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PHARMACOTHERAPY OF DIABETES Abdulraof Almahfouz, MB, BCh, BAO ABIM, FACP, FACE Consultant Endocrinologits Head, Section of Endocrinology King Faisal Specialist Hospital & RC
Hypoglycemic agents in 1993 Oral • Sulphonyluria • Glyburide, glipizide and Gliclazide • Metformin Injectables-Insulin • Short acting-Regular, Actrapid • Intermediate acting- NPH, Insulitard
Hypoglycemic agents in 2021 Oral • Metformin • Sulphonyluria • Glyburide, Glipizide, Gliclazide, Glimeperide • Miglitinides-Repaglinide, Nateglinide • Thiazolidenediones-Pioglitazone • Alpha glucosidase inhibitors • DPPIV inhibitors • Sitagliptin, Vildagliptin, Saxagliptin, Lenagliptin, Alogliptin • SGLT2 inhibitors • Dapagliflozin, Canagliflozin, Empagliflozin Injectables • GLP1 analogues • Exenatide, liraglutide, Lixisenatide, Dulaglutide, Semaglutide • Insulins • Short • Regular • Lispro. Aspart, Glulisine • Superfast-Aspart • Intermediate • NPH,NPL • Long acting • Glargine100, Detemire • Glargine300, Degludec
Multiple defects contribute to the progression of type 2 diabetes mellitus Adapted from DeFronzo RA. Diabetes. 2009;58:773-95. Hyperglycaemia Decreased Insulin Secretion Increased Glucagon Secretion Neurotransmitter Dysfunction Decreased Incretin Effect Increased Hepatic Glucose Production Decreased Glucose Uptake Increased Glucose Reabsorption Increased Lipolysis Islet-a cell Pathogenesis of Type 2 Diabetes – The Ominous Octet
Metformin • 50-60% absorbed • Half life is 6 hours • 90% is eliminated in urine • Side effects: • GI-Abdominal discomfort, diarrhea and nausea. Less with XR form • Metallic taste • B12 deficiency • Start slowly and increase dose weekly • Contraindications: • Hypoxic state eg HF, Respiratory failure, septicemia • Renal and liver disease
Metformin • Reduces Insulin Resistance • Decreases mainly Fasting hyperglycemia but also postprandially • Requires some circulating Insulin for its action • Does not cause weight gain andcan cause weight loss • Improves lipid profile • Improves vascular risk factors such as PAI1, fibrinogen and platelet aggregation
Metformin • Decreases hepatic glucose production • Increases insulin mediated glucose uptake • Increases intestinal glucose utilization • Decreases Fasting insulin • Increase GLP1 secretion
Sulphonylurias • HbA1c reduction- 1.5% • UKPDS- HbA1c < 7% • 50% at 3 years • 34% at 6 years • 24% at 9 years • In Adopt ( Rosiglitazone, Glyburide, Metformin ), secondary failure (FBG > 180 ) at 5 years • Rosiglitazone-15% • Metformin-21 % • Glyburide-34% • At 4 years, prportion of patients with A1c < 7 % • Rosiglitazone 40% • Metformin-34% • Glyburide- 26%
Adverse effects • Beta cell apoptosis increased by suphonyluria and decreased by metformin • Hypoglycemia • More with glyburide • Weight gaain • With all • Controversy • CV
Glinides • Half life 1.5 to 1.8 hours-Hence its postprandial effect • Weaker than sulphonylurias • Less hypoglycemia than sulphonyluria • Nateglinide less potent than repglinide • Useful in elderly and with erratic time of meals
Sulphonylurias and Glinides
• November 2010 to December 2012 • 6042 participants. • Adults with type 2 diabetes • Baseline HbA1c 7.2% • Elevated cardiovascular risk • Mean age, 64.0 years • median duration of diabetes, 6.3 years; • 42%with macrovascular disease • Follow-up was 6.3 years • 5mg of linagliptin once daily (n = 3023) or 1 to 4mg of glimepiride JAMA September 24, 2019 Volume 322, Number 12
JAMA September 24, 2019 Volume 322, Number 12
Thiazolidinediones • PPARg activators • Improve insulin sensitivity in muscle, fat and liver • Decrease FFA • Decrease Triglycerides by 15-20% and LDL by 10% • Decrease liver fat • Well tolerated • No renal dosing needed • Lowering of BG peaks at 10-14 weeks • Durability is better than Sus or Metformin • ? Cardiovascular benefit
Down side of TZDs • Weight gain • Fluid retention • Heart failure • Osteoporosis • ? Cancer
N Engl J Med 2006;355:2427-43. A Diabetes Outcome Progression Trial
N Engl J Med 2006;355:2427-43.
N Engl J Med 2006;355:2427-43.
N Engl J Med 2006;355:2427-43.
