Recent advances in Treatment of Diabetes Mellitus

Recent advances Diabetes Mellitus

 Why need newer drugs?

Limitations of existing drugs:

Insulins: Repeated injections, Lipodystrophy, insulin resistance, cannot mimic the physiological nature of insulin release

OHAs: Adverse effect profile-unacceptable: weight gain; abdominal distention and flatulence with acarbose

Basic pathology is left unaltered, no strategy available to protect beta cells

Type I DM

1. Insulin Degludec (sept 2015)

Degludec is injected subcutaneously:

1. forms multihexameric complexes that slow absorption;
   1. binds to albumin

these two characteristics contribute to the prolonged effect of Degludec (>24 h at steady state).

• Common adverse reactions (excluding hypoglycaemia) reported with insulin Degludec included nasopharyngitis, upper respiratory tract infection, headache, sinusitis, diarrhoea, and gastroenteritis. Hypersensitivity, lipodystrophy, injection-site reactions, weight gain, and peripheral oedema were also reported

• Inhaled insulin
  • Inhaled insulin (Afrezza) (June 2014) is formulated for inhalation using a manufacturer-specific device.
  • In combination with a long-acting
  • More rapid onset and shorter duration than injected insulin analogues
  • Adverse events include cough and throat irritation
  • It should not be used in individuals who smoke and those who quit smoking less than 6 months ago

• Artificial Pancreas

• Gad vaccine
  • Autoantigen GAD (glutamic acid decarboxylase)-vaccine is safe for children at high risk for developing type 1 diabetes
  • The drug is given before onset of type 1 diabetes.
  • Phase 2b
  • Results by 2020

Type II DM

1. GLP1 receptor agonists

• GLP-1 is a naturally occurring hormone responsible for the incretin effect.
• The insulinotropic effect of GLP-1 is glucose dependent in that insulin secretion at fasting glucose concentrations, even with high levels of circulating GLP-1, is minimal
• Insulin secretion occurs in 2 phases.
•  1^st phase – immediate rise in insulin after meal lasting approximately 10 minutes.
•  2^nd phase – insulin is released more slowly for a prolonged period.
•  T2DM – markedly reduced first­ phase insulin secre­tion & ↑ second­ phase
•  Prolonged ele­vation of insulin from persistent hyperglycaemia leads to beta­ cell toxicity and ultimately contributes to insulin resistance.
•  Interventions that mimic normal first ­phase insulin secretion, rather than the second phase, have been correlated with improved glucose tolerance.
• Albiglutide Weekly (apr 2014)
• Dulaglutide Weekly (sept 2014)
• Exenatide   Weekly (2011)
• Liraglutide Daily (jan 2010)
• Lixisenatide Daily (July 2016)
• Semaglutide once weekly (Dec 2017)

Semaglutide

specifically indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

ITCA-650

• FDA has accepted NDA filing for the drug ITCA 650 (continuous subcutaneous delivery of exenatide) in 2017.
• The drug therapy is designed to utilize a subcutaneous osmotic mini-pump for continuous delivery of exenatide drug for a period of one year.
• The FREEDOM clinical trial program conducted for ITCA 650 demonstrated highest HbA1c reductions in patients receiving combination dose of metformin.
• ITCA 650 is the first once/twice yearly, injection-free GLP-1 therapy available globally

• DPP4 inhibitors

2. GLP­1 is degraded by dipeptidyl peptidase (DPP)­4, resulting in a shorter half­ life
3. This has led to the development of DPP­4 inhibitors, which inhibit the degradation of GLP­ 1
   1. Alogliptin 25 Daily (jan 2013)
   1. Linagliptin 5 Daily (may 2011)
   1. Saxagliptin 2.5–5 Daily (July 2009)
   1. Sitagliptin 25–100 12–16
   1. Vildagliptin 50–100 Twice daily Europe 2007

