Recent advances in the management of Diabetes Mellitus

Recent advances in the management of Diabetes Mellitus

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  RECENT ADVANCES IN MANAGEMENTOF DIABETES MELLITUS Dr.Shaila Banu Final year Post Graduate Dpt of Pharmacology GMC , ATP
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  Learning Objectives ● DefineDiabetes mellitus ● Enumerate Goals ● Outline Therapy available for Type 1 & Type 2 ● Compare & contrast conventional insulins & newer analogues ● Classify Oral antidiabetic drugs
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  DIABETES MELLITUS • Syndrome :metabolic, vascular and neuropathic components – interrelated • Metabolic disorder: hyperglycemia (fasting plasma glucose >126 mg/dl and/or >200 mg/dl 2 hours after 75 g of oral glucose) due to defects in insulin secretion , insulin action or both • Coronary artery disease = diabetes • Metabolic syndrome: Type 2 Diabetes Mellitus, Central obesity, Hypertension, Hyperlipidemia [hypertriglyceridemia , reduced HDL]
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  History ●Diabetes : syphon(to pass through) Appolonius of Memphis. “Pissing evil”(17 th century) ●Mellitus: Honeyed Thomas wills
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  TYPES ● TYPE I: Absolute insulin deficiency / Autoimmune disease ● TYPE 2 : Insulin resistance , inadequate insulin secretory response ● TYPE 3 : β cell, insulin action , exocrine pancreas, drugs, infection ● GESTA TIONAL DIABETES
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  Therapy of diabetes: Comprehensive Diabetic care ● the symptoms related to hyperglycemia (fatigue, polyuria, weight loss) ● To prevent or reduce the acute metabolic decompensation and chronic end-organ complications. Components of Comprehensive Diabetic Care Management of diabetes Glycemic control Diet /life style exercise /drugs Treat associated conditions Dyslipidemia Hypertension Obesity Screen for / manage complications Retinopathy Neuropathy Nephropathy CVS Disease Others
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  Treatment Goals INDEX GOAL 1.Hb A1C < 7.0 % 2. Pre-prandial plasma glucose 90–130 mg/dL 3. Peak post prandial plasma glucose <180 mg/dL 4. Blood pressure <130/80 mm of hg 5. LDL-C <100 mg/dL 6. HDL-C >40 mg/dL 7. Triglycerides <150 mg/dL ● ● ● ● To maintain normoglycemia to normalize Hb A1c To prevent complications To improve QOL
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  Modalities of treatment
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  Insulin No single eventin the history of medicine has changed the lives of so many people ,so suddenly – Stephen Hume
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  Insulin ● Evolution ofinsulin : Exogenous insulin available for more than 90 yrs ● Top medical breakthroughs ● Most powerful diabetic agent ● Limited only by hypoglycemia
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  Clinical use • Mealtime insulin: rapid & short acting •Basal insulin : IA& LA Based on species of origin Human Porcine Bovine Classify ??
