bromocriptine for the management of diabetes in 2009. It is a centrally acting antidiabetic agent which if given in the morning would reset the abnormally elevated sympathetic drive in the hypothalamus in patients with T2DM. This in turn would result in reducing the hepatic glucose output. It has also shown not only to augment the release of insulin but also to increase its sensitivity in the peripheral tissues. The addition of bromocriptine to poorly controlled type2 diabetic patients treated with diet alone, metformin, sulfonylureas, or thiazolidinediones produces a 0.5–0.7 decrement in HbA1c.

The doses used to treat diabetes(up to 4.8mg daily) are much lower than those used to treat Parkinson's disease, and apart from nausea, the drug is well-tolerated. The novel mechanism of action, good side effect profile, and its effects to reduce cardiovascular event rates make it an attractive option for the treatment of type2 diabetes.[36]

Financial support and sponsorship

Nil.

Conflicts of interets

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure2], [Figure3], [Figure4]
 
 
    Tables

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Abstract
Introduction
Role Of Oral Ant...
Guidelines for I...
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Sodium glucose C...
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