• The FDA has issued a warning that this class of drugs is rarely associated with severe joint pain.
• Patients treated with saxagliptin had an increase in hospitalization for heart failure
• Na+-Glucose Transporter 2 Inhibitors
  • SGLT2 is a Na+-glucose cotransporter located almost exclusively in the proximal portion of the renal tubule
  • SGLT2 accounts for 80%–90% of glucose reclamation
    • Canagliflozin (Apr 2013)
    • dapagliflozin (Jan 2014)
    • Empagliflozin (Aug 2014)
    • Ertugliflozin (Dec 2017)

• SGLT2 inhibitors reduce the burden on the proximal renal tubules.
• SGLT2 inhibitors reduce central sympathetic overactivity, probably by suppressing renal afferent signaling to the brain.
• A mild state of ketosis also contributes to reduction of sympathetic tone.
• Decreased sympathetic outflow from the brain to the kidney alters the pressure–natriuresis relationship so that the kidneys excrete more sodium and water at a given pressure, thereby improving fluid retention.
• It may also suppress the renal renin–angiotensin system (RAS) and augment circulating natriuretic peptide levels by attenuating renal neprilysin activity, thereby correcting the imbalance between the natriuretic peptide/soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway and the RAS pathway, leading to cardiovascular and renal protection.

Adverse events

• There is a small (1%–2%) increase in lower urinary tract infections and a 3%–5% increase in genital mycotic infections (FDA warning)
•  Urine glucose losses cause mild diuresis, which can lead to hypotension
•  Potency decreases by 40%–80% across the spectrum of stage 3 kidney disease
•  Increase the risk of fractures (FDA warning), affect mineral balance and circulating levels of parathyroid hormone and 1,25-hydroxy vitamin D
•  Diabetic ketoacidosis
•  Canagliflozin is associated with an increased risk of lower extremity amputation.

Recently Approved FDC – type II DM

• Sitagliptin + Simvastatin 2011
• Linagliptin + Metformin 2012
• Dapagliflozin + Metformin 2014
• Empagliflozin + Metformin 2015
• Insulin degludec + Liraglutide 2016
• Insulin glargine + lixisenatide 2016
• Dapagliflozin +Saxagliptin 2017

Drugs in pipeline

1. Sotagliflozin –
   1. oral inhibitor of sodium–glucose cotransporters 1 and 2 (SGLT1 and SGLT2)
   1. SGLT1 inhibition reduces glucose absorption in the proximal intestine
   1. SGLT2 inhibition decreases renal glucose reabsorption.

• Dual PPAR alpha/gamma agonist à Saroglitazar
  • first in class drug – dual PPAR agonist at the subtypes α (alpha) and γ (gamma) of the peroxisome proliferator-activated receptor (PPAR).
  •  Agonist action at PPARα lowers high blood triglycerides,
  •  Agonist action on PPARγ improves insulin resistance and consequently lowers blood sugar.
  •  The results of phase 3 clinical trials indicate that saroglitazar is devoid of conventional side effects of fibrates and pioglitazone
  •  Approved in India 2013 for diabetic dyslipidemia and hypertriglyceridemia in T2DM not controlled by statin therapy
  •  Phase II US – for NASH in 2016

Human Embryonic Stem Cells (HESCs)

• Stem cells can provide a non-exhausting source of the degenerated β cells in T2D patients – cultivated & transplanted
•  Researchers are trying to develop and establish functional β cell mass from different types of somatic stem cells, which can prove to be a miraculous therapy.
•  Mesenchymal Stem Cells (MSCs) [bone marrow, adipose tissue, umbilical cord or its blood, fibroblasts and liver cells] – glucose induced insulin-secreting cells, arrest insulin resistance, recovery of liver and pancreas damage and to cure diabetic ulcers and limb ischemia.
•  MSCs transplantation also leads to elevation of GLUT4, insulin receptor substrate 1 (IRS-1) and Akt (protein kinase B).
•  Limitations of the use of stem cells are the ethical issues involved. Safety issues involved must be considered prior to clinical application.

American Diabetes Association 2017 guidelines: