Incretins and alpha glucosidase inhibitors.pptx

Diabetes mellitus

1. INCRETIN THERAPY AND ALPHA-GLUCOSIDASE INHIBITORS

2. Introduction The term ‘ incretin ’, first described in 1932, refers to hormones released from the gut that regulate the insulin response to a meal. Glucose-dependent insulinotropic polypeptide (GIP) was the first gut hormone to be isolated. GIP and glucagon-like peptide-1 ( GLP-1 ), the second intestinal hormones discovered, are called incretins . They modulate the insulin secretory response to the products within the nutrients in the food.

3. Incretin Effect The incretin effect describes the phenomenon whereby oral glucose elicits higher insulin secretory responses than does intravenous glucose, despite inducing similar levels of glycaemia, in healthy individuals. These beneficial actions of are based on activation of the “ entero -insular axis” of glucose homeostasis and is estimated to be responsible for at least 50% of insulin secretion.

4. GIP GIP is a 42 amino acid peptide produced by the K cells of the duodenum and jejunum . The half-life of GIP is 4 to 7 min The GIPR is expressed in many tissues including the pancreas, adipose tissue, gastro-intestinal tract, heart, pituitary gland, adrenal cortex, and the brain. Stimulates insulin response from beta cells in a glucose dependent manner. Has minimal effects on gastric emptying. Has no significant effects on satiety or body weight. GIP acts glucagonotropically during euglycemia and hypoglycemia but not during hyperglycemia. Normal levels but decresed responsiveness in T2DM. Amino acids are weak stimuli. Fat is a more potent stimulator of GIP secretion than carbohydrates in humans. GLP-1 GLP-1 is a 30 amino acid peptide produced by the L cells , enteroendocrine cells of the distal ileum and colon. The half-life of GLP-1 is 1 to 2 min GLP-1R is expressed in the pancreas, gastrointestinal tract, kidneys, heart, and CNS. Stimulates insulin response from beta cells in a glucose dependent manner. Inhibits gastric emptying. Reduces food intake and body weight . Inhibits glucagon secretion from alpha cells during hyperglycemia but not during euglycemia and hypoglycemia. Deficient in T2DM.

5. Incretin Secretion in Type 2 Diabetes T2DM is characterized by a severely impaired or absent GIP insulinotropic effect . GIP secretion and fasting levels are increased in both the impaired and diabetic state. In the case of GLP-1, their secretion in patients with T2DM is impaired but the insulinotropic and glucagon-suppressive actions are preserved. Loss of insulinotropic effect has been speculated to occur as a result of either chronic desensitization of GIPRs or a reduction in the expression of GIPRs on pancreatic beta cells . This desensitization process is mediated by several mechanisms like receptor internalization, down-regulation and uncoupling from G proteins. Another mechanism is GLP-1 can activate the G proteins Gaq and Gas, whereas GIP can only activate Gas. In individuals with type 2 diabetes with chronic hyperglycaemia or in those treated with sulfonylureas , pancreatic beta cells are chronically depolarised , which in turn leads to a switch from Gas to Gaq as the major pathway for stimulating insulin secretion . GIP receptor signalling is progressively impaired under such conditions, while GLP-1 receptor signalling remains (partially) active through Gaq . This is seen in transgenic mouse models not confirmed in humans. Due to these reasons GIP has not been targeted in diabetic management. Diabetologia (2023) 66:1780–1795

6. Insulinotropic Mechanism of Action

7. Non- Insulinotropic Actions of GLP-1

8. GLP-1 RA on pancreas Inhibition of glucagon secretion secondary to the increase in insulin secretion cannot explain the effects because a similar reduction in glucagon levels has also been reported in patients with type 1 diabetes. Co-administration of a somatostatin receptor 5 antagonist abolishes the effects of GLP-1 on glucagon secretion in the isolated perfused pancreas suggests that the glucagonostatic effect of GLP-1 is secondarily mediated through an increase in somatostatin release from pancreatic δ cells . Protect beta cells from apoptosis. To stimulate beta -cell proliferation by upregulation of the beta -cell transcription factor pancreatic duodenal homeobox-1 protein (PDX-1 ) which is known to augment insulin gene transcription and up-regulate glucokinase and glucose transporter2 (GLUT2) .