A Glucosidase Inhibitors • Post prandial glucose reduction of 2 mmol and A1c reduction of 0.6-0.7 % is expected. • Less effective than all antidiabetic agents ( HbA1c of 0.2 % difference ) • Decreases PP Triglycerides but no effect on LDL • Minimal or no weight changes • Very safe • Abdominal distension, flatulence and diarrhea are frequent side effects- 50 % • Discontinuation rate of 25% • Pneumatosis cystiodes Intestinalis • Concurrent administration of Anti acids or bile acids resins reduce the effectiveness of aGI • Contraindicated in patients with malabsorption, inflammatory bow disease and colonic ulceration
Eu heart journal. 2004. 25. 10
Acarbose for Prevention of Type 2 Diabetes Mellitus The STOP-NIDDM randomised trial Results ▪ Placebo 42% ▪ Acarbose 32% ▪ Higher proportion on acarbose reverted to normal GT The Lancet, 15 June 2002, p 2072-2077
Effect of Acarbose on the Probability of Remaining Free of Cardiovascular Disease
Effect of Acarbose on the Probability of Remaining Free of Hypertension
Incretins
400 Type 2 diabetes Normal 0 120 240 360 -60 0 60 120 180 240 300 Delayed and reduced Postprandial hyperglycemia Minutes 300 200 100 Mitrakou A et al. Diabetes. 1990;39:1381-1390 pmol/L mg/dL Glucose Insulin -60 0 60 120 180 240 300 60 30 45 High and not suppressed Minutes fmol/L Glucagon
Placebo GLP-1 Nauck MA, et al. Diabetologia. 1993;36:741-744. Minutes *P <.05 Insulin Glucagon Fasting Glucose 250 150 5 250 200 100 50 40 30 20 10 0 mU/L 20 15 10 0 60 120 180 240 15.0 12.5 10.0 7.5 5.0 200 150 100 50 Infusion * * * * * * * * * * * * * * * * * * * mmol/L mg/dL pmol/L pmol/L Effect declines as glucose reaches normal n = 10
Meal Intestinal GIP and GLP-1 release GIP and GLP-1 Actions DPP-4 Enzyme GIP-(1–42) GLP-1(7–36) Intact GIP-(3–42) GLP-1(9–36) Metabolites Rapid Inactivation Half-life* GLP-1 ~ 2 minutes GIP ~ 5 minutes Deacon CF et al. Diabetes. 1995;44:1126–1131. *Meier JJ et al. Diabetes. 2004;53:654–662.
Time, min IR Insulin, mU/L nmol/L 0.6 0.5 0.4 0.3 0.2 0.1 0 80 60 40 20 0 180 60 120 0 The Incretin Effect in Subjects Without and With Type 2 Diabetes Control Subjects (n=8) Patients With Type 2 Diabetes (n=14) Time, min IR Insulin, mU/L nmol / L 0.6 0.5 0.4 0.3 0.2 0.1 0 80 60 40 20 0 180 60 120 0 Oral glucose load Intravenous (IV) glucose infusion Incretin Effect The incretin effect is diminished in type 2 diabetes. Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag. Permission pending.
Incretin Effect is Impaired in Type 2 Diabetes • Secretion of GLP-1 impaired • β-cell sensitivity to GLP-1 decreased • Secretion of GIP normal (or slightly impaired) • Effect of GIP abolished or grossly impaired • Inhibition of glucagon is impaired • The defect is secondary to diabetes • The loss occurs at even slight hyperglycaemia
Action of GLP1
Pharmacokinetics and Pharmacodynamics of DPPIV Inhibitors
DPPIV + Metformin or pioglitazone
Triple Combination with DPP4I
DPPIV Inhibitors • Well tolerated • No hypoglycemia except with SU or Insulin • No weight gain. ? Minimal wt loss • Pancreatitis and pancreatic ca- No evidence
GLP-1RAs vary in molecular structure and size GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; IgG4 Fc, immunoglobulin-G4 fragment crystallisable; kDa, kilodalton. Full reference list can be found in the slide notes. Liraglutide (3.75 kDa, 97% homology) Semaglutide (4.11 kDa, 94% homology) Lixisenatide (4.86 kDa, ~50% homology) Exenatide (4.19 kDa, 53% homology) Dulaglutide (~63 kDa, 90% homology) Exendin-based GLP-1RAs Human GLP-1 analogues Small Large Albiglutide His Gly Thr ThrSer Phe GluGly Asp Leu Ser Lys Gln Met Glu Glu Ala Val Glu Arg Phe Leu Ile GluTrpLeu Pro Lys GlyGly Asp SerSerGly AlaPro Pro Pro Ser His Gly Thr Thr Ser Phe Glu Gly Asp Leu Ser Lys Gln Met Glu Glu Ala Val Glu Arg Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys Phe Leu His Ala Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Glu Glu Phe Ile Ala Trp Leu Val Arg Gly Gly Arg His Aib Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Phe Lys Glu Ile Ala Trp Leu Gly Val Gly Arg Arg His Gly Thr ThrSer Phe Glu Gly AspVal Ser Ser Tyr Leu Glu Glu Ala Ala Gln Lys Phe Glu Ile Ala TrpLeu Gly Val GlyGly Lys PheIle Ala TrpLeu Gly Val GlyGly Lys Glu Ser Tyr Leu Glu Glu Ala Ala Gln Lys Ser His Gly Thr ThrSer Phe Glu Gly AspVal Linker peptide Modified IgG4 Fc domain His Gly Thr Thr Ser Phe Glu Gly AspValSerSerTyrLeuGluGly Ala Ala Gln Lys PheGlu Ile Ala Trp Leu Gly Val Gly Arg Lys His Gly Thr Thr Ser Phe Glu Gly Asp ValSerSerTyrLeuGluGly Ala Ala Gln Lys Phe Glu Ile AlaTrp Leu Asp Val Gly Arg Lys ALBUMIN