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  TIME COURSE OFACTION ONSET PEAK DOA REGULAR 30-45 m 2 -4 h 5-8 h LISPRO 15 m 1-1.5 h 2-5 h ASPART 15 m 1 h 3-5 h GLULISINE 15 m 1-1.5 h 1-2 h NPH 1- 2 h 6-12 h 18-24 h ULTRALENTE 4 -6 h 16-18 h 20-36 h GLARGINE 2 -5 h FLAT 18- 24 DETEMIR 1- 2 h FLAT 6-24
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  Traditional Insulin preparations ●Short Acting : Insulin Regular ● Intermediate Acting : Isophane Insulin Suspension ( NPH) , Insulin Zinc Suspension ( Lente) ● Slow Acting : Extended Insulin Zinc Suspension ( Ultralente)
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  Ideal insulin ● Shouldmatch the physiological insulin secretion ● 50% in basal conditions ● Remainder in response to meals ● Secretion : Pulsatile ● Biphasic • Acute insulin response : rapid 1st phase 5-10 mins / suppress HGO /
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  Traditional insulins ●Traditional insulins: Solutions of regular insulin, dissolved in a buffer at neutral pH ●Forms a hexamer when stored in the presence of Zn ions ( self aggregation ) ● S/C Injection : dissociate into dimers & then into monomers / time : 30 - 45 mins
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  Limitations of regularinsulins ●Regular insulin : Delayed onset [1/2 hr -1 hr ] POST PRANDIAL HYPERGLYCEMIA ● Peak : 2-3 hrs ● Duaration of action : 5-8 hrs HYPOGLYCEMIA LATE POST PRANDIAL has to be administered 30-45 mins before meals : dose cannot be adjusted according to size of meals ● Absorption varies with injection site and exercise
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  Insulin analogs Rapid actingLispro Aspart Glulisine Long acting Glargine Detemir Ultra long acting Degludec Inhaled insulin Afrezza Insulin combinations Mixture : short acting (25%–50%) and long acting (50%–75%)
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  Designer insulins Modified recombinantinsulins ●Regular insulin : altered through an amino acid / substitution / addition / deletion ●Rearrangement impart a particular physicochemical /PK property ●Proline and lysine at b 28 and b 29
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  Rapid acting analogues ●Rapidonset : 5 - 15 mins – better postprandial control ●PEAK : 1-2 hrs, DURATION : 4-5 hrs - decreased risk of late postprandial hypoglycemia ●Mimics physiology : less propensity to cause hexamers , Dissociate rapidly / associate with less cohesive force - Physical & chemical stability - faster absorption .
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  MODIFIED LONG ACTING ANALOGUES ●Substitution of Glycine for Asparagine at A 21 / Provides Stability + 2 Arginines at B Chain ● Addition of Fatty Acid to the Amino Group Of Lys B 29 / Myristoylated Insulin
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  DETEMIR ● New long-actinginsulin analogue threonine in B30 replaced by Myrsitic acid ● Addition of C-14 fatty acid chain to the amino group of LYS B 29 / Myristoylated insulin ●Increase self aggregation in SC tissue & reversible binding to albumin ● Detemir : has the Most reproducible effect of the IA& LA insulins
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  GLARGINE pH 4.0 SCTissue pH 7.4 MICRO-PRECIPITATION MAY CAUSE VARIABILITY IN ABSORPTION, HENCE, IN ACTION DETEMIR PH 7.4 SC Tissue pH 7.4 Binding to Albumin No Precipitation MORE PREDICTABLE IN ABSORPTION, HENCE IN ACTION MECHANISM
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  Insulin Degludec Newest ULTRAlongacting basal insulin, ● Modified insulin with one amino acid deleted (threonine at position B30) and is conjugated to hexadecanedioic acid via γ-l-glutamyl spacer at the amino acid lysine at position B29. ● Active at a physiologic pH, forms multihexamers complexes that slow absorption on subcutaneous injection ; Also binds well to albumin ● These two characteristics contribute to the prolonged effect of degludec (>24 h at steady state). T 1 ⁄ 2- (25-40 hr) /100U & 200U/ML[PEN] ● Unlike Glargine it is effective at physiological pH ● less severe hypoglycemia than glargine. ● Unlike Glargine & Detemir, it can be mixed with other insulins
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  Glargine, Degludec, andDetemir have minimal peak activity at steady- state A major concern about all newer insulin analogues is their altered mitogenic properties and resultant risk of carcinogenicity on long term use.
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  Inhaled insulin ● Recentlyintroduced Afrezza Meal time insulin ● FDA approval in both type 1 and type 2 diabetes [ Add on therapy for uncontrolled type 2]. ● Monomeric formulation ● Decreases the risk of hypoglycemia and weight gain ● Kinetics similar to ultra short acting insulins / Alternative to ultra SA insulins [ More rapid onset and shorter duration than injected insulin analogues ] / ● Used in combination with a long-acting insulin in type 1 DM. ● It is not widely used / Expensive ● Adverse events include cough and throat irritation. Not to be used in individuals who smokers, Asthma ,COPD .