9. Gastrointestinal effects of GLP-1 RA Potent inhibitor of several gastrointestinal functions such as gastric acid secretion gastric emptying and motility there by slowing the entry of nutrients into the circulation and contributing to the normalization of blood glucose levels. Deceleration of gastric emptying by GLP-1 is believed to be mediated by an inhibition of vagal activation . GLP-1 is thought to be an important mediator of “ ileal brake effect ”— the inhibition of gastric emptying by humoral and neural signals from the lower parts of the small intestine. Effect of GLP-1 on gastric motility is subject to rapid tachyphylaxis and tends to wane with continued exposure to high GLP-1 plasma concentrations.

10. CNS effects of GLP-1 RA 3 potential sources of central nervous GLP-1 action have been suggested: local production of GLP-1 in the brainstem, from where the peptide is believed to be transported along axonal networks into the CNS ; studies in humans have demonstrated that peripherally produced GLP-1 can access the brain through certain areas that lack a typical blood–brain barrier, such as the area postrema and the subfornical organs; receptors on peripheral nerve ends in the gut mucosa, the portal venous bed as well as the vagal nerve are held to project to certain areas within the hypothalamus to exert action on appetite regulation and glucose metabolism. Significant reductions of appetite sensations and food intake has been demonstrated during the exogenous administration of supraphysiologic amounts of GLP-1. These effects were found to be dose-dependent , and significant effects on food intake have only been observed with relatively high doses

11. Cardiovascular effects of GLP-1 RA GLP-1Rs are present on human cardiac myocytes , endothelial cells and vascular smooth muscle cells.

12. GLP-1 RA on kidney GLP-1 receptors are expressed in vascular smooth muscle cells, macrophages, T-lymphocytes and PCT. Binding of GLP-1 or GLP-1 receptor agonists activates the cAMP /Protein kinase A signaling pathway with phosphorylation of sodium-hydrogen exchanger 3 resulting in reduction in sodium, bicarbonate and fluid reabsorption in the proximal tubule. This partly explains why GLP-1RAs have subtle antihypertensive effects. Decreases inflammation.

13. Classification of GLP-1 RAs

14. Comparison between short-acting and long-acting GLP-1 RAs

15. Exenatide The first incretin-related therapy available for patients with type 2 diabetes. Naturally occurring peptide from the saliva of the Gila Monster. Has an approximate 53% amino acid homology with GLP-1. Resistant to DPP-IV inactivation. Half-life of 2.4 hours. Following injection, present in plasma for up to 10 hours Twice a day administration by subcutaneous injection. A formulation of exenatide ( exenatide LAR) has potential for once weekly subcutaneous injection . Primarily cleared by kidneys. Recommended for twice-daily administration starting at 5 μg twice daily, which may be increased to 10 μg twice daily after one month if well tolerated by the patient.

16. SIDE EFFECTS Nausea(40%- 50%) more common during the initial weeks of therapy and then decline. Adding exenatide to sulfonylurea increased the incidence of mild to moderate hypoglycemia . Exenatide is renally cleared and is not tolerated in the setting of advanced kidney disease ( eGFR <30 mL/min per 1.73 m2). Pancreatitis has been reported as a rare side effect of exenatide therapy principally through post marketing surveillance (6 times more common than other GLP-1 RA). Activation of ductal cell GLP-1Rs by exenatide might be a causative factor.

17. Liraglutide The structure of liraglutide is based on native GLP-1 with an Arg34Lys substitution and an addition of a 16-carbon fatty acid side-chain at Lys26, leaving liraglutide with a 97% homology with native GLP-1. The fatty acid side-chain enables the compound to be bound non-covalently to albumin and ensures that only 1–2% of liraglutide is circulating as free peptide in plasma after s.c . injection. Maximum plasma concentration is reached after 10 to 14 h, and it has a half-life of 11 to 13 h . Liraglutide is administered as an injection of 0.6 mg/day as the starting dose for 1 week and thereafter titrated to 1.2 mg/day. If it is well tolerated and further effect is needed, the dose can be further uptitrated to 1.8 mg/ day

18. Dulaglutide once weekly It consists of two GLP-1 moieties covalently linked to a human immunoglobulin G ( IgG ) 4-Fc heavy chain, which acts as an inert plasma carrier . The combination of large size, which limits renal clearance, and three amino acid substitutions (compared with native human GLP-1), which promote DPP-4 resistance, substantially prolongs biological activity . As a result, the half-life of dulaglutide is ∼90 h, and a once-weekly dosing ensures continued exposure of the GLP1Rs . The recommended starting dose of Dulaglutide is 0.75 mg, which can be increased to 1.5 mg dose for additional glycemic control.