Significant *vs. comparator; #change in HbA1c from baseline for overall population (LEAD-4,-5) add-on to diet and exercise failure (LEAD-3); or add-on to previous OAD monotherapy (LEAD-2,-1) Marre et al. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046–55 (LEAD-5); Buse et al. Lancet 2009; 374:39–47 (LEAD-6)
HbA1c reduction by baseline category – 52 weeks Pratley et al. Int J Clin Pract 2011;65:397–407
Dulaglutide weekly vs Liraglutide daily ( AWARD 6) Thelancet.Vol 384 October 11, 2014
Semaglutide Sustain studies
Semaglutide weight change
Dulaglutide Program 45 Study Comparator Background Award 1 Dulaglutide vs Exenatide On top of pioglitazone and metformin Award 2 Dulaglutide vs Insulin Glargine On top of metformin and Glimeperide Award 3 Dulaglutide monotherapy vs metformin Award 4 Dulaglutide ss Insulin glargine In combination with prandial lispro Award 5 Dulaglutide vs Sitagliptin Metformin Award 6 Dulaglutide vs Liraglutide Metformin Award 7 Dulaglutide vs Insulin Glargine Moderate to severe CKD Award 8 Dulaglutide added to Glimepiride Award 9 Dulaglutide added to Insulin Glargine Award 10 Dulaglutide added to SGLT2I
Efficay of Dulaglutide Diabetes Metab Res Rev 2016; 32: 776–790.
Weight change with Dulaglutide Diabetes Metab Res Rev 2016; 32: 776–790.
Nausea with GLP1RA
49 • Adapted from: 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21; 4. Marsenic O. Am J Kidney Dis 2009;53:875–83. In normal renal glucose handling, 90% of glucose is reabsorbed by SGLT21–4 Remaining glucose is reabsorbed by SGLT1 (10%) Majority of glucose is reabsorbed by SGLT2 (90%) Proximal tubule Minimal to no glucose excretion SGLT2 Glucose Glucose filtration
50 • *Increases urinary volume by only ~1 additional void/day (~375 mL/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes. SGLT2Is lowers HbA1c with the additional benefits of weight loss and blood pressure reduction1 Glycaemic control SGLT2Is:1 • Acts independently of insulin mechanisms to reduce HbA1c via the kidney • Works regardless of β-cell function • Has a low propensity for hypoglycaemia Weight loss • Urinary excretion of ~70 g glucose/day with dapagliflozin corresponds to loss of 280 Kcal/day*1 (1 g glucose = ~4 Kcal) • 1 lb (0.45 kg) of body fat equates to ~3500 calories2 Blood pressure reduction • SGLT2Is increases diuresis and is associated with significant reductions in systolic blood pressure1
Weight Loss with Dapa on Top of Metformin over 4 years Dapagliflozin is not indicated for the management of obesity.2 Weight change was a secondary endpoint in clinical trials.2,3 A Phase III, multicentre, randomised, double-blind, parallel-group, 52-week, glipizide-controlled, non-inferiority study with a double-blind extension to evaluate the efficacy and safety of dapagliflozin 10 mg + metformin (1500–2000 mg/day) versus glipizide + metformin (1500–2000 mg/day) in patients with inadequate glycaemic control (HbA1c >6.5% and ≤10%) on metformin alone. Data are adjusted mean change from baseline derived from a longitudinal repeated-measures mixed model. 1. Del Prato S, et al. Presented at the 73rd American Diabetes Association Scientific Sessions, Chicago, USA. 21–25 June 2013. Abstract 62-LB; 2. Nauck MA, et al. Diabetes Care 2011;34:2015–22; 3. Dapagliflozin. Summary of product characteristics, 2014; 4. Bailey CJ, et al. Lancet 2010;375:2223–33. At 52 weeks, dapagliflozin was associated with weight loss of –3.2 kg versus weight gain of +1.4 kg with glipizide (p<0.0001)2
Side effects • Genital mycotic infections • UTI • DKA
Management of Type 2 DM Lifestyle Modification Metformin Dual therapy Triple therapy Basal insulin Basal Bolus insulin
Criteria for Choosing HypoglycemicAgent Efficacy Safety Weight Side effect Cost Durability Others
Baseline HbA1c Category Change From Baseline in HbA 1c (%) 117 112 179 167 82 82 33 21 <7% ≥7 to <8% ≥8 to <9% 9% –0.14 –0.59 –1.11 –1.76 –0.26 –0.53 –1.13 –1.68 –2.0 –1.8 –1.6 –1.4 –1.2 –1.0 –0.8 –0.6 –0.4 –0.2 0.0 Sitagliptin + metformin Sulfonylurea + metformin n = Baseline HbA1c and glycemic response aSitagliptin 100 mg/day with metformin (≥1500 mg/day); bSpecifically glipizide Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.
