Changing Paradigms of Type 2 Diabetes: Newer Treatments on the board

Diabetes is a major killer worldwide and its unprecedented rise poses a serious threat to mankind. According to recent estimation, 387 million people worldwide are affected from the disease with a prevalence rate of 8.3% and 46.3% still remains undiagnosed. Population survey by the Indian Council of Medical Research suggested that India currently has 65.1 million diabetes patients. The selection and application of a glucose lowering therapy are dependent on a number of considerations like the severity of hyperglycemia, hepatic and renal associated functions, risk of hypoglycemia, body mass index, ability to self monitor the blood glucose level, and also the cost of the medication. Lifestyle modification and metformin remain first-line interventions for type 2 diabetes management. Other class of agents currently are sulfonylureas (Glimepiride, Gliclazide), Meglitinides (repaglinide, nateglinide), thiazolidinediones (Pioglitazone), alpha glucosidase inhibitors  (acarbose, voglibose), and insulins. There remain a lot of unmet needs in the therapeutics of type 2 Diabetes. In spite of many therapeutic options a large number of patients do not achieve desired glycemic goals. The drugs used for the treatment of type 2 diabetes poses limitations in the sense that they have significant side effects especially hypoglycemia and weight gain. There are unique challenges of diabetes management in Indians because of early onset of diabetes, poor beta cell function, increased insulin resistance and greater abdominal adiposity seen in our population. In the last decade, several new classes of oral and subcutaneous glucose-lowering therapies have emerged with varying efficacy and safety profiles. The expanding array of new type 2 diabetes agents and how to combine them effectively is complex. This review gives an overview of the newer therapies and their current place in type 2 diabetes management.

Incretin Based Therapies

The incretins are peptide hormones released into the circulation, in response to luminal nutrients, minutes after a meal. In humans, the major incretins are glucagon-like peptide-1 (GLP-1) secreted by the L cells in the ileum and colon and glucose dependent insulinotropic polypeptide (GIP) secreted by the K cells in the duodenum. Hormonal effects on multiple organs are found to be exhibited by both GLP-1 and GIP and stimulate insulin secretion in a glucose-dependent manner along with appetite suppression and delayed gastric emptying. As a result of these combined effects, significant contribution has been made for the control of postprandial glucose resulting in a better glycemic control with relatively low risk of hypoglycemia. The incretins are predominant gut borne mediators of insulin release, and GLP-1 deals with glucagon suppression.

GLP-1 represents a clinically better therapeutic option over GIP as its insulinotropic effects are preserved in type 2 diabetes while GIP activity is impaired. However both incretins are rapidly inactivated in vivo by the enzyme DPP-IV. Two approaches considered to enhance the incretin effect in type 2 diabetes are to either administer GLP-1 receptor agonists that are

resistant to cleavage by DPP4, or to inhibit DPP4 enzyme activity. These pharmacological approaches thereby effectively increase the half-life and circulating levels of the incretins

DPP-4 inhibitors

DPP-4 inhibitors are oral agents that prevent rapid breakdown of physiological GLP-1. Various DPP-4 inhibitors currently available in Indian market are sitagliptin, vildagliptin, saxagliptin, linagliptin, teneligliptin and gemigliptin. HbA1c improvements of up to 1 percent are observed with weight neutrality. They are well-tolerated with minimal side-effects. There is no hypoglycemia risk unless combined with sulfonylureas or insulin. DPP-4 inhibitors may be initiated as second-line or third-line therapy and in addition to insulin.The cardiovascular safety studies like TECOS using sitagliptin and SAVOR-TIMI 53 study using saxagliptin showed that the risk of adverse cardiovascular outcomes was non-inferior to placebo and there was no significant increase in pancreatitis or pancreatic cancer. Cost remains a major concern as of today, in India monthly cost of most gliptins remains approximately 1200 rupees, except teneligliptin which is much cheaper alternative.