19. Semaglutide Both oral and injectable preparations: Approved for type 2 diabetes. Only the injectable form is approved for the treatment of obesity . Half life is 1 week. Time to maximum concentration for oral drug was 1 hour and 24 hours for subcutaneous once weekly dosing. Dose: Injectable- The initial dose is 0.25 mg sc once weekly for four weeks. The dose is increased at four-week intervals (0.5, 1, 1.7, 2.4 mg) to the recommended dose of 2.4 mg once weekly. Dose: Oral- 3 mg once daily for 30 days and then increase to 7 mg once daily. If not meeting glycemic goals after 30 days on 7 mg dose, increase dose as tolerated to 14 mg once daily . Oral semaglutide 14 mg od is equivalent to sc semaglutide 0.5mg once weekly.

20. Structure of semaglutide Substitution of Ala with Aib at position 8 increases enzymatic (DPP4) stability. Attachment of a linker and C18 di -acid chain at position 26 provides strong binding to albumin. Substitution of Lys with Arg at position 34 prevents C18 fatty acid binding at the wrong site.

21. Structure of SNAC Orally administered semaglutide is co-formulated with an absorption enhancer, SNAC , which promotes absorption of semaglutide across gastric mucosa. SNAC has previously been co-formulated with heparin, ibandronate and vitamin B12 to increase drug absorption. Oral protein-based drug absorption is limited because of degradation in the stomach due to low pH, proteolytic enzyme activity, and limited permeability across the gastrointestinal (GI) epithelium. Co-formulation of GLP-1 RA with an absorption enhancer is necessary to achieve adequate bioavailability after oral administration.

22. Mechanism of absorption of semaglutide and SNAC co-formulation tablet When co‑formulated with 300 mg SNAC, 1% of semaglutide is usually absorbed in the stomach

23. GLP-1 RAs clinical trial programme PIONEER 1-10 with oral semaglutide

24. Overview of the Key Features, General Characteristics, Dosing, and Duration of the GLP-1 RAs Approved Globally for the Treatment of Patients with T2DM

25. Approved for obesity Liraglutide : SCALE trial (2015) Dose 3 mg Mean weight loss 8.4 +/- 7.3 kg > 5% weight loss in 63.2% > 10% weight loss in 33.1 % Approved for obesity in adolescents (12-18yrs) in 2020 Injectable Semaglutide : STEP-1 clinical trial Dose 2.4 mg Mean change from baseline 15.3 kg > 5% weight loss in 86.4% > 10% weight loss in 69.1% > 15% weight loss in 50.5% GLP-1 RA decreases gastrointestinal motility and hence increases the time for nutrient absorption. It promotes satiety and resting metabolic rate and lowers plasma concentrations of free fatty acids The weight loss benefits associated with GLP-1 RAs are likely to be due to suppressed appetite, reduced body fat and improved endothelial function.

26. S ummary for GLP1 agoni s t s Renal composite outcome improvement: liraglutide, dulaglutide & injectable s emaglutide only MACE superiority : liraglutide, dulaglutide & albiglutide HFH reduction : only albiglutide S troke s reduced : s emaglutide & dulaglutide MI reduced : albiglutide CV death reduced by liraglutide Gall s tone s more with liraglutide compared to placebo D iabetic retinopathy complication s more with s emaglutide compared to placebo.

27. CVOT trials Trial Inclusion criteria outcomes other s ELIXA ( Lixisenatide) n= 6068, 2.1yrs T2DM with Acute coronary event within 180 days 1 °outcome: MACE : no significant difference (13.4% in Lixisenatide , 13,2% in placebo) HR 1.02 P <0.001 for non-inferiority , p=0.81 for superiority. HFH: No difference Major deficiency : Very high rate of discontinuation( 45% in placebo, 43% in Lixisenatide) LEADER (liraglutide) n= 9340. 3.8yrs T2DM ≥50yrs with existing CVD, or age ≥ 60yrs with multiple CV RFs MACE : 13% in liraglutide; 14.9% in placebo (HR 0.87 , P< 0.001 for noninferiority, P= 0.01 for superiority ) ↓ All cause mortality (15%reduction): 8.2 % in liraglutide ,9.6% in placebo, HR: 0.85, P=0.02 for superiority) ↓ CV death ( 22 %reduction): 4.7% in liraglutide, 6.0% in placebo ,HR:0.78 , P= 0.007 for superiority) Incidence of composite outcome of renal or retinal microvascular events- lower in liraglutide group: 16%reduction. Lower rate of nephropathy events in liraglutide group 22 %reduction Retinopathy events were non significantly higher in liraglutide group than placebo(p=0.33) Advere events : GI events; Acute gall stone disease - liraglutide> placebo

