GLP-1-based therapies in the management of type 2 diabetes Makbul Aman Mansyur Division Endocrine & Metabolism Department of Internal Medicine Faculty of Medicine Hasanuddin University/ RSUP Dr. Wahidin Sudirohusodo Makasar
What would your ideal diabetes drug do? Effective in lowering HbA1c No hypoglycaemia No effect on weight/ weight loss? Reduce CV risk Also reduce lipids and B.P.? Few/ no side effects Safe 2
Evolution of type 2 DM management REDUCE. HbA 1c The lower the better HbA 1c The lower the better But w/o hypos and weight gain CV risk BP LDL Glycemic, but use agents with proven safety and efficacy Til 2008 2008-.. 2017!
Diabetes Medications Canagliflozin Alogliptin 2013 Dapagliflozin Empagliflozin Albiglutide Dulaglutide Afrezza inhaled insulin 2014 Insulin 1922 SUs 1957 Metformin AGIs 1995 Sitagliptin 2006 Saxagliptin 2009 Linagliptin 2011 U-300 Glargine Insulin Degludec Basaglar 2015 Semaglutide Ertugliflozin Fiasp Admelog 2017 1960 1995 2000 2005 2010 2015 2016 2017 Glinides TZDs 1997 Exenatide Pramlintide 2005 Liraglutide 2010 2012 Exenatide LAR 2016 Glargine/lixisenatide Degludec/liraglutide
ADA Guideline 2018: Pharmacological approaches to Glycemic Treatment Table 8.1-Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes Efficacy Hypoglycemi a Weight change CV effects Renal effects ASCVD CHF CKD progression Metformin High No Neutral Potential benefit Neutral Neutral SGLT-2 inhibitor Intermediat e No Loss Benefit: Canaglifozin, Empaglifozin Benefit: Canagliflozin Empaglifozin Benefit: Canagliflozin Empaglifozin GLP-1 RAs High No Loss Benefit: Liraglutide Neutral: Lixitenatide, exenatide extended release Neutral Benefit: Liraglutide DPP-4 inhibitor Intermediat e No Neutral Neutral Potential risk: Saxagliptin, alogliptin Neutral Thiazolidinedio nes High No Gain Potential Benefit: Pioglitazone Increased risk Neutral Sulphonylureas (2 nd gen) High Yes Gain Neutral Neutral Neutral A new table was added (Table 8.1) to summarize the drug-specific and patient factors of antihyperglycemic agents including CV and renal effects of drugs with additional considerations. *See ref. 31 for description of efficacy. FDA approved for CVD benefit CKD, Insulins chronic kidney disease; CVD, cardiovascular Highest disease; DKA, diabetic Yes ketoacidosis; DKD, diabetic Gain kidney disease; NASH, Neutral nonalcoholic steatohepatitis;ras, receptor Neutral agonists; SQ, subcutaneous; T2DM, type 2 diabetes Neutral Diabetes Care 2018;41(Suppl. 1):S1 S155
What is glucagon-like peptide-1? A 31 amino acid peptide Cleaved from proglucagon in L-cells in the gastrointestinal tract (and neurones in the hindbrain/hypothalamus) 1 Secreted in response to meal ingestion (direct luminal and indirect neuronal stimulation) 2 Member of the incretin family incretins are natural glucoregulatory peptides GIP (glucose-dependent insulinotropic polypeptide) is another incretin 2 1. Drucker et al. Proc Natl Acad Sci U.S.A 1987;84:3434 8; 2. Drucker & Nauck. Lancet 2006;368:1696 705
GLP-1 Modulates Numerous Functions GLP-1: Secreted upon the ingestion of food Promotes satiety and reduces appetite Alpha cells: Postprandial glucagon secretion Beta cells: Enhances glucosedependent insulin secretion Liver: Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169
