April-May-2015

NEWER DRUGS IN DIABETES MELLITUS

Authors: Dr. Atul Gogia, Dr. S.P. Byotra

Diabetes mellitus is a chronic disease that occurs when the pancreas is no longer able to make insulin, or when the body cannot make good use of the insulin it produces. Worldwide, more than 371 million people live with Diabetes, with the number increasing each passing day (China leads with > 92 million and India follows a close second with 63 million). The prevalence stands at 8.3%, with 50% cases remaining undiagnosed.

The normal glucose homeostasis depends on the synergy between:
  1. The glucose (food) intake
  2. Glucose release by Liver (Glycogenolysis, when blood sugar falls down)
  3. Pancreatic hormones:
    1. Insulin–causing uptake of glucose in the cells
    2. Glucagon–causing release of glucose from liver and muscle when blood sugar goes down.

A derangement in any of the 3 factors can cause hyperglycemia, leading to T2DM. Hence we have 3 core pathophysiological defects in T2DM:
    1. Islet cell dysfunction:

      a. Beta cell dysfunction causing reduced secretion of Insulin

    b. Alpha cell dysfunction causing increased secretion of Glucagon.
  1. Insulin Resistance (even in the presence of adequate amounts of Insulin, the body cells don’t respond to it, hence no glucose influx inside the cells)
  2. Increased Hepatic Gluconeogenesis (accentuated by increased Glucagon).

Hyperglycemia is the main cause of various short term and long term complications (ACS/CVS/PVD/Neuropathy/Nephropathy/Retinopathy). The main objective in the treatment of T2DM is to prevent/delay the onset/progression of complications. The ADA defines T2DM on the basis of HbA1c (>=6.5), Fasting BS (>=126 mg/dl) or Post-prandial BS (>=200 mg/dl). DeFronzo’s Ominous Octet led to the realization that there are a multitude of other factors involved in the pathophysiology of Diabetes. One of them is “Gut derived”, later known as Incretin.
The so called “Incretin Effect” was first demonstrated in 1964, when McIntyre & Elrick independently and simultaneously reported that oral administration of glucose induced a greater insulin response than IV infusion of glucose. That Incretin effect is reduced in diabetics was subsequently reported by Perley and Kipnis in 1967. They estimated that 50% of the insulin secreted after an oral glucose load was released by gastrointestinal factors. DPP4 enzyme was discovered in the same year. Couple of years later in 1969, Unger and Eisentraut mentions of the “Entero-Insular axis” in their works and studied the effects of Gastrin, secretin, and pancreozymin in dogs.
Incretins or “Gut derived hormones” regulate glucose homeostasis by effect on Islet cells. As seen in the Incretin effect, ingestion of food is followed by release of Incretin hormones (GLP-1 and GIP), which in turn stimulates the beta cell to secrete Insulin (increasing glucose utilization by cells) and decreases secretion of Glucagon (which decreases Hepatic GNG), in turn regulating glucose levels in the body. The Incretin effect in both diabetics and non-diabetics was more scientifically measured against increasing glucose loads by Michael Nauck in 1986. He also reported the glucose dependent mode of action of GLP-1.
Incretins have a very short half life (GLP-1 of ~2-3 minutes and GIP of ~ 7 minutes). They’re rapidly broken down by DPP4 (Di-peptidyl Peptidase 4) enzyme. DPP4 is present in multiple places in the body, primarily in 2 forms – a soluble form and a membrane bound form. DPP4 also plays role in Chemotaxis of T-cells. Sulphonylurea may need to be reduced to avoid hypoglycaemia. Clinical trials have demonstrated a reduction in both fasting and postprandial glucose concentrations, a 1–2% reduction in HbA1c concentrations, and a moderate weight loss of 2–5 kg. Side-effects of exenatide include nausea and less commonly, vomiting or diarrhoea, particularly when starting therapy. It is recommended that treatment is initiated with a dose of 5 mg twice daily which may be increased to 10 mg twice daily approximately 1 month later. A recent study of once-weekly dosing using a sustained release formulation of exenatide showed improvements in glycaemic control, no increased risk of hypoglycaemia, and similar reductions in body weight.
Liraglutide, another incretin mimetic, is administered once daily, is not excreted by the kidneys, is not subjected to DPP-4 degradation, and may be a promising alternative. It provides greater improvements in glycaemic control, induces weight loss, improves obesity-related risk factors, and reduces pre-diabetes. It is also associated with reductionsin HbA1c and blood pressure. |
In summary, incretin therapy appears to offer an effective alternative to the currently available hypoglycaemic agents. Continued evaluation and further long-term studies will confirm its safety and clinical role. One of the ways of enhancing endogenous levels of Incretins is via inhibition of DPP4. Higher levels of Incretins improve satiety, increase Insulin response after meal and diminish Glucagon toxicity, thus preventing hyperglycemia.