28. LEADER trial subgroup analysis

29. Liraglutide and renal outcomes

30. Trial Inclusion criteria outcomes SUSTAIN 6 (Semaglutide injectable) n=3297, 2.1yrs T2DM ≥50yrs with existing CVD, or CKD ≥ stage 3 or age ≥ 60yrs with multiple CV RFs ↓3 point MACE : 6.6% in semaglutide vs 8.9% in placebo (HR:0.74, P< 0.001 for non inferiority ) -26% RRR ↓non fatal stroke : 39%reduction (HR:0.61, p=0.04 for superiority) New or worsening nephropathy were lower in semaglutide (3.8%) than placebo(6.1%) HR: 0.64% P=0.005 ,36%reduction Non significant ↓ in non fatal MI No significant difference in all cause mortality, cv death, HFH Diabetic retinopathy : 3% (50pts) in semaglutide group, 1.8%in placebo

31. Trial Inclusion criteria Outcomes EXSCEL ( exenatide once weekly) n= 14,752, 3.2yrs Adults with T2DM(A1C 6.5-10) D esigned such that 70% had previous CV events and 30% had no prior H/O CV events MACE : 11.4% in exenatide group vs 12.2% in placebo (HR: 0.91 P< 0.001 for non inferiority ) HFH – similar b/n group s No difference in retinopathy or related complication s PIONEER 6 ( oral semaglutide) n= 3183, 15.9mnths ≥50yrs with H/O established CVD or CKD ≥60yrs with CV RFs MACE: 3.8% in oral semaglutide group and 4.8% in placebo group (HR: 0.79; p < 0.001 for non- inferiorty ) HARMONY (albiglutide) n= 9463, 1.6yrs ≥40yrs old T2DM Established coronary, cerebrovascular or peripheral arterial disease with A1C >7 3 point MACE: 22 %RRR in albiglutide (7%)group than placebo(9%) (HR: 0.78 , P< 0.0001 for non inferiority, p=0.0006 for superiority ) 22 % reduction in urgent revascularization 2 5 % reduction in MI No difference in stroke, CV death, All cause mortality HFH: reduced

32. Trial Inclusion criteria 1 ° Outcome 2 ° Outcomes REWIND (Dulaglutide) n= 9901, 5.4yrs Age ≥50yrs CVD(31%pt s ) OR CV RFs(69%pt s ) T2DM (A1C ≤9.5) BMI ≥23 0-2 OADs ± basal insulin for ≥ 3m 3 point MACE: 12% in dulaglutide group, 13.4% in placebo group (HR: 0.88, p = 0.026) ( met MACE criteria for superiority & non- inferiorty ) 1 °ly by ↓in nonfatal s troke s All-cause mortality did not differ in 2 groups. No difference in HFH 2 °renal composite outcome ( 2 3%↓ ) of ne w onset macroalbuminuria, sustained↓ in eGFR of> 30% or need for chronic renal replacement therapy – significantly ↓in dulaglutide group. 1°ly by reduction in ne w macroalbuminuria

33. Data on GLP-1 RA use in patients with CKD (based on European Union label)

34. Indications In the consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE), GLP-1 RA is recommended as monotherapy in individuals with HbA1c>7.5%. GLP-1 RA is recommended in pre-diabetic patients if glycaemia is not normalised with medications such as metformin and acarbose

35. Indications for oral semaglutide

36. GLP-1 RAS USE IN SPECIAL POPULATIONS Used in patients with asymptomatic and stable CAD no clear evidence regarding their usage in acute myocardial infarction . Elderly: relatively low risk of hypoglycaemia and glycaemic variability without overt GI side effects to prevent malnutrition and worsening frailty. specifically considered in patients with cognitive problems. GLP-1 RAs are known to have low risk of hypoglycaemia and offer least glycaemic variability . Polycystic Ovary Syndrome: both body weight and glycemic control. modest decrease in BP and improvement in hyperlipidaemia The evidence on the use of GLP-1 RAs for the treatment of PCOS in women is currently available only for exenatide BID and liraglutide OD.

37. Contraindications/limitations Prior serious hypersensitivity. T1DM or diabetic ketoacidosis Pancreatitis Renal impairment severe GI diseases . increased risk of cholelithiasis . Personal or family history of MTC or in patients with MEN2. GLP1 plays a role in regulation of C cells in the rodent but not in the human.

38. Patient-Related Factors: ability of the patient to self-inject , meal patterns adherence to the pre-specified time of injection, frequency of contact with healthcare providers, cost-effectiveness Certain GLP-1 RAs require manual dexterity as a few of them need needle attachment, reconstitution and priming prior to injection. Liraglutide is effective with all kinds of meal patterns adopted by patients. Exenatide BID may benefit patients who consume heavy breakfast and dinner .

39. DRUG RECONSTITUTION OR MIXING REQUIRED AUTOMSTIC DOSE ADMINISTRATION PRIME DEVICE BEFORE USE NEEDLE ATTACHMENT REQUIRED DOSE SELECTION REQUIRED SINGLE USE DAILY Exenatide No No Yes Yes, needles not included Yes No Liraglutide No No Yes Yes, needles not included Yes No Lixisenatide No No Yes Yes, needles not included Yes No ONCE-WEEKLY Exenatide Yes No No Yes, needles included No Yes Exenatide (prefilled pen) Yes Yes No No, preattached hidden needle No Yes Dulaglutide No Yes No No, preattached hidden needle No Yes Semaglutide no no yes Yes, needles included yes no

40. Barriers to bridges in GLP-1 RA therapy

41. Antibody formation As with other peptides (e.g. insulin), repeated injection into the subcutaneous compartment can lead to antibody formation by the immune system. Exenatide has 53% amino acid sequence homology to GLP-1. With exenatide ( unretarded ), approximately 45% of patients develop antibodies. This number increases to 60–75% with the extended-release preparation (exenatide once weekly). In those with high- titre antibodies, there is less clinical effectiveness of exenatide treatment. Liraglutide has 97% amino acid sequence homology with GLP-1. Up to 8% of liraglutide -treated patients develop antibodies.

42. Tirzepatide Tirzepatide is a dual GIPR/GLP-1R agonist. A synthetic linear fatty acid modified peptide containing 39 amino acids, based on the native GIP sequence. It is attached to a 20-carbon fatty diacid moiety, which binds to albumin, prolonging its half-life to 5 days and thus enabling once weekly dosing . Tmax is 1-2 days Steady state concentration reached in 4 weeks Primarily excreted through urine and faeces . Affinity: GIP R > GLP 1 R In vitro, the aff i nity of tirzepatide is comparable to natural GIP for the GIPR and ~5-fold weaker than natural GLP-1 for the GLP-1R

43. GLP-1 and GIP Dual Agonism PreClinical Studies with co-administration of GIP and GLP-1 showed an additive cAMP response . S ynergistic effects on insulin synthesis , insulin secretion, and expression of genes associated with beta cell differentiation and survival. The co-infusion significantly inhibited glucagon secretion and potentiated insulin secretion. These effects were superior compared to infusion of either peptide alone. The co-administration augmented reductions in food intake, body weight and fat mass , and this was the rationale for the development of a unimolecular dual incretin receptor agonists (i.e., a single molecular structure with agonistic properties both at the GLP-1R and the GIPR) for the treatment of type 2 diabetes and obesity.

44. Change from baseline in HbA1c in SURPPASS Tirzepatide at all doses was noninferior and superior to semaglutide in SURPASS-2.

45. Change from baseline in body weight in SURPPASS Reductions in body weight were greater with tirzepatide than with semaglutide in SURPASS-2

46. Other clinical trials with tirzepatide

47. Adverse effects MC: Gastrointestinal- Mild to moderate, during the dose-escalation period Hypoglycemia: No significant difference between tirzepatide and placebo Rare: Hypersensitivity reactions Pancreatitis Acute gall bladder disease Increased incidence of thyroid C-cell tumours in rats. C/I in patients with a family or personal history of MTC.

48. FDA Recommendations In May 2022, the FDA approved Tirzepatide ( Mounjaro ) for the treatment of Type 2 diabetes in adults. The recommended starting dosage is 2.5 mg injected subcutaneously once weekly at any time of day, with or without meals . After 4 weeks , increase to 5 mg injected subcutaneously once weekly . If additional glycemic control is needed, increase the dosage in 2.5 mg increments after at least 4 weeks on the current dose. The maximum dosage is 15 mg subcutaneously once weekly .

49. DIPEPTIDYL PEPTIDASE-IV INHIBITORS ( gliptins ) DPP-IV inhibitors raise GLP-1 levels 2- to 3-fold , with subsequent HbA1c reductions of approximately 0.7-1%. Oral administration Weight neutral D o not require titration Associated with a low incidence of hypoglycemia or gastrointestinal side effects

50. Mechanism of Action DPP-4 inhibitors act to prevent the aminopeptidase activity of DPP-4. The enzyme is found free in the circulation and tethered to endothelia and other epithelial cells especially in the intestinal mucosa. DPP-4 cleaves the N-terminal dipeptide from peptides that have either an alanine or a proline residue penultimate to the N-terminus. The incretins GLP-1 and GIP are prime targets for DPP-4, and DPP-4 inhibitors more than double their circulating concentrations  enhance nutrient-induced insulin secretion. Increased insulin biosynthesis and increased β-cell mass have also been noted in some animal studies. Increased GLP-1 concentrations also suppress excessive glucagon secretion. The elevation of GLP-1 levels produced by DPP-4 inhibitors is not generally sufficient to create a measurable satiety effect or sufficient slowing of gastric emptying to cause any nausea, and body weight is usually little changed or slightly reduced. Because the incretin -mediated effect of DPP-4 inhibitors potentiates glucose-dependent insulin secretion, the activity period of these agents is mostly prandial .

51. Despite vildagliptin having relatively short half-life, its interaction with DPP-4 is of longer duration, because it forms a covalent bond with DPP-4 that only slowly dissociates , explaining a duration of action that persists over the time characterized by high plasma concentrations

52. Adverse effects a good safety profile  similar to those with placebo. Low risk of serious hypoglycemia unless administered along with an agent that itself carries significant risk of hypoglycemia. Some hyperplasia of the exocrine pancreas, and can increase the risk of acute pancreatitis in T2DM  should be stopped if pancreatitis is suspected. Serious hypersensitivity reactions have been reported, including anaphylaxis, angioedema, and exfoliative skin conditions with sitagliptin , but causality has not been substantiated due to the rarity of events .

53. Trial Inclusion criteria 1 ° outcome 2 ° outcome SAVOR-TIMI 53 (Saxagliptin) n=1649 ; 2.1 years T2DM (A1C : 6.5-12) H/O established CVD Or Multiple CV RFs 3point MACE- 7.3% in Saxagliptin group vs 7.2% in placebo group (HR: 1, p=0.99 for superiority & p< 0.001 for non-inferiority ) primary end point + HFH, Coronary re-vascularisation, hospitalisation for UA- 12.8% in Saxagliptin group vs 12.4% in placebo group (HR: 1.02; p= 0.66) HFH: 3.5% in Saxagliptin vs 2.8% in placebo group (HR: 1.27, p =0.007) EXAMINE (Alogliptin) n= 5380 ; 1.5 yr T2DM (A1C : 6.5 -11) H/O ACS within 15-90 days 3point MACE- 11.3% in Alogliptin group vs 11.8% in placebo group (HR: 0.96; p< 0.001 for non-inferiority ) 2° : 1°end points + urgent revascularization due to UA- no significant difference b/n alogliptin and placebo TECOS (sitagliptin) n=14.671, 3 yrs T2 DM with established CVD & >50 yrs age, A1C-6.5 to 8.0% 4 point MACE:11.4% in sitagliptin group, 11.6% in placebo(HR-0.98, P< 0.001 for noninferiority No significant difference in rate of HFH, composite outcome of HFH or CV death, All cause mortality

54. Linagliptin CARMELINA CAROLINA DESIGN, SETTING, AND PARTICIPANTS Randomized, placebo-controlled, multicenter noninferiority trial , n=6991, Adults with T2DM A1c of 6.5% to 10.0%, high CV risk and high renal risk. ESRD were excluded Randomized, double-blind, active-controlled, noninferiority trial, with participant screening ; n=6042 , 6.3 yrs Adults with T2 DM, A1c of 6.5% to 8.5%, and high CV risk INTERVENTIONS linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care 5 mg of linagliptin od(n = 3023) or 1 to 4 mg of glimepiride od (n = 3010) in addition to usual care MAIN OUTCOMES AND MEASURES 1 ° outcome: time to 1 st occurrence of the composite of CV death, nonfatal MI, or nonfatal stroke(3point MACE) 2 ° outcome : time to 1st occurrence of death due to RF, ESRD, or sustained 40 % ↓ in eGFR from baseline. Primary outcome: Time to 1st occurrence of cv d eath, nonfatal MI, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride 60

55. CARMELINA CAROLINA Outcomes 1 ° outcome : in 1 2 .4% In linagliptin, 1 2 . 1% in placebo (HR: 1.0 2 , P< 0.001 for non inferiority ) 2 ° outcome : no statistically significant difference in time to first occurrence of death due to renal failure, ESRD, or sustained 40 % decrease in eGFR from baseline Primary outcome : in 11.8% in linagliptin, 12% in glimiperide group(HR:0.98, p< 0.001 for non inferiority Results Among adults with T2DM and high CV and renal risk, linagliptin added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 year Among adults with relatively early T2DM and elevated CV risk, the use of linagliptin Vs glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome 61