Effect of GLP-1 in human body Drucker DJ. Cell metabolism 3, 153 165, march 2006
The effect of GLP-1 is glucosedependent Mean (SE); n=10; *p<0.05; type 2 diabetes patients (n=10) Nauck et al. Diabetologia 1993;36:741 4
Incretins: Role in Glucose Homeostasis GI tract Food ingestion Release of gut hormones Incretins 1,2 Pancreas 2,3 Active GLP-1 & GIP DPP-4 enzyme Inactive GLP-1 Inactive GIP Glucose Dependent Insulin from beta cells (GLP-1 and GIP) Beta cells Alpha cells Glucose Dependent Glucagon from alpha cells (GLP-1) Glucose uptake by peripheral tissue 2,4 Blood glucose Glucose production by liver 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876 913. 2. Ahrén B. Curr Diab Rep. 2003;2:365 372. 3. Drucker DJ. Diabetes Care. 2003;26:2929 2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430 441. 10
GLP-1 is normally degraded by the DPP-4 Enzyme DPP-4 inhibitor GLP-1 agonist (resistant to DPP-4 degradation) Meal DPP-4 Enzyme Release of Active GLP-1 Rapid Inactivation Inactive GLP-1
Insulin (pmol/l) Insulin (pmol/l) Insulin response to GLP-1 in type 2 diabetes Physiological levels of GLP-1 1 (15 mm hyperglycaemic clamp) Pharmacological levels of GLP-1 2 (15 mm hyperglycaemic clamp) 6000 GLP-1 infusion period (0.5 pmol/kg/min) 6000 GLP-1 infusion period (1.0 pmol/kg/min) 5000 4000 Plasma GLP-1: 46 pmol/l Healthy 5000 4000 Plasma GLP-1: 126 pmol/l T2DM 3000 3000 2000 2000 1000 Plasma GLP-1: 41 pmol/l T2DM 1000 0 0 30 60 90 120 Time (min) 0 0 45 90 135 180 Time (min) GLP-1, glucagon-like peptide 1, T2DM, type 2 diabetes mellitus 1. Højberg PV et al. Diabetologia 2009;52:199 207; 2. Vilsbøll T et al. Diabetologia 2002;45:1111 1119
Impaired GLP-1 physiology in type 2 diabetes is compensated by a GLP-1 receptor agonist GLP-1RA provides a higher level of GLP-1, which can help restore patients insulin response and improve clinical outcomes 1 3 Approximate pharmacological level of GLP- 1 required by people with type 2 diabetes 1 Diagrammatic representation of GLP-1 levels 1,2,3,6 DPP-4 inhibitors indirectly raise GLP-1 to modest levels, which may not be enough for people with impaired GLP-1 sensitivity 1,4,5 GLP-1 receptor agonists directly increase GLP-1, providing the higher levels needed for a near-normal insulin response 1 3 1 Pratley et al. Lancet 2010;375:1447 56; 2 Degn et al. Diabetes 2004;53:1187 94; 3 Vilsbøll et al. Diabetologia 2002;45:1111 9; 4 Ahrén. Diabetes Care 2007;301344 50; 5 Drucker. Diabetes Care 2003;26:2929 40; 6 Victoza SPC: http://www.ema.europa.eu/humandocs/pdfs/epar/victoza/h-1026-pi-en.pdf
http://www.medscape.com/viewarticle/835947
FDA-approved drugs GLP-1 Receptor Agonists Short-Acting Long-Acting Exenatide (Byetta) Lixisenatide (Adlyxin) Liraglutide (Victoza) Exenatide-LAR (Bydureon) Albiglutide (Tanzeum) Dulaglutide (Trulicity) Half-life 2 5 h 12 h several days Fasting BG Modest reduction Strong reduction A1C Modest reduction Strong reduction Postprandial hyperglycemia Strong reduction Gastric emptying rate Deceleration Modest reduction No effect Blood pressure Reduction Reduction Weight reduction 1 5 kg 2 5 kg Nausea Heart rate 20% 50%; slowly attenuates (weeks/months) 20% 40%; quickly attenuates ( 4 8 weeks) No/small increase (0-2 bpm) Moderate increase (2-5 bpm) Meier JJ. Nat Rev Endocrinol. 2012;8(12):728-742. Lund A, et al. Eur J Intern Med. 2014;25(5):407-414.