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  INHALED INSULINS
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  New for Type1 DM ● Faster acting aspart [Fiasp] has added
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  • Oral insulin[Oramed’s] is currently in a pivotal clinical study going through FDAregulatory channels and is considered a game-changer . An orally ingestible insulin capsule (ORMD-0801). [Protein oral delivery technology (POD) ].
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  New for Type1 DM Otelixizumab Teplizumab Intravenous humanised
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  ● Nasal spray ●Patches ● Artificial pancreas ● Transplant beta cells ●Personalised medicine [grouping of diseases, targeted therapy , developments in genetics and big data ]
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  INSULIN PATCH
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  TRANSPLAT BETA CELLS
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  Mixtures : 70% NPH 50% NPH , , 30% REG 50% REG Lispro 75% Lispro Protamine , 25%
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  Non-Insulin Antidiabetic Drugs
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  ORAL : 1. Insulin secretagogues:
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  KATP Channel Modulators: Sulfonylureas 1.Tolbutamide, Tolazamide, And Chlorpropamide : Rarely Used Now 2.Glipenclamide,Glipizide,Gliclazide,Glimepiride are used now
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  KATP Channel Modulators:Nonsulfonylureas Repaglinide. Oral insulin secretagogue of the Meglitinide class, stimulates insulin release by closing KATP channels ● Metabolized by the liver (CYP3A4) to inactive derivatives, ~10% is metabolized by the kidney ● Hypoglycemia , weight gain Nateglinide : orally effective insulin secretagogue, block KATP channels ● Rapid but less-sustained secretion of insulin ● Effective in reducing postprandial glycemic elevations in patients with type 2 diabetes. ● It is metabolized primarily by hepatic CYPs (2C9, 70%; 3A4, 30%) and should be used cautiously in patients with hepatic insufficiency. ● Hypoglycaemia , weight gain
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  Thiazolidinediones Ligands for thePPAR γ receptor : Rosiglitazone And Pioglitazone MOA: Activate PPAR γ receptors- adipocyte differentiation, increased tissue sensitivity to insulin [ liver, adipose tissue, and skeletal muscle] ● Pioglitazone reduces plasma triglycerides by 10%–15%, raises HDLcholesterol levels, and increases LDL cholesterol. ADR: Weight gain and Edema ● Increased incidence of heart failure of up to 2-fold [plasma volume expansion] ● Rosiglitazone increased the risk of cardiovascular events (myocardial infarction, stroke). FDA has lifted the previous ban ● Increased risk of bone fracture in women ● Affect transaminases, liver function monitored
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  GLP-1–Based Agents ●Incretins [GI hormones releasedafter meals and stimulate insulin secretion
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  Liraglutide ●The liraglutide peptideis a long-acting, DPP-4-resistant form of GLP- 1, but with a Lys34Arg substitution and addition of an α-glutamic acid spacer coupled to a C16 fatty acyl group at Lys26. . ●The pharmacodynamic profile of liraglutide mimics GLP-1 and exenatide. ●Improvement in glycemic control and weight loss ●Adjunctive therapy in patients not achieving glycemic control with
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  Albiglutide : Fusionprotein , two sequential GLP-1 moieties linked to human albumin; The GLP-1 sequences are modified to prevent DPP-4 cleavage. Dulaglutide : Fusion protein consisting of two linked molecules that have a modified version of GLP-1 linked to the fc portion of a human immunoglobulin; Lixisenatide : A slightly longer form of exenatide GLP-1RA s : Pharmacodynamics are comparable to each other & can be used with other oral antidiabetic agents and basal insulin. ● While all of the GLP-1RAS have demonstrated efficacy as monotherapy, none is considered as a first- line agent. ● The differences in efficacy are small relative to the overall effect of the drugs, and definitive differences await more comprehensive studies.
