{"id":308,"date":"2020-02-16T10:38:34","date_gmt":"2020-02-16T05:08:34","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=308"},"modified":"2020-02-16T10:38:34","modified_gmt":"2020-02-16T05:08:34","slug":"recent-advances-in-treatment-of-diabetes-mellitus","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/recent-advances-in-treatment-of-diabetes-mellitus\/","title":{"rendered":"Recent advances in Treatment of Diabetes Mellitus"},"content":{"rendered":"\n

Recent advances Diabetes Mellitus<\/em><\/strong><\/p>\n\n\n\n

 Why need newer drugs?<\/em><\/strong><\/em><\/strong><\/p>\n\n\n\n

Limitations of existing drugs:<\/em><\/strong><\/p>\n\n\n\n

Insulins: Repeated injections, Lipodystrophy, insulin resistance, cannot mimic the physiological nature of insulin release<\/em><\/p>\n\n\n\n

OHAs: Adverse effect profile-unacceptable: weight gain; abdominal distention and flatulence with acarbose<\/em><\/p>\n\n\n\n

Basic pathology is left unaltered, no strategy available to protect beta cells<\/em><\/p>\n\n\n\n

Type I DM<\/strong><\/p>\n\n\n\n

  1. Insulin Degludec (sept 2015)<\/strong><\/li><\/ol>\n\n\n\n

    Degludec is injected subcutaneously:<\/p>\n\n\n\n

    1. forms multihexameric complexes that slow absorption;
      1. binds to albumin<\/li><\/ol><\/li><\/ol>\n\n\n\n

        these two characteristics contribute to the prolonged effect of Degludec (>24 h at steady state).<\/p>\n\n\n\n

        • 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<\/li><\/ul>\n\n\n\n
          • Inhaled insulin<\/strong>
            • Inhaled insulin (Afrezza) (June 2014) is formulated for inhalation using a manufacturer-specific device.<\/li><\/ul>
              • In combination with a long-acting<\/li><\/ul>
                • More rapid onset and shorter duration than injected insulin analogues<\/li><\/ul>
                  • Adverse events include cough and throat irritation<\/li><\/ul>
                    • It should not be used in individuals who smoke and those who quit smoking less than 6 months ago<\/li><\/ul><\/li><\/ul>\n\n\n\n
                      • Artificial Pancreas<\/strong><\/li><\/ul>\n\n\n\n
                        \"\"<\/figure>\n\n\n\n
                        • <\/li><\/ul>\n\n\n\n
                          \"\"<\/figure>\n\n\n\n
                          • Gad vaccine<\/strong>
                            • Autoantigen GAD (glutamic acid decarboxylase)-vaccine is safe for children at high risk for developing type 1 diabetes<\/li><\/ul>
                              • The drug is given before onset of type 1 diabetes.<\/li><\/ul>
                                • Phase 2b<\/li><\/ul>
                                  • Results by 2020<\/li><\/ul><\/li><\/ul>\n\n\n\n

                                    Type II DM<\/strong><\/p>\n\n\n\n

                                    1. GLP1 receptor agonists<\/strong><\/li><\/ol>\n\n\n\n
                                      • GLP-1 is a naturally occurring hormone responsible for the incretin effect.<\/li>
                                      • 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<\/li>
                                      • Insulin secretion occurs in 2 phases.<\/li>
                                      •  1st<\/sup> phase – immediate rise in insulin after meal lasting approximately 10 minutes.<\/li>
                                      •  2nd<\/sup> phase – insulin is released more slowly for a prolonged period.<\/li>
                                      •  T2DM – markedly reduced first\u00ad phase insulin secre\u00adtion & \u2191 second\u00ad phase<\/li>
                                      •  Prolonged ele\u00advation of insulin from persistent hyperglycaemia leads to beta\u00ad cell toxicity and ultimately contributes to insulin resistance.<\/li>
                                      •  Interventions that mimic normal first \u00adphase insulin secretion, rather than the second phase, have been correlated with improved glucose tolerance.<\/li>
                                      • Albiglutide Weekly (apr 2014)<\/li>
                                      • Dulaglutide Weekly (sept 2014)<\/li>
                                      • Exenatide   Weekly (2011)<\/li>
                                      • Liraglutide Daily (jan 2010)<\/li>
                                      • Lixisenatide Daily (July 2016)<\/strong><\/li>
                                      • Semaglutide once weekly (Dec 2017)<\/strong><\/li><\/ul>\n\n\n\n
                                        \"\"<\/figure>\n\n\n\n