Reduction of HbA1c with LiraglutideAccording to Baseline HbA1c Liraglutide + met + rosiglitazone 0 -2.5 -2.0 -1.5 -1.0 -0.5 Change in HbA 1c (%) Baseline HbA1c Quartile 1 <7.4 7.4–8.3 8.3–9.2 ≥9.2 1.8 mg 1.2 mg Baseline HbA1c Quartile 2 Baseline HbA1c Quartile 3 Baseline HbA1c Quartile 4 2.3% Zinman B, et al. Diabetologia 2008; 51 (Suppl. 1): S359 (Abstract 898) (LEAD-4)
Effect on body weight across the Liraglutide Trials trials All subjects. *Significant vs. comparator Marre et al. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473– 81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52: 2046–55 (LEAD-5); Buse et al. Lancet 2009; 374:39–47 (LEAD-6)
0 5 10 15 20 Biphasic insulin Glinide SU Basal insulin DPP-4i GLP-1RA TZD AGI Odds ratio vs. placebo Hypoglycaemic risk of antihyperglycaemic agents added to metformin – network meta-analysis AGI, α-glucosidase inhibitor; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; SU, sulphonylurea; TZD, thiazolidinedione Liu SC et al. Diabetes Obes Metab 2012;14:810–820 Low risk of hypoglycaemia with GLP-1RAs High increased risk vs placebo Low increased risk vs placebo
1. The ACCORD Study Group. N Engl J Med 2008;358:2545–59; 2. Duckwoth et al. (VADT Study group) N Eng J Med 2009;360:120; 3. The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560–72 Severe Hypoglycaemic events in ACCORD, ADVANCE and VADT
Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046-2055 (LEAD-5); Buse et al. Lancet 2009;374 (9683):39–47 (LEAD-6); Pratley et al. Lancet 2010;375:1447–56 (lira vs sita) Rates of minor hypoglycaemia throughout the liraglutide clinical development programme Lira, liraglutide; met, metformin; sita, sitagliptin; SU, sulphonylurea; TZD, thiazolidinedione
Many therapies result in weight gain over time Glibenclamide (n=277) Years from randomisation Insulin (n=409) Metformin (n=342) Conventional treatment (n=411); diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/L UKPDS: up to 8 kg in 12 years ADOPT: up to 4.8 kg in 5 years Weight (kg) Rosiglitazone Metformin Glibenclamide Change in weight (kg) 0 1 5 0 3 6 9 12 8 7 6 4 3 2 Years 0 1 2 3 4 5 96 92 88 0 100 UKPDS 34. Lancet 1998:352:854–65. n=at baseline; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43
Effect on body weight across the LEAD trials All subjects. *Significant vs. comparator Marre et al. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52: 2046–55 (LEAD-5); Buse et al. Lancet 2009; 374:39–47 (LEAD-6)
Common Side effects of Hypoglycemic Agents • Metformin • GI, Lactic acidosis • Sulphonyluria • Hypoglycemia • Thiazolidenedione • Fluid retention, heart failure, osteoporosis • DPPIV Inhibitors • GLP1 agonists • Nausea, vomiting and diarrhea • SGLT2 Inhibitors • Mycotic infections and HTI • Increased LDL
Cost SR • Sulphonyluria 30 • Metformin 30 • Pioglitazone 60 • DPPIV inhibitors 100 • SGLT2 Inhibitors 160 • GLP1 agonists 500
OTHER ADD ON BENEFITS
Other Factors to consider in choosing Anti Diabetic Medications Weight BP CV benefits Renal Benefits Lipid
PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT
Intensifying to injectable therapies (1 of 2) Pharmacologic Approaches to Glycemic Management: Standards of Medical Care in Diabetes - 2021. Diabetes Care 2021;44(Suppl. 1):S111-S124
Intensifying to injectable therapies (2 of 2) Pharmacologic Approaches to Glycemic Management: Standards of Medical Care in Diabetes - 2021. Diabetes Care 2021;44(Suppl. 1):S111-S124
Slide no 73 Thank You Early use of GLP-1RA in T2DM

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Pharmacotherapy updatedof DM revised.pdf

  • 1.