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  Adverse Effects :Nausea and vomiting [neural activation of specific CNS neurons]. ● GI side effects. ● Hypoglycemia associated with GLP-1 agonist treatment is rare, but the combination of GLP-1 agonist with sulfonylurea drugs causes an increased rate of hypoglycemia compared to sulfonylurea treatment alone. ● Because of the reliance on renal clearance, exenatide, and probably lixisenatide, should not be given to persons with moderate-to-severe renal failure (creatinine clearance < 30 mL/min). ● possible association of exenatide treatment with pancreatitis; ● The GLP-1 receptor is expressed by thyroid C cells. Although there is not an established clinical association with medullary carcinoma of the thyroid, GLP-1 agonists should not be given to these patients.
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  DPP-4 Inhibitors ● Dipeptidyl peptidaseIV : serine protease . ● inactivation of GLP-1 and GIP. ●Sitagliptin, Saxagliptin, Linagliptin, alogliptin & Vildagliptin
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  • Mechanism ofAction: Alogliptin, linagliptin, and sitagliptin are competitive inhibitors of DPP-4; vildagliptin and saxagliptin bind the enzyme covalently. • 2-fold elevation of active GIP and GLP-1 and is associated with increased insulin secretion, reduced glucagon levels, and improvements in both fasting and postprandial hyperglycemia. • No direct effects on insulin sensitivity, gastric motility, or satiety& No effect body weight. • DPP-4 inhibitors, used as monotherapy in type 2 diabetic patients, reduce
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  ● SGLT2 isa Na+-glucose cotransporter : proximal portion of the renal tubule. ●SGLT 2 is a high-affinity, low- capacity transporter that moves glucose against a concentration gradient from the tubular lumen using energy generated from Na+ flux through the epithelial cells. ● Renal retention of glucose is nearly complete in nondiabetic persons, Na+Glucose Transporter 2 Inhibitors
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  Pramlintide ● A Syntheticform of amylin with several amino acid modifications to improve bioavailability ● acts through the amylin receptor in specific regions of the hindbrain. Activation of the amylin receptor reduces glucagon secretion, delays gastric emptying, and fosters a feeling of satiety. ● Subcutaneous injection prior to meals. Adverse Effects: nausea and hypoglycemia. ● Prandial insulin doses be reduced 30%–50% at the time of pramlintide initiation and then retitrated. ● Contraindicated in patients with gastroparesis or other disorders of motility. Pramlintide is a pregnancy category C drug. ● Therapeutic Uses: Pramlintide is approved for treatment of Type 1 and 2 diabetes as an adjunct in patients who take insulin with meals.
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  Bile Acid–Binding Resins Colesevelam: Approved for the treatment of type 2 diabetes . Mechanism of Action. Bile acid metabolism is abnormal in patients with type 2 diabetes .Reduce intestinal glucose absorption, also act as signaling molecules through nuclear receptors, some of which may act as glucose sensors. ● Colesevelam is provided as a powder for oral solution and as 625-mg tablets; ● dyspepsia, abdominal pain, and nausea affecting up to 10% of treated patients. ● increase plasma triglycerides ● Pregnancy category B drug & has no contraindications in patients with renal or liver disease. Therapeutic Uses. Treatment of hypercholesterolemia and may be used for treatment of type 2 diabetes as an adjunct to diet and exercise. In clinical trials, colesevelam reduced A1c by 0.5% when added to metformin, sulfonylurea, or insulin treatment in type 2 diabetic patients.
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  Bromocriptine ● Approved forthe treatment of type 2 diabetes ●Bromocriptine is an established treatment of parkinson disease and hyperprolactinemia ●Effects on blood glucose are modest and may reflect an action in the CNS. ●The dose range for bromocriptine is 1.6 to 4.8 mg, taken with food in the morning within 3 h of awakening. ● Side effects include nausea, fatigue, dizziness,
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  COMBINATION ANTIDIABETICS 1. Thiazolidinedione+ Biguanide DPP-4 inhibitors + Biguanide SGLT2 inhibitor + Biguanide DPP-4 inhibitor + SGLT2 inhibitor GLP-1 agonist + Degludec insulin GLP-1 agonist + Glargine insulin 2. 3. 4. 5. 6.