GLP-1 Agonists Exenatide (Byetta ) Liraglutide (Victoza ) Exenatide LAR (Bydureon ) Albiglutide (Tanzeum ) Dulaglutide (Trulicity )
Liraglutide A once-daily human GLP-1 analogue for the treatment of type 2 diabetes
Therapeutic indications Liraglutide is indicated for treatment of adults with type 2 diabetes to achieve glycaemic control: In combination with: Metformin or a sulphonylurea, in patients with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin or sulphonylurea In combination with: Metformin and a sulphonylurea or metformin and a thiazolidinedione in patients with insufficient glycaemic control despite dual therapy Victoza Summary of Product Characteristics
Liraglutide dosing Starting once-daily liraglutide is easy *Some patients may benefit from an increase in dose from 1.2 mg to 1.8 mg and, based on clinical response after at least 1 week, the dose can be increased to 1.8 mg to further improve glycaemic control Victoza Summary of Product Characteristics
Method of administration Prefilled, disposable pen for s.c. injection Contains 18 mg liraglutide in 3 ml 0.6 mg selected 1.2 mg selected Once-daily s.c. injection Select dose (0.6, 1.2 or 1.8 mg) Inject at any time, independent of mealtimes (preferably same time each day) Can use needles up to length of 8 mm and as thin as 32G Abdomen, thigh or upper arm Can change site and timing without dose adjustment 1.8 mg selected Victoza Summary of Product Characteristics
GLP-1 RA Contraindications Black Box Warning Adverse Effects Monitoring Interactions Family hx of medulary thyroid carcinoma, multiple endocrine neoplasia syndrome type 2* Risk of thyroid tumors (shown in animal models)* Nausea, vomiting, diarrhea, decreased appetite, weight loss, pancreatitis FBG, A1C, SCr, BUN - Agents that induce hypoglycemia - GLP-1 agonists may reduce rate of absorption of orally administered drugs Clinical pearls - Low hypoglycemia risk - Injectable - Avoid in patients with gastroparesis - May need to reduce dose of insulin and/or secretagogues - Pregnancy category C - All available as SC pens - 1-1.5 % in A1C * Contraindications and black box warning not reported for exenatide IR
Liraglutide improves HbA 1c by up to 2.5% in poorly controlled patients Nauck et al. IDF 20 th World Diabetes Congress 2009;P-1400
Liraglutide is effective across the continuum of care in type 2 diabetes Novo Nordisk. Liraglutide Approved Label in Iran. STF Q2 2013
GLP- RA THERAPY BEYOND GLYCEMIA 24
GLP-1 action in the cardiovascular system Davidson MH, The American Journal of Cardiology (www.ajconline.org) Vol 108 (3S) August 2, 2011
Potential indirect cardiovascular effects of glucagon-like peptide-1 receptor (GLP-1R) agonists. John R. Ussher, and Daniel J. Drucker Circ Res. 2014;114:1788-1803 Copyright American Heart Association, Inc. All rights reserved.
CV Protection 27
Is there any cardiovascular benefit of GLP-1 agonist therapy?
LEADER Trial 9,340 T2D patients with high CVD risk Mean age 64 yrs, A1c 8.7%, BMI 32.5 Randomized to liraglutide 1.8mg or placebo (double blind)
CV death reduced by 22% N Engl J Med 2016;375:311-322.
Other findings of LEADER Trial All cause death reduced by 15% Total myocardial infarctions reduced by 14% No significant difference in nonfatal MI, stroke, or hospitalization for heart failure N Engl J Med 2016;375:311-322.