GLP-1 agonists

GLP-1 agonists, which are administered subcutaneously, have a similar mechanism of action to physiological GLP-1, i.e., increased insulin secretion, decreased glucagon, reduced hepatic glucose output and gastric emptying and a feeling of satiety, but without rapid degradation by DPP-4 enzyme in the small intestine, and are either short-acting or long-acting. HbA1c reductions are up to 2 percent with weight loss varying between 1–8 kg has been seen in clinical trials. Risk of hypoglycemia is low unless they are combined with sulfonylureas or insulins. GLP-1 agonists currently available in Indian market are liraglutide, dulaglutide (once a week therapy), and lixisenatide.

Gastrointestinal side-effects especially nausea and vomiting occur in approximately 30 per cent of patients on initiation but improve after a few weeks allowing dose escalation and tend to occur less with longer-acting GLP-1 agonists. GLP-1 agonists are generally not recommended in patients with severe renal impairment and there is a small risk of acute pancreatitis with these agents. Again cost is a major concern with these molecules in our population.

SGLT2 inhibitors

The sodium glucose co-transporter 2 (SGLT2) inhibitors are the newest class of diabetes therapy and improve glycemic control by increasing urinary glucose excretion through inhibition of SGLT2 receptors in the proximal renal tubule. SGLT2 receptors are responsible for reabsorption of approximately 90 per cent of filtered plasma glucose and SGLT1 receptors in the distal segment of the proximal tubule reabsorb the remaining 10 per cent.

Currently several SGLT2 inhibitors are available like canagliflozin, dapagliflozin, and empagliflozin and they are associated with HbA1c improvement of around 1.0 to 2.0 per cent with weight loss of 1–5 kg due to urinary calorie loss and changes in body fat composition. There is very little risk of hypoglycemia unless these agents are combined with sulfonylureas or insulin. Efficacy is diminished by worsening renal impairment (eGFR<60ml/ min/1.73m2). Genital mycotic and urinary tract infections are the most common side-effect especially in women but generally mild in severity. Volume depletion (hypotension, hypovolaemia and dehydration) is sometimes seen in practice and avoided by adequate hydration and care with diuretic therapy. Modestly beneficial effects on blood pressure and triglyceride levels have been noted in clinical studies although LDL cholesterol increases.

Newer insulins

Insulin degludec (Tresiba) is the newer ultra-long-acting insulin. It forms soluble multi-hexamer assemblies following subcutaneous injection, which results in an ultra-long, peak-free pharmacokinetic profile with a half-life of 25 hours and duration of action of more than 42 hours. Degludec allows flexibility in injection timing and less frequent nocturnal hypoglycemia has been observed in some studies compared to other basal insulins such as insulin glargine (Lantus). However, it is more expensive than other basal insulins such as NPH insulin, glargine and detemir (Levemir). Insulin degludec and insulin aspart are available as a premix co-formulation (Ryzodeg).

Recently, combinations of long acting basal insulin and a GLP-1 analogue have been approved in USA. Insulin glargine and lixisenatide (LixiLan) and Insulin degludec and liraglutide (Xultophy) are fixed combination that reduces daily insulin requirements, however these combinations are yet not available in Indian market.

Inhaled insulins

The newest mode of delivering pre-prandial boluses is inhaled insulin. The first inhaled insulin and inhaler were approved and brought to market in 2006 (Exubera).They were removed from the market within about a year because of poor sales. A new inhaled insulin and inhaler were approved in 2014 (Afrezza), however not yet available in Indian market. The inhaled insulins have a profile that is similar to the very rapid-acting analogs. Inhaled insulin offers an alternative noninvasive option for pre-meal insulin administration, with glycemic efficacy similar or slightly less than subcutaneous regular insulin and increased patient acceptability. Periodic testing of pulmonary function is required.

Conclusions

Following diagnosis, the management of type 2 diabetes has become increasingly more complex in recent years due to the numerous classes of glucose-lowering therapies available. Each class exerts one or more effects on the different pathophysiological mechanisms contributing to hyperglycaemia. The choice of therapy needs to be individually tailored to the type 2 diabetes patient based on factors such as duration of diabetes, weight, hypoglycemia risk, frequency of injections and ability to inject. Inevitably patients will require multiple therapies as disease progresses and combinations need to be carefully considered to achieve glycaemic targets without unnecessarily increasing adverse events such as hypoglycemia, weight gain and cardiovascular disease risk. Cardiovascular risk reduction must be included in the therapeutic management.