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  Dual PPAR agonists:Current Status ● Saroglitazar ● Only drug approved till date for Diabetic dyslipidaemia ● Indigenously developed NCE by any Indian company ● Approved for use in India by the DCGI in 2013 ● Phase II trials for NASH [Non alcoholic steatohepatitis] in US ( june,2016) ●Diabetic dyslipidemia and hypertriglyceridemia in T2DM not controlled by statin therapy
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  OTHERS ● Muraglitazar Meta-analysis ofthe phase 2 and 3 clinical trials revealed that it was associated with a greater incidence of MI, stroke, TIA and CHF when compared to placebo or pioglitazone ● Aleglitazar: Abandoned due to CAD Tesaglitazar: no longer studied, discontinued: renal toxicity
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  Newer potential targetsin DM
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  IRTK (Insulin receptortyrosine kinase and insulin mimetics
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  New potential targetsof carbohydrate metabolism
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  New potential targetsof lipid metabolism
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  New drugs forcomplications & vaccines ● Arxxant (also known as ruboxistaurin) has been submitted to the FDA (Food and Drug Administration) for approval in treating diabetic eye disease . Failed ● Diabetes vaccines Recombinant Human Glutamic Acid Decarboxylase-65 (rhGAD65) Phase 3 , Antibodies against GAD - 80–90% type 1 DM To slow or prevent autoimmune destruction of pancreatic islet cells amongst recent-onset type 1 diabetes mellitus ,subcutaneously - disappointing results. In 2013, a new trial in combination with vitamin D and the anti-inflammatory drug Ibuprofen
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  Emerging Therapies forDiabetes : what does our Goodman.G say ? ● Immunomodulatory approaches : To prevent or block the autoimmune process central to type 1 diabetes, ● Activators of GK, glucagon antagonists, and inhibitors of 11β-hydroxysteroid dehydrogenase [inactive cortisone to active cortisol]are being investigated as novel therapies for type 2 diabetes ● Advances in protein chemistry have allowed the development of peptides that activate more than one receptor to improve glucose regulation. ● Most of these incorporate GLP-1 receptor agonism with the capacity to activate receptors for glucagon, GIP, or gastrin. These compounds have been potent in pre-clinical models and are now in human trials. Some drugs developed for type 2 diabetes are being tested as adjunctive therapy for type 1 diabetes
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  ● Insulin Pumps:CSII ●Dexcom G5 Mobile Continuous Glucose Monitoring System, Approved December 20, 2016 [Sensor, transmitter , compatible smart phone,or a smart watch ] ●FreeStyle Libre Flash Glucose Monitoring System , Approved September 27, 2017 [sensor plus mobile reader ] ● InPen system[ smart insulin pen] : FDAapproved in 2017 for apple iOS and for android version in 2018 , is the first reusable insulin injector pen Newer Insulin delivery systems & glucose monitors
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  Insulin & Pregnancycategory [ Not used after 2015 ] INSULIN PREGNANCY CATEGORY Regular B[U-100,500] LOW RISK Aspart B LOW RISK Lispro B [U- 100,200] LOW RISK Glulisine C NO HUMAN DATA NPH B LOW RISK Glargine NO HUMAN DATA [Prev C] NO WELL CONTROLLED CLINICAL STUDIES Detemir B LOW RISK Degludec C [U-100 ,200] NO HUMAN DATA Inhaled insulin C NO HUMAN DATA
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  To summarise Diabetes isa metabolic disorder Discovery of insulin : major breakthrough Progressed from animal insulins to recombinant insulins - insulin analogs - inhaled insulins Not far off from oral insulins & regrowth of beta cells In Type 2 Insulin secretagogues , sensitizers ,newer GLP 1 analogs ,DPP 4 INHIBITORS , SGLT 1 inhibitors, pramlintide ,colesevelam, bromocriptine and the other
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  REFERENCES 1. The PharmacologicalBasis of Therapeutics – Goodman & Gilman 2. Rang & Dales Pharmacology 3. Essentials of Medical Pharmacology – KD tripathi 4. Internet - Journals
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  NOTHING LIKE DIET,EXERCISE & ADHERENCE TO LIFE STYLE CHANGES thank you