What to expect with GLP-1RAs? Greater or similar glycaemic efficacy versus conventional T2DM therapies Weight loss versus the weight gain seen with conventional T2DM therapies Blood pressure reductions Improvements in beta-cell function (as measured by HOMA-B) Low risk of hypoglycaemia Mild and transient GI side-effects Greater achievement of clinically relevant composite endpoints compared with conventional T2DM therapies
GLP-1 RA vs. sulphonylurea As add-on to metformin (LEAD-2) Outcome Liraglutide 1.2 mg (n=241) Liraglutide 1.8 mg (n=242) Glimepiride 4 mg (n=244) HbA 1c change from baseline (%) HbA 1c <7.0% (% patients) Weight change from baseline (kg) 1.0 1.0 1.0 35.3 42.4 36.3 2.8 * 2.6 * +1.0 *Significant vs. glimepiride Nauck et al. Diabetes Care 2009;32:84 90 (LEAD-2)
GLP-1 RA vs. thiazolidinedione As add-on to metformin +/- SU (LEAD-1) Outcome Liraglutide 1.2 mg (n=228) Liraglutide 1.8 mg (n=234) Rosiglitazo ne 4 mg (n=232) HbA 1c change from baseline (%) HbA 1c <7.0% (% patients) Weight change from baseline (kg) *Significant vs. rosiglitazone 1.1* 1.1* 0.4 35 42 22 +0.32* -0.23* +2.11 Marre et al. Diabetic Med 2009;26:268 78 (LEAD-1)
GLP-1 RA vs. DPP-4 inhibitor or TZD As add-on to metformin (DURATION-2) Outcome Exenatide 2 mg once weekly (n=170) Sitagliptin 100 mg (n=172) Pioglitazon e 45 mg (n=172) HbA 1c change from baseline (%) HbA 1c <7.0% (% patients) Weight change from baseline (kg) -1.5* -0.9-1.2 ~60* ~30 ~45-2.3* -0.8 +2.8 *Significant vs. both sitagliptin and pioglitazone Bergenstal et al. Lancet 2010; 376:431-9.
GLP-1 RA vs. basal insulin As add-on to metformin +/- SU (DURATION-3) Outcome Exenatide 2 mg once-weekly (n=233) Insulin glargine once-daily (n=223) HbA 1c change from baseline (%) 1.5* 1.3 HbA 1c <7.0% (% patients) 60* 48 Weight change from baseline (kg) 2.6 * +1.4 *Significant vs. insulin glargine Diamant et al. Lancet 2010;375:2234 43
Type 2 diabetes treatment efficacy: summary Change in HbA 1c (%) Change in body weight (kg) Risk of hypoglycaemia SUs High Gain Moderate TZDs High Gain Low GLP-1RAs High Loss Low DPP-4Is Intermediate Neutral Low Insulin Highest Gain High Inzucchi et al. Diabetes Care2015;38:140-149
Set up position of GLP-1 agonist treatment based on recent guideline
Rationale for Combining GLP-1 RAs and Basal Insulin: Complementary Effects Characteristic GLP-1 RA Basal Insulin MOA Glucose profile glucose-dependent pancreatic insulin secretion glucose-dependent glucagon secretion gastric emptying satiety/ appetite Short-acting agents: PPG excursions Long-acting agents: PPG and FPG Mimics basal rate of endogenous insulin glucose disposal hepatic glucose production FPG Body weight weight weight Injection frequency SubQ 1-2/day or 1/week SubQ 1-2/day Effect on pancreatic beta cells May improve beta cell function Anderson SL, Trujillo JM. Diabetes Spectrum. 2016; 29:152-160. Vedtofte L, et al. Exper Rev Clin Pharmacol. 2015;8:273-282. Rests beta cells Reduces glucose toxicity
Summary GLP-1 agonists not only help reduce plasma glucose levels in type-2 diabetics, but also help improve markers of cardiovascular function including blood pressure, cholesterol, and weight loss. GLP-1 agonists are shown to have positive effects on cardiovascular outcomes and reduce the risk for heart failure These benefits to cardiovascular health are independent of GLP-1 agonists effect on glucose control and add important cardiocascular effects for type-2 diabetics.
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