    PHARMACOTHERAPY OF DIABETES Abdulraof Almahfouz,MB, BCh, BAO ABIM, FACP, FACE Consultant Endocrinologits Head, Section of Endocrinology King Faisal Specialist Hospital & RC
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    Hypoglycemic agents in1993 Oral • Sulphonyluria • Glyburide, glipizide and Gliclazide • Metformin Injectables-Insulin • Short acting-Regular, Actrapid • Intermediate acting- NPH, Insulitard
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    Hypoglycemic agents in2021 Oral • Metformin • Sulphonyluria • Glyburide, Glipizide, Gliclazide, Glimeperide • Miglitinides-Repaglinide, Nateglinide • Thiazolidenediones-Pioglitazone • Alpha glucosidase inhibitors • DPPIV inhibitors • Sitagliptin, Vildagliptin, Saxagliptin, Lenagliptin, Alogliptin • SGLT2 inhibitors • Dapagliflozin, Canagliflozin, Empagliflozin Injectables • GLP1 analogues • Exenatide, liraglutide, Lixisenatide, Dulaglutide, Semaglutide • Insulins • Short • Regular • Lispro. Aspart, Glulisine • Superfast-Aspart • Intermediate • NPH,NPL • Long acting • Glargine100, Detemire • Glargine300, Degludec
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    Multiple defects contributeto the progression of type 2 diabetes mellitus Adapted from DeFronzo RA. Diabetes. 2009;58:773-95. Hyperglycaemia Decreased Insulin Secretion Increased Glucagon Secretion Neurotransmitter Dysfunction Decreased Incretin Effect Increased Hepatic Glucose Production Decreased Glucose Uptake Increased Glucose Reabsorption Increased Lipolysis Islet-a cell Pathogenesis of Type 2 Diabetes – The Ominous Octet
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    Metformin • 50-60% absorbed •Half life is 6 hours • 90% is eliminated in urine • Side effects: • GI-Abdominal discomfort, diarrhea and nausea. Less with XR form • Metallic taste • B12 deficiency • Start slowly and increase dose weekly • Contraindications: • Hypoxic state eg HF, Respiratory failure, septicemia • Renal and liver disease
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    Metformin • Reduces InsulinResistance • Decreases mainly Fasting hyperglycemia but also postprandially • Requires some circulating Insulin for its action • Does not cause weight gain andcan cause weight loss • Improves lipid profile • Improves vascular risk factors such as PAI1, fibrinogen and platelet aggregation
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    Metformin • Decreases hepaticglucose production • Increases insulin mediated glucose uptake • Increases intestinal glucose utilization • Decreases Fasting insulin • Increase GLP1 secretion
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    Sulphonylurias • HbA1c reduction-1.5% • UKPDS- HbA1c < 7% • 50% at 3 years • 34% at 6 years • 24% at 9 years • In Adopt ( Rosiglitazone, Glyburide, Metformin ), secondary failure (FBG > 180 ) at 5 years • Rosiglitazone-15% • Metformin-21 % • Glyburide-34% • At 4 years, prportion of patients with A1c < 7 % • Rosiglitazone 40% • Metformin-34% • Glyburide- 26%
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    Adverse effects • Betacell apoptosis increased by suphonyluria and decreased by metformin • Hypoglycemia • More with glyburide • Weight gaain • With all • Controversy • CV
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    Glinides • Half life1.5 to 1.8 hours-Hence its postprandial effect • Weaker than sulphonylurias • Less hypoglycemia than sulphonyluria • Nateglinide less potent than repglinide • Useful in elderly and with erratic time of meals
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    • November 2010to December 2012 • 6042 participants. • Adults with type 2 diabetes • Baseline HbA1c 7.2% • Elevated cardiovascular risk • Mean age, 64.0 years • median duration of diabetes, 6.3 years; • 42%with macrovascular disease • Follow-up was 6.3 years • 5mg of linagliptin once daily (n = 3023) or 1 to 4mg of glimepiride JAMA September 24, 2019 Volume 322, Number 12
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    JAMA September 24,2019 Volume 322, Number 12
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    Thiazolidinediones • PPARg activators •Improve insulin sensitivity in muscle, fat and liver • Decrease FFA • Decrease Triglycerides by 15-20% and LDL by 10% • Decrease liver fat • Well tolerated • No renal dosing needed • Lowering of BG peaks at 10-14 weeks • Durability is better than Sus or Metformin • ? Cardiovascular benefit
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    Down side ofTZDs • Weight gain • Fluid retention • Heart failure • Osteoporosis • ? Cancer
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    N Engl JMed 2006;355:2427-43. A Diabetes Outcome Progression Trial
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    N Engl JMed 2006;355:2427-43.
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    N Engl JMed 2006;355:2427-43.
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    N Engl JMed 2006;355:2427-43.
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    A Glucosidase Inhibitors •Post prandial glucose reduction of 2 mmol and A1c reduction of 0.6-0.7 % is expected. • Less effective than all antidiabetic agents ( HbA1c of 0.2 % difference ) • Decreases PP Triglycerides but no effect on LDL • Minimal or no weight changes • Very safe • Abdominal distension, flatulence and diarrhea are frequent side effects- 50 % • Discontinuation rate of 25% • Pneumatosis cystiodes Intestinalis • Concurrent administration of Anti acids or bile acids resins reduce the effectiveness of aGI • Contraindicated in patients with malabsorption, inflammatory bow disease and colonic ulceration
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    Eu heart journal.2004. 25. 10
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    Acarbose for Preventionof Type 2 Diabetes Mellitus The STOP-NIDDM randomised trial Results ▪ Placebo 42% ▪ Acarbose 32% ▪ Higher proportion on acarbose reverted to normal GT The Lancet, 15 June 2002, p 2072-2077
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    Effect of Acarboseon the Probability of Remaining Free of Cardiovascular Disease
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    Effect of Acarboseon the Probability of Remaining Free of Hypertension
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    400 Type 2 diabetes Normal 0 120 240 360 -600 60 120 180 240 300 Delayed and reduced Postprandial hyperglycemia Minutes 300 200 100 Mitrakou A et al. Diabetes. 1990;39:1381-1390 pmol/L mg/dL Glucose Insulin -60 0 60 120 180 240 300 60 30 45 High and not suppressed Minutes fmol/L Glucagon
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    Placebo GLP-1 Nauck MA, etal. Diabetologia. 1993;36:741-744. Minutes *P <.05 Insulin Glucagon Fasting Glucose 250 150 5 250 200 100 50 40 30 20 10 0 mU/L 20 15 10 0 60 120 180 240 15.0 12.5 10.0 7.5 5.0 200 150 100 50 Infusion * * * * * * * * * * * * * * * * * * * mmol/L mg/dL pmol/L pmol/L Effect declines as glucose reaches normal n = 10
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    Meal Intestinal GIP and GLP-1 release GIP andGLP-1 Actions DPP-4 Enzyme GIP-(1–42) GLP-1(7–36) Intact GIP-(3–42) GLP-1(9–36) Metabolites Rapid Inactivation Half-life* GLP-1 ~ 2 minutes GIP ~ 5 minutes Deacon CF et al. Diabetes. 1995;44:1126–1131. *Meier JJ et al. Diabetes. 2004;53:654–662.
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    Time, min IR Insulin, mU/L nmol/L 0.6 0.5 0.4 0.3 0.2 0.1 0 80 60 40 20 0 180 60 120 0 TheIncretin Effect in Subjects Without and With Type 2 Diabetes Control Subjects (n=8) Patients With Type 2 Diabetes (n=14) Time, min IR Insulin, mU/L nmol / L 0.6 0.5 0.4 0.3 0.2 0.1 0 80 60 40 20 0 180 60 120 0 Oral glucose load Intravenous (IV) glucose infusion Incretin Effect The incretin effect is diminished in type 2 diabetes. Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag. Permission pending.
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    Incretin Effect isImpaired in Type 2 Diabetes • Secretion of GLP-1 impaired • β-cell sensitivity to GLP-1 decreased • Secretion of GIP normal (or slightly impaired) • Effect of GIP abolished or grossly impaired • Inhibition of glucagon is impaired • The defect is secondary to diabetes • The loss occurs at even slight hyperglycaemia
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    DPPIV + Metforminor pioglitazone
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    DPPIV Inhibitors • Welltolerated • No hypoglycemia except with SU or Insulin • No weight gain. ? Minimal wt loss • Pancreatitis and pancreatic ca- No evidence
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    GLP-1RAs vary inmolecular structure and size GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; IgG4 Fc, immunoglobulin-G4 fragment crystallisable; kDa, kilodalton. Full reference list can be found in the slide notes. Liraglutide (3.75 kDa, 97% homology) Semaglutide (4.11 kDa, 94% homology) Lixisenatide (4.86 kDa, ~50% homology) Exenatide (4.19 kDa, 53% homology) Dulaglutide (~63 kDa, 90% homology) Exendin-based GLP-1RAs Human GLP-1 analogues Small Large Albiglutide His Gly Thr ThrSer Phe GluGly Asp Leu Ser Lys Gln Met Glu Glu Ala Val Glu Arg Phe Leu Ile GluTrpLeu Pro Lys GlyGly Asp SerSerGly AlaPro Pro Pro Ser His Gly Thr Thr Ser Phe Glu Gly Asp Leu Ser Lys Gln Met Glu Glu Ala Val Glu Arg Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys Phe Leu His Ala Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Glu Glu Phe Ile Ala Trp Leu Val Arg Gly Gly Arg His Aib Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Phe Lys Glu Ile Ala Trp Leu Gly Val Gly Arg Arg His Gly Thr ThrSer Phe Glu Gly AspVal Ser Ser Tyr Leu Glu Glu Ala Ala Gln Lys Phe Glu Ile Ala TrpLeu Gly Val GlyGly Lys PheIle Ala TrpLeu Gly Val GlyGly Lys Glu Ser Tyr Leu Glu Glu Ala Ala Gln Lys Ser His Gly Thr ThrSer Phe Glu Gly AspVal Linker peptide Modified IgG4 Fc domain His Gly Thr Thr Ser Phe Glu Gly AspValSerSerTyrLeuGluGly Ala Ala Gln Lys PheGlu Ile Ala Trp Leu Gly Val Gly Arg Lys His Gly Thr Thr Ser Phe Glu Gly Asp ValSerSerTyrLeuGluGly Ala Ala Gln Lys Phe Glu Ile AlaTrp Leu Asp Val Gly Arg Lys ALBUMIN