                                        Semaglutide<\/strong><\/p>\n\n\n\n

                                        specifically indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.<\/p>\n\n\n\n

                                        contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).<\/p>\n\n\n\n

                                        ITCA-650<\/strong><\/p>\n\n\n\n

                                        • FDA has accepted NDA filing<\/strong> for the drug ITCA 650 (continuous subcutaneous delivery of exenatide) in 2017.<\/strong><\/li>
                                        • The drug therapy is designed to utilize a subcutaneous osmotic mini-pump for continuous delivery of exenatide drug for a period of one year.<\/strong><\/li>
                                        • The FREEDOM clinical trial program conducted for ITCA 650 demonstrated highest HbA1c reductions in patients receiving combination dose of metformin.<\/li>
                                        • ITCA 650 is the first once\/twice yearly, injection-free GLP-1 therapy available globally<\/li><\/ul>\n\n\n\n
                                          • DPP4 inhibitors<\/strong><\/li><\/ul>\n\n\n\n
                                            1. GLP\u00ad1 is degraded by dipeptidyl peptidase (DPP)\u00ad4, resulting in a shorter half\u00ad life<\/li>
                                            2. This has led to the development of DPP\u00ad4 inhibitors, which inhibit the degradation of GLP\u00ad 1
                                              1. Alogliptin 25 Daily (jan 2013)<\/strong><\/li><\/ol>
                                                1. Linagliptin 5 Daily (may 2011)<\/li><\/ol>
                                                  1. Saxagliptin 2.5\u20135 Daily (July 2009)<\/li><\/ol>
                                                    1. Sitagliptin 25\u2013100 12\u201316<\/li><\/ol>
                                                      1. Vildagliptin 50\u2013100 Twice daily Europe 2007<\/li><\/ol><\/li><\/ol>\n\n\n\n
                                                        \"\"<\/figure>\n\n\n\n
                                                        • The FDA has issued a warning that this class of drugs is rarely associated with severe joint pain.<\/strong><\/li>
                                                        • Patients treated with saxagliptin had an increase in hospitalization for heart failure<\/strong><\/li>
                                                        • Na+-Glucose Transporter 2 Inhibitors<\/strong>
                                                          • SGLT2 is a Na+-glucose cotransporter located almost exclusively in the proximal portion of the renal tubule<\/li><\/ul>
                                                            • SGLT2 accounts for 80%\u201390% of glucose reclamation
                                                              • Canagliflozin (Apr 2013)<\/li><\/ul>
                                                                • dapagliflozin (Jan 2014)<\/li><\/ul>
                                                                  • Empagliflozin (Aug 2014)<\/li><\/ul>
                                                                    • Ertugliflozin (Dec 2017)<\/li><\/ul><\/li><\/ul><\/li><\/ul>\n\n\n\n
                                                                      \"\"<\/figure>\n\n\n\n
                                                                      • SGLT2 inhibitors reduce the burden on the proximal renal tubules.<\/li>
                                                                      • SGLT2 inhibitors reduce central sympathetic overactivity, probably by suppressing renal afferent signaling to the brain.<\/li>
                                                                      • A mild state of ketosis also contributes to reduction of sympathetic tone.<\/li>
                                                                      • Decreased sympathetic outflow from the brain to the kidney alters the pressure\u2013natriuresis relationship so that the kidneys excrete more sodium and water at a given pressure, thereby improving fluid retention.<\/li>
                                                                      • It may also suppress the renal renin\u2013angiotensin 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.<\/strong><\/li><\/ul>\n\n\n\n

