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Glp1 and insulin
- 2. aa NUMBERNUMBER of Reasonsof Reasons 0 0 0 *All estimates are presented as comparative rates International Diabetes Federation. IDF Diabetes Atlas. 5th edition. 2012 NORTH AMERICA AND CARIBBEAN MIDDLE EAST AND NORTH AFRICA EUROPE WESTERN PACIFIC SOUTH AND CENTRAL AMERICA AFRICA SOUTH-EAST ASIA WORLD 371 million people living with diabetes 38 million 26 million 15 million 34 million 55 million 70 million 132 million 3 7 1, 0 0 0, 0 0 0
- 3. The diabetes pandemic – IDF Diabetes Atlas 5th edition 0 100 200 300 400 500 600 Diabetes 2011 2030 Source: IDF, Diabetes Atlas, Fifth edition *IGT = Impaired glucose tolerance 2011: 366 million people with diabetes 2030: 552 million people with diabetes
- 4. Type 2 diabetes is a progressive disease 4 Conceptual representation adapted from Ramlo-Halsted BA, Edelman SV. Prim Care 1999;26(4):771–789. © 1999 Elsevier Insulin level Insulin resistance Hepatic glucose production Postprandial glucose Fasting plasma glucose Beta-cell function Progression of Type 2 Diabetes Impaired Glucose Tolerance Diabetes Diagnosis Diabetes 4–7 years Development of Macrovascular Complications Development of Microvascular Complications
- 5. Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
- 6. It is all about Balancing glycaemic control and side effects
- 8. Choice of therapy after metformin? DPP-4i, dipeptidyl peptidase-4 inhibitor; GI, gastrointestinal; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycosylated haemoglobin; SU, sulphonylurea; TZD, thiazolidinedione; , weight gain; , weight loss; , weight neutral↑ ↓ ↔ SU TZD DPP-4i GLP-1RA Insulin (basal( Efficacy (↓HbA1c( High High Intermediate High Highest Hypoglycaemia risk Moderate Low Low Low High Weight effect ↑ ↑ ↔ ↓ ↑ Major side effects Hypoglycaemi a Oedema Heart failure Bone fractures Rare GI Hypoglycaemia Inzucchi SE et al. Diabetologia 2012;55:1577–1596
- 9. Pharmacokinetic profiles: short- vs. long-acting GLP-1RAs Category Agent Half-life Cmax Short- acting <24 hours Exenatide BID1 2.4 hours 2 hours Lixisenatide2 2.7–4.3 hours 1.25–2.25 hours Long- acting ≥24 hours Liraglutide3 13 hours 8–12 hours Dulaglutide4 90 hours 24–48 hours Albiglutide5,6 6–7 days 3–5 days Exenatide OW7 7–14 days 6–7 weeks BID, twice daily; OW, once weekly
- 10. Victoza - better HbA1c reduction (vs. comparators) across LEAD trials 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). HbA1c, glycosylated haemoglobin; DPP-4, dipeptidyl petidase-4; MET, metformin; OAD, oral anti-diabetic drug; SU, sulphonylurea; TZD, thiazoladinedione. 1. Garber A et al. Lancet 2009;373:473–481; 2. Nauck M et al. Diabetes Care 2009;32;84–90; 3. Marre M et al. Diabet Med 2009;26;268–278; 4. Zinman B et al. Diabetes Care 2009;32:1224–1230; 5. Russell-Jones D et al. Diabetologia 2009;52:2046–2055; 6. Buse JB et al. Lancet 2009;374:39– 47. Baseline HbA1c (%) 8.3 8.18.68.58.38.68.58.2 8.28.6 8.6 8.48.4 8.4 8.2 8.1 * * * * * * * * SU combination LEAD-13 Met combination LEAD-22 Met + TZD combination LEAD-44 Met + SU combination LEAD-55 Monotherapy LEAD-31 Met ± SU combination LEAD-66 Liraglutide 1.8 mgLiraglutide 1.2 mg Glimepiride Rosiglitazone Glargine Placebo Exenatide
- 11. Victoza - better Weight effects across LEAD trials Liraglutide 1.8 mgLiraglutide 1.2 mg Glimepiride Rosiglitazone Glargine Placebo Exenatide SU combination LEAD-13 Met combination LEAD-22 Met + TZD combination LEAD-44 Met + SU combination LEAD-55 Monotherapy LEAD-31 Met ± SU combination LEAD-66 Changeinbodyweight(kg) *p≤0.0001 vs active comparator; † p≤0.01, ††† p≤0.0001 vs placebo (active comparators vs placebo not shown) Data from core trials MET, metformin; SU, sulphonylurea; TZD, thiazoladinedione. † * ** * † * ††† * * * * 1. Garber A et al. Lancet 2009;373:473–481; 2. Nauck M et al. Diabetes Care 2009;32;84–90; 3. Marre M et al. Diabet Med 2009;26;268–278; 4. Zinman B et al. Diabetes Care 2009;32:1224–1230; 5. Russell-Jones D et al. Diabetologia 2009;52:2046–2055; 6. Buse JB et al. Lancet 2009;374:39– 47.
- 12. Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2; change in body weight by weight loss quartile) Increasing body weight loss Changeinbodyweight(kg) The 25% of subjects who lost most weight lost a mean of 7.7 kg -7.7 -3.7 -1.8 +1.3 Q1 Q4Q3Q2 Liraglutide 1.8 mg + metformin Q1: mean weight change for the 25% of subjects who had the smallest weight loss Q2: mean weight change for the 25% of subjects who had >25–≤50% weight loss Q3: mean weight change for the 25% of subjects who had >50–≤75% weight loss Q4: mean weight change for the 25% of subjects who had the largest weight loss
- 13. HbA1c(%) 8.3 8.8 9.5 7.0 7.4 7.3 7.2 7.5 7.7 8.2 7.3 8.3 8.8 9.5 7.4 6.5 7.2 7.87.8 6.7 0.0 7.3 6.7 7.8 6.9 8.3 7.2 8.7 7.5 9.5 7.9 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 ≤7.5% >7.5−8.0% >8.0−8.5% >8.5−9.0% >9.0%Baseline HbA1c (%) Liraglutide 1.8 mgLiraglutide 1.2 mg Sitagliptin 100 mg Diabetes disease progression ADA target HbA1c ≤ 7% Liraglutide reduced HbA1c more effectively than sitagliptin across baseline HbA1c after 26 weeks Pratley et al. Lancet 2010;375:1447–56 (Lira vs. DPP-4i);
- 14. Add-on to metformin: Victoza vs. Sitagliptin+SU Results published on ClinicalTrials.gov on the 5th of February 2013 Sitagliptin±SU Liraglutide Difference, 95% CI ∆HbA1c (%), bsl 8.2% -1.32 -1.42 0.09 [-0.05; 0.23]* HbA1c <7% (%) 62.8 72.3 -9.5 [-17.4; -1.5] HbA1c <6.5% (%) 33.8 38.3 -4.5 [-12.7; 3.7] ∆FPG (mmol/L), bsl 9.6 mmol/L -1.9 -2.2 0.33 [0.03; 0.63] Nausea/vomitin g (%) 3/2 19/6 - Hypoglycaemia (%) 12.6 4.6 -
- 15. Improvement in glycaemic control and weight change with basal insulin Studies of basal insulin plus OAD therapy ReductioninHbA1c Philis-Tsimikas 2006 Hermansen 2006 Riddle 2003 –2.0 –1.5 –1.0 –0.5 0 0.5 1.0 1.5 2.0 2.5 3.0 Insulin detemir NPH insulin Insulin glargine 4.0 3.5 Rosenstock 2008 *p<0.005, **p<0.001 * ** Gaininweight(kg) ** Philis-Tsimikas et al. Clin Ther 2006;28:1569–81; Hermansen et al. Diabetes Care 2006;29:1269–74; Riddle et al. Diabetes Care 2003;26:3080– 6; Rosenstock et al. Diabetologia 2008;51:408–16 OAD, oral antidiabetic drug
- 16. Levemir consistently shows a weight benefit when compared to NPH or glargine Adapted from Mitri and Hamdy. Expert Opin Drug Saf 2009;8:573–84 DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide 1; SU, sulphonylurea; TZD, thiazolidinedione
- 17. Insulin secretion (glucose-dependent) Glucagon secretion (glucose-dependent) Body weight PPG/FPG Low risk of hypoglycaemia GLP-1–Based Therapies Potential Benefits of Combining Insulin With GLP-1RAs Ahluwalia & Vora. Diabetes Ther. 2011;2:146–161; Inzucchi et al. Diabetes Care. 2012;35:1364–1379. Basal Insulin Therapy Potentially complementary benefits if used in combination GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; FPG, fasting plasma glucose; PPG, post-prandial glucose.
- 19. -1.7 -0.8 -0.7 -0.7 -1.0 -0.7 -0.4 -0.4 -1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 Addition of GLP-1RAs to Basal Insulin: Change in HbA1c BL, baseline; GLP-1RAs, glucagon-like peptide-1 receptor agonists; HbA1c, glycosylated haemoglobin. Buse et al. At 30 weeks n=137 BL: 8.4 n=122 BL: 8.5 HARMONY-6 At 26 weeks n=279 BL: 8.4 n=278 BL: 8.4 ChangefrombaselineinHbA1c(%) GetGoal-L At 24 weeks n=327 BL: 8.4 n=166 BL: 8.4 Exenatide Placebo Insulin lispro Albiglutide Lixisenatide p<0.001 P<0.001p<0.001 (non-inferiority) Buse et al. Ann Intern Med. 2011;154:103–12; Rosenstock et al. Diabetes. 2012;61(Suppl 1):A15(55-OR); Riddle, Aronson et al. Diabetes Care 2013; Epub ahead of print; Riddle, Forst et al. Diabetes Care 2013; Epub ahead of print. GetGoal-Duo1 At 24 weeks n=215 BL: 7.6 n=221 BL: 7.6 P<0.001
- 20. Addition of GLP-1RAs to Basal Insulin: Change in Body Weight Buse et al. At 30 weeks n=137 BL: 95.4 n=122 BL: 93.4 HARMONY-6 At 26 weeks n=279 BL: 92.5 n=278 BL: 91.6 Changefrombaselineinweight(kg) BL, baseline; GLP-1RAs, glucagon-like peptide-1 receptor agonists. Exenatide Placebo Insulin lispro Albiglutide Lixisenatide GetGoal-Duo1 At 24 weeks n=327 BL: 87.4 n=221 BL: 86.8 p<0.001 p<0.001 p<0.001 P=0.0012 GetGoal-L At 24 weeks n=166 BL: 89.1 n=215 BL: 87.5 Buse et al. Ann Intern Med. 2011;154:103–12; Rosenstock et al. Diabetes. 2012;61(Suppl 1):A15(55-OR); Riddle, Aronson et al. Diabetes Care 2013; Epub ahead of print; Riddle, Forst et al. Diabetes Care 2013; Epub ahead of print.
- 21. Addition of Insulin to GLP-1RA and Addition of GLP-1RA to Insulin in Type 2 Diabetes Inzucchi et al. Diabetologia. 2012;55:1577–1596. GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycosylated haemoglobin. Addition of insulin to GLP-1RA + metformin HbA1c significantly reduced Body weight not increased Hypoglycaemia risk low Addition of insulin to GLP-1RA + metformin HbA1c significantly reduced Body weight not increased Hypoglycaemia risk low Addition of GLP-1RA to insulin + metformin HbA1c significantly reduced Body weight significantly reduced Hypoglycaemia risk not increased Addition of GLP-1RA to insulin + metformin HbA1c significantly reduced Body weight significantly reduced Hypoglycaemia risk not increased
- 22. Combining Victoza with insulin Levemir: summary • Significant further improvements in glycaemic control • Initial weight loss observed with Victoza+metformin was maintained with Levemir • Very low rate of hypoglycaemia This study supports the treatment approach: Bain et al. Diabetologia 2011;54(Suppl. 1):S37; Rosenstock et al. Diabetes 2011;60(Suppl. 1): A76 (276-OR) Metformin Metformin+Victoza Metformin+Victoza+Levemir
- 23. Take Home Messages • Need to tailor treatment to patient • Early treatment with GLP-1 (after metformin) is effective in reducing A1c and weight with no risk for hypoglycaemia • Need of polypharmacy • Combining GLP-1 with basal insulin has a positive synergistic effect • Victoza and Levemir combination proved further improvement in A1c, weight and low risk for hypoglycaeima
Editor's Notes
- We are only in 2011 and We almost reached IDF 2007 assumptions for 2025: 380 million
- Development and Progression of Type 2 Diabetes and Related Complications Both insulin resistance and β-cell dysfunction start early – and well before diabetes is diagnosed – leading to rises in fasting plasma glucose (FPG) and postprandial glucose (PPG) levels This conceptual diagram shows a proposed paradigm on the development and progression of pathophysiology in type 2 diabetes1 The horizontal axis in the figure shows the years before and after diagnosis of diabetes Insulin resistance begins years before diagnosis. Insulin resistance rises during disease development and continues to rise during impaired glucose tolerance (IGT). Over time, insulin resistance remains stable during the progression of type 2 diabetes1 The insulin secretion rate increases to compensate for the decrease in insulin effectiveness due to insulin resistance. β-cell function can decrease even as insulin secretion increases. At the time of diagnosis of type 2 diabetes and 6 years afterward about 50% and 73% of β-cell function have been lost, respectively.2 Over time, β-cell compensatory function deteriorates and insulin secretion decreases. β-cell function progressively fails1,2 Initially, FPG is maintained in near-normal ranges. The pancreatic β cells compensate by increasing insulin levels, leading to hyperinsulinaemia. This compensation keeps glucose levels normalised for a time, but as β cells begin to fail, IGT develops with mild post-prandial hyperglycaemia. As the disease progresses, the β cells continue to fail, resulting in higher PPG levels. With continued loss of insulin secretory capacity, fasting glucose and hepatic glucose production increase1 Once β cells cannot secrete sufficient insulin to maintain normal glycaemia at the fasting or post-prandial stage, type 2 diabetes (hyperglycaemia) becomes evident Insulin resistance and β-cell dysfunction are established well before type 2 diabetes is diagnosed1 References Ramlo-Halsted BA et al. Prim Care 1999;26:771–789 Bell DS. Treat Endocrinol 2006;5:131–137
- Ultimately, more intensive insulin regimens may be required (see Figure 3.) Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a 2-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycaemia (e.g. HbA1c ≥10.0-12.0%). Consider beginning with insulin if patient presents with severe hyperglycemia (≥300-350 mg/dl [≥16.7-19.4 mmol/l]; HbA1c ≥10.0-12.0%) with or without catabolic features (weight loss, ketosis, etc).
- Some older therapies have been associated with1–5: Weight gain Hypoglycaemia Oedema The ideal 2L agent would have: High efficacy in reducing HbA1c Low risk