56. Differences of incretin -based therapies

57. α – GLUCOSIDASE INHIBITORS Studies conducted in the late 1970s noted that inhibitors of intestinal α - glucosidase enzymes could retard the final steps of carbohydrate digestion with consequent delay to the absorption of sugars. By the early 1980s it was demonstrated that this approach could reduce post - prandial hyperglycemia in diabetes. Acarbose , the first α - glucosidase inhibitor, was introduced in the early 1990s. Subsequently , two further agents, miglitol and voglibose , were introduced

58. Mode of action α- Glucosidase inhibitors competitively block small intestine brush border α- glucosidases that are necessary to hydrolyze di -, oligo -, and polysaccharides to monosaccharides for absorption. Normally, carbohydrates are primarily and rapidly absorbed in the first half of the small intestine. With AGI, carbohydrate absorption and digestion occur throughout the small intestine, resulting in a slower absorption and a blunting of the postprandial rise in plasma glucose.

59. β- glucosidases (e.g. lactases) are not inhibited and therefore lactose absorption is not affected. Intestinal glucose absorption is also not affected. α – glucosidase inhibitors can only be effective if the patient is consuming complex digestible carbohydrate. By moving glucose absorption more distally along the intestinal tract, α – glucosidase inhibitors may alter the release of glucose - dependent intestinal hormones such as GIP and GLP - 1 which enhance nutrient - induced insulin secretion.

60. Pharmacokinetics Acarbose is degraded by amylases in the small intestine and by intestinal bacteria; less than 2% of the unchanged drug is absorbed along with some of the intestinal degradation products. Absorbed material is mostly eliminated in the urine within 24 hours. Miglitol is almost completely absorbed and eliminated unchanged in the urine . Voglibose is poorly absorbed by the gastrointestinal tract and hardly metabolized.

61. Uses α- Glucosidase inhibitors can be used as monotherapy , usually for people with T2DM with postprandial hyperglycemia but only slightly raised fasting glycemia . Commonly used as add-on to other therapies to target post- prandial hyperglycemia. When starting an α- glucosidase inhibitor, the person should be advised a diet containing complex digestible carbohydrate . α- Glucosidase inhibitors should be taken with meals, starting with a low dose (e.g. 50 mg/day acarbose ) and slowly uptitrated over several weeks. Monitoring of postprandial glycemia is often helpful. Multiple studies have shown that the decline in HbA1C usually ranges from 0.5 to 1.5%. No weight gain or frank hypoglycemia.

62. Comparative studies between 𝛂- glucosidase inhibitors In nondiabetic subjects, voglibose seemed slightly less potent than acarbose , with no difference in side effects. Miglitol gave softer stool and slightly less flatulence than acarbose . In type 2 diabetic patients, voglibose was associated with less gastrointestinal side effects than acarbose , but was also less effective in reducing PPG excursion.

63. Benefits of 𝛂- glucosidase inhibitors in elderly patients Acarbose could be a first-line drug for elderly type 2 diabetic patients because of the low hypoglycemic and drug interaction risks. Postprandial hypotension is an important clinical problem causing syncope and falls in the elderly population. By slowing the rate of absorption, the acute rise in splanchnic blood flow is blunted.

64. Impaired glucose tolerance and prevention of type 2 diabetes The STOP-NIDDM trial :- acarbose in preventing or delaying the development of T2DM in subjects with impaired glucose tolerance (IGT). On the basis of a single OGTT , acarbose reduced the risk of developing T2DM by 25% . If two positive OGTTs were used to confirm the diagnosis of T2DM, the relative risk reduction was 36.4%. The beneficial effect of acarbose was independent of age, sex, and BMI. A carbose treatment was associated with a significant increase in the reversion of IGT to normal glucose tolerance. In those with IGT , acarbose is effective in decreasing the risk of hypertension and cardiovascular complications. Voglibose is also effective in decreasing the risk of diabetes in subjects with IGT.

65. Contraindications Intestinal malabsorption syndromes IBD Colonic ulceration Partial intestinal obstruction Cirrhosis severe renal impairment ( creatinine clearance < 25mL/min) pregnant or lactating women, and in children below 12 years of age, because of a lack of data in these groups.