                                                                        Adverse events<\/strong><\/p>\n\n\n\n

                                                                        • There is a small (1%\u20132%) increase in lower urinary tract infections and a 3%\u20135% increase in genital mycotic infections (FDA warning)<\/li>
                                                                        •  Urine glucose losses cause mild diuresis, which can lead to hypotension<\/li>
                                                                        •  Potency decreases by 40%\u201380% across the spectrum of stage 3 kidney disease<\/li>
                                                                        •  Increase the risk of fractures (FDA warning), affect mineral balance and circulating levels of parathyroid hormone and 1,25-hydroxy vitamin D<\/li>
                                                                        •  Diabetic ketoacidosis<\/li>
                                                                        •  Canagliflozin is associated with an increased risk of lower extremity amputation.<\/li><\/ul>\n\n\n\n

                                                                          Recently Approved FDC \u2013 type II DM<\/strong><\/p>\n\n\n\n

                                                                          • Sitagliptin + Simvastatin 2011<\/li>
                                                                          • Linagliptin + Metformin 2012<\/li>
                                                                          • Dapagliflozin + Metformin 2014<\/li>
                                                                          • Empagliflozin + Metformin 2015<\/li>
                                                                          • Insulin degludec + Liraglutide 2016<\/li>
                                                                          • Insulin glargine + lixisenatide 2016<\/li>
                                                                          • Dapagliflozin +Saxagliptin 2017<\/li><\/ul>\n\n\n\n

                                                                            Drugs in pipeline<\/strong><\/p>\n\n\n\n

                                                                            1. Sotagliflozin \u2013<\/strong>
                                                                              1. oral inhibitor of sodium\u2013glucose cotransporters 1 and 2 (SGLT1 and SGLT2)<\/li><\/ol>
                                                                                1. SGLT1 inhibition reduces glucose absorption in the proximal intestine<\/li><\/ol>
                                                                                  1. SGLT2 inhibition decreases renal glucose reabsorption.<\/li><\/ol><\/li><\/ol>\n\n\n\n
                                                                                    • Dual PPAR alpha\/gamma agonist <\/strong>\u00e0 Saroglitazar<\/strong>
                                                                                      • first in class drug – dual PPAR agonist at the subtypes \u03b1 (alpha) and \u03b3 (gamma) of the peroxisome proliferator-activated receptor (PPAR).<\/li><\/ul>
                                                                                        •  Agonist action at PPAR\u03b1 lowers high blood triglycerides,<\/li><\/ul>
                                                                                          •  Agonist action on PPAR\u03b3 improves insulin resistance and consequently lowers blood sugar.<\/li><\/ul>
                                                                                            •  The results of phase 3 clinical trials indicate that saroglitazar is devoid of conventional side effects of fibrates and pioglitazone<\/li><\/ul>
                                                                                              •  Approved in India 2013 for diabetic dyslipidemia and hypertriglyceridemia in T2DM not controlled by statin therapy<\/strong><\/li><\/ul>
                                                                                                •  Phase II US \u2013 for NASH in 2016<\/li><\/ul><\/li><\/ul>\n\n\n\n

                                                                                                  Human Embryonic Stem Cells (HESCs)<\/strong><\/p>\n\n\n\n

                                                                                                  • Stem cells can provide a non-exhausting source of the degenerated \u03b2 cells in T2D patients \u2013 cultivated & transplanted<\/li>
                                                                                                  •  Researchers are trying to develop and establish functional \u03b2 cell mass from different types of somatic stem cells, which can prove to be a miraculous therapy.<\/li>
                                                                                                  •  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.<\/li>
                                                                                                  •  MSCs transplantation also leads to elevation of GLUT4, insulin receptor substrate 1 (IRS-1) and Akt (protein kinase B).<\/li>
                                                                                                  •  Limitations of the use of stem cells are the ethical issues involved. Safety issues involved must be considered prior to clinical application.<\/li><\/ul>\n\n\n\n

                                                                                                    American Diabetes Association 2017 guidelines:<\/p>\n\n\n\n

                                                                                                    \"\"<\/figure>\n\n\n\n
                                                                                                    \"\"<\/figure>\n\n\n\n
                                                                                                    \"\"<\/figure>\n","protected":false},"excerpt":{"rendered":"

                                                                                                    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 Insulin Degludec[…]\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","footnotes":""},"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/308"}],"collection":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/comments?post=308"}],"version-history":[{"count":0,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/308\/revisions"}],"wp:attachment":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media?parent=308"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/categories?post=308"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/tags?post=308"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}