There are 4 DPP4 inhibitors in the Indian market:

  1. Sitagliptin
  2. Vildagliptin
  3. Saxagliptin
  4. Linagliptin
A 5th DPP4-I was approved by USFDA in 2013 – Alogliptin.
Even though all the molecules inhibit DPP4, there is a potential difference between them in the strength and extent of DPP4 inhibition, thus determining the dosage pattern and efficacy of the molecule. Based on the pharmacokinetics, Sitagliptin turned out to the ideal DPP4-I with a 96% DPP4 enzyme inhibition at an OD dose for 24 hours ! It is not appreciably metabolized in the liver and the major excretion is via kidneys (80% unchanged). Linagliptin is the only DPP4-I with fecal excretion.
Alogliptin, a newer entry in the Gliptin class of drugs, got USFDA approval in 2013. Though the PK profile is similar to Sitagliptin, various meta-analysis (Gooben Graber, Patil etc) have shown increased risk of CV events with Alogliptin (Gooben Graber showed an RR of 4.64 with Alogliptin). Various studies have also shown an increase in BP with Alogliptin (whereas Sitagliptin has shown decrease in BP among other pleotropic benefits). Vildagiptin, Saxagliptin and Linagliptin have no separate studies in ESRD/Dialysis yet. Also since all the gliptins apart from Linagliptin are excreted by Kidneys, a dose reduction is recommended according to the Creatinine Clearance status. Even Linagliptin’s AUC increases in the tune of 71% in moderate renal failure, but no lower dose is available. Moving from Gliptins to Insulin, Insulin was discovered by Banting and Best in 1921 and it has continuously evolved since. From the invention of artificial human insulin, to various short acting (Lispro, Aspart, Glulisine) to many long acting similar (Glargine, Detemir, Degludec).
Among the newer ones, Glargine and Detemir are peakless Insulins and thus considerably safer than conventional ones. Also, apart from Glargine and Detemir, newer formulations of mixed Insulin (NPH/Regular/Lispro/Aspart) have increased their availability to 24 hours with single doses with lower within subject variability.

Table 2 Pharmacokinetics of new insulin analogues

Drug                                      Onset (min)                        Peak (h)               Duration (h)

Rapid-acting

Lispro                                    5–15                                      2                              4

Aspart                                   5–15                                      2                              4

Glulisine                               5–15                                      2                              4

Basal

Glargine                               15                                           Flat                         24

Detemir                               15                                           Flat                         24

Analogue mixture

Biphasic insulin

Lispro                                    5–15                                      2–4                         18

Biphasic insulin

Aspart                                   5–15                                      2–4                         20–24


The most recently launched is Degludec, with inhalable ones promising an exciting future. Among the Incretin based therapies, new DPP4-I like Omarigliptin, Gemigliptin etc. are in the pipeline. In the injectable GLP1RAs, there are Albiglutide, and Lixisenatide coming up.
Therapies based on different MoA like SGLT2 inhibitions are also promising starts (Canagliflozin, Dapagliflozin etc.)

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