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    Significant *vs. comparator;#change in HbA1c from baseline for overall population (LEAD-4,-5) add-on to diet and exercise failure (LEAD-3); or add-on to previous OAD monotherapy (LEAD-2,-1) Marre et al. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046–55 (LEAD-5); Buse et al. Lancet 2009; 374:39–47 (LEAD-6)
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    HbA1c reduction bybaseline category – 52 weeks Pratley et al. Int J Clin Pract 2011;65:397–407
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    Dulaglutide weekly vsLiraglutide daily ( AWARD 6) Thelancet.Vol 384 October 11, 2014
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    Dulaglutide Program 45 Study ComparatorBackground Award 1 Dulaglutide vs Exenatide On top of pioglitazone and metformin Award 2 Dulaglutide vs Insulin Glargine On top of metformin and Glimeperide Award 3 Dulaglutide monotherapy vs metformin Award 4 Dulaglutide ss Insulin glargine In combination with prandial lispro Award 5 Dulaglutide vs Sitagliptin Metformin Award 6 Dulaglutide vs Liraglutide Metformin Award 7 Dulaglutide vs Insulin Glargine Moderate to severe CKD Award 8 Dulaglutide added to Glimepiride Award 9 Dulaglutide added to Insulin Glargine Award 10 Dulaglutide added to SGLT2I
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    Efficay of Dulaglutide DiabetesMetab Res Rev 2016; 32: 776–790.
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    Weight change withDulaglutide Diabetes Metab Res Rev 2016; 32: 776–790.
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    49 • Adapted from:1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21; 4. Marsenic O. Am J Kidney Dis 2009;53:875–83. In normal renal glucose handling, 90% of glucose is reabsorbed by SGLT21–4 Remaining glucose is reabsorbed by SGLT1 (10%) Majority of glucose is reabsorbed by SGLT2 (90%) Proximal tubule Minimal to no glucose excretion SGLT2 Glucose Glucose filtration
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    50 • *Increases urinary volumeby only ~1 additional void/day (~375 mL/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes. SGLT2Is lowers HbA1c with the additional benefits of weight loss and blood pressure reduction1 Glycaemic control SGLT2Is:1 • Acts independently of insulin mechanisms to reduce HbA1c via the kidney • Works regardless of β-cell function • Has a low propensity for hypoglycaemia Weight loss • Urinary excretion of ~70 g glucose/day with dapagliflozin corresponds to loss of 280 Kcal/day*1 (1 g glucose = ~4 Kcal) • 1 lb (0.45 kg) of body fat equates to ~3500 calories2 Blood pressure reduction • SGLT2Is increases diuresis and is associated with significant reductions in systolic blood pressure1
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    Weight Loss withDapa on Top of Metformin over 4 years Dapagliflozin is not indicated for the management of obesity.2 Weight change was a secondary endpoint in clinical trials.2,3 A Phase III, multicentre, randomised, double-blind, parallel-group, 52-week, glipizide-controlled, non-inferiority study with a double-blind extension to evaluate the efficacy and safety of dapagliflozin 10 mg + metformin (1500–2000 mg/day) versus glipizide + metformin (1500–2000 mg/day) in patients with inadequate glycaemic control (HbA1c >6.5% and ≤10%) on metformin alone. Data are adjusted mean change from baseline derived from a longitudinal repeated-measures mixed model. 1. Del Prato S, et al. Presented at the 73rd American Diabetes Association Scientific Sessions, Chicago, USA. 21–25 June 2013. Abstract 62-LB; 2. Nauck MA, et al. Diabetes Care 2011;34:2015–22; 3. Dapagliflozin. Summary of product characteristics, 2014; 4. Bailey CJ, et al. Lancet 2010;375:2223–33. At 52 weeks, dapagliflozin was associated with weight loss of –3.2 kg versus weight gain of +1.4 kg with glipizide (p<0.0001)2
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    Side effects • Genitalmycotic infections • UTI • DKA
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    Management of Type2 DM Lifestyle Modification Metformin Dual therapy Triple therapy Basal insulin Basal Bolus insulin
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    Criteria for ChoosingHypoglycemicAgent Efficacy Safety Weight Side effect Cost Durability Others
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    Baseline HbA1c Category Change From Baseline in HbA 1c (%) 117112 179 167 82 82 33 21 <7% ≥7 to <8% ≥8 to <9% 9% –0.14 –0.59 –1.11 –1.76 –0.26 –0.53 –1.13 –1.68 –2.0 –1.8 –1.6 –1.4 –1.2 –1.0 –0.8 –0.6 –0.4 –0.2 0.0 Sitagliptin + metformin Sulfonylurea + metformin n = Baseline HbA1c and glycemic response aSitagliptin 100 mg/day with metformin (≥1500 mg/day); bSpecifically glipizide Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.