66. Adverse effects Gastrointestinal If the dosage is too high (relative to the amount of complex carbohydrate in the meal), undigested oligosaccharides pass into the large bowel. These are fermented, causing flatulence, abdominal discomfort and sometimes diarrhea , but usually ameliorating with slower titration and time. Agents affecting gut motility or cholestyramine is not recommended along with these drugs. High dosages of acarbose can occasionally increase liver enzyme concentrations , it is recommended to measure transaminase concentrations periodically in those receiving a maximum dosage (200 mg acarbose three times daily). Raised liver enzymes should remit as the dosage is reduced, otherwise alternative causes of hepatic dysfunction should be considered. Pneumatosis cystoides intestinalis / pneumatosis coli / pseudolipomatosis / intestinal emphysema (rare, 30 case reports)

67. The proper use of AGI requires attention on two major points: To be effective, they must be administered at the onset of meals with the first bite and not later than 15 min after meals. Therapy must be initiated with a low dose and titrated upward slowly based on PPG as well as gastrointestinal tolerance. Recommended doses are as follows: 25–100 mg three times daily for acarbose ; The maximum recommended dose for patients <60 kg is 50 mg three times daily The maximum recommended dose for patients >60 kg is 100 mg three times daily 25–100 mg three times daily for miglitol 0.2 mg three times daily for voglibose

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69. ROS production is reduced . The oxLDL -mediated activation of monocytes and macrophages and the consecutive activation of adhesion molecules such as VCAM-1, MCP-1, E- selectin , and ICAM-1 is reduced. This results in a reduction of monocyte accumulation in the vascular wall. Endothelial cells express more eNOS , produce more NO, and suppress endothelin formation that overall lead to vascular smooth muscle relaxation and endothelium-derived . M2 macrophages instead of M1 macrophages preferentially form from monocytes . The reduced exposure to ROS slows the process of foam cell formation and reduces caspase -mediated apoptosis of foam cells and the formation of necrosis in the core of atherosclerotic plaques . Reduces vascular smooth muscle proliferation and possible migration into plaques. The integrity of endothelial cells was stabilized . Plaque hemorrhage was reduced by semaglutide . The reduced expression of MMP preserves intact fibrous caps and prevents plaque rupture . The overall result is a slowing of plaque progression and plaque stabilization.

70. Anti- lipolytic mechanism of GLP-1 and its analogues are by its insulinotropic action. Genes encoding various enzymes involved in adipogenesis , such as fatty acid synthetase (FASN), are transcribed and activated by insulin to stimulate adipogenesis . Insulin can reduce ATGL transcription through the mTORc1-mediated pathway, thereby inhibiting lipolysis and promoting triglyceride storage. High plasma insulin levels lead to the dephosphorylation of acetyl- CoA carboxylase , thereby promoting acetyl- CoA converting to malonyl-CoA and the conversion of carbohydrates into fatty acids.

71. Hepatic Health GLP-1 RAs may play a role in protecting both lean and fatty livers from ischemic injury by inhibiting cell death and stimulating lipolysis. GLP-1 RAs can reduce hepatic steatosis and improve survival by enhancing the unfolded protein response by promoting macroautophagy . In addition, they improve insulin resistance and insulin sensitivity to prevent the progression of non-alcoholic fatty liver disease (NAFLD). The unique ability of GLP-1 RAs to promote weight loss, improve glycaemic control and potentially reverse hepatocyte injury, liver inflammation, and liver fibrosis makes them a novel and attractive therapeutic option for the treatment of NASH. Currently, there is limited clinical experience with GLP-1 RAs in patients with severe hepatic impairment.

72. Exenatide once-weekly Contains exendin-4 (i.e. the same active substance as exenatide twice daily) encased in microspheres made of biodegradable polymer poly( d,l-lactideco-glycolide ). The peptide has a sustained release from the microspheres in three phases: initial release (first 48 h), diffusion (∼2 weeks), and erosion release (∼7 weeks). When administered once weekly (2 mg per dose), the mean plasma concentrations of exenatide reach therapeutic levels after ∼2–4 weeks. Steady-state levels are obtained once microsphere dissolution begins after ∼6–7 weeks. Plasma levels of exenatide gradually decrease over 3 months once treatment is discontinued .

73. Albiglutide once weekly Albiglutide (previously named albugon ) is generated in the yeast species Saccaromyces cerevisiae by recombinant DNA technology and the resulting therapeutic fusion protein consists of two sequential copies of modified human GLP-1 linked to human albumin, which owing to molecular size limits the renal elimination. Peak plasma levels of albiglutide are achieved 2–5 days after s.c . injection, and the halflife is ∼5–8 days, making it suitable for once-weekly dosing. The recommended weekly dose is 30 mg, with the possibility of up-titration to 50 mg based on individual glycemic response.