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    Reduction of HbA1cwith LiraglutideAccording to Baseline HbA1c Liraglutide + met + rosiglitazone 0 -2.5 -2.0 -1.5 -1.0 -0.5 Change in HbA 1c (%) Baseline HbA1c Quartile 1 <7.4 7.4–8.3 8.3–9.2 ≥9.2 1.8 mg 1.2 mg Baseline HbA1c Quartile 2 Baseline HbA1c Quartile 3 Baseline HbA1c Quartile 4 2.3% Zinman B, et al. Diabetologia 2008; 51 (Suppl. 1): S359 (Abstract 898) (LEAD-4)
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    Effect on bodyweight across the Liraglutide Trials trials All subjects. *Significant vs. comparator Marre et al. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473– 81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52: 2046–55 (LEAD-5); Buse et al. Lancet 2009; 374:39–47 (LEAD-6)
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    0 5 10 15 20 Biphasic insulin Glinide SU Basal insulin DPP-4iGLP-1RA TZD AGI Odds ratio vs. placebo Hypoglycaemic risk of antihyperglycaemic agents added to metformin – network meta-analysis AGI, α-glucosidase inhibitor; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; SU, sulphonylurea; TZD, thiazolidinedione Liu SC et al. Diabetes Obes Metab 2012;14:810–820 Low risk of hypoglycaemia with GLP-1RAs High increased risk vs placebo Low increased risk vs placebo
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    1. The ACCORDStudy Group. N Engl J Med 2008;358:2545–59; 2. Duckwoth et al. (VADT Study group) N Eng J Med 2009;360:120; 3. The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560–72 Severe Hypoglycaemic events in ACCORD, ADVANCE and VADT
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    Marre et al.Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046-2055 (LEAD-5); Buse et al. Lancet 2009;374 (9683):39–47 (LEAD-6); Pratley et al. Lancet 2010;375:1447–56 (lira vs sita) Rates of minor hypoglycaemia throughout the liraglutide clinical development programme Lira, liraglutide; met, metformin; sita, sitagliptin; SU, sulphonylurea; TZD, thiazolidinedione
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    Many therapies resultin weight gain over time Glibenclamide (n=277) Years from randomisation Insulin (n=409) Metformin (n=342) Conventional treatment (n=411); diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/L UKPDS: up to 8 kg in 12 years ADOPT: up to 4.8 kg in 5 years Weight (kg) Rosiglitazone Metformin Glibenclamide Change in weight (kg) 0 1 5 0 3 6 9 12 8 7 6 4 3 2 Years 0 1 2 3 4 5 96 92 88 0 100 UKPDS 34. Lancet 1998:352:854–65. n=at baseline; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43
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    Effect on bodyweight across the LEAD trials All subjects. *Significant vs. comparator Marre et al. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52: 2046–55 (LEAD-5); Buse et al. Lancet 2009; 374:39–47 (LEAD-6)
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    Common Side effectsof Hypoglycemic Agents • Metformin • GI, Lactic acidosis • Sulphonyluria • Hypoglycemia • Thiazolidenedione • Fluid retention, heart failure, osteoporosis • DPPIV Inhibitors • GLP1 agonists • Nausea, vomiting and diarrhea • SGLT2 Inhibitors • Mycotic infections and HTI • Increased LDL
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    Cost SR • Sulphonyluria 30 •Metformin 30 • Pioglitazone 60 • DPPIV inhibitors 100 • SGLT2 Inhibitors 160 • GLP1 agonists 500
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    Other Factors toconsider in choosing Anti Diabetic Medications Weight BP CV benefits Renal Benefits Lipid
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    PHARMACOLOGIC APPROACHES TOGLYCEMIC TREATMENT
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    Intensifying to injectabletherapies (1 of 2) Pharmacologic Approaches to Glycemic Management: Standards of Medical Care in Diabetes - 2021. Diabetes Care 2021;44(Suppl. 1):S111-S124
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    Intensifying to injectabletherapies (2 of 2) Pharmacologic Approaches to Glycemic Management: Standards of Medical Care in Diabetes - 2021. Diabetes Care 2021;44(Suppl. 1):S111-S124
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    Slide no 73 ThankYou Early use of GLP-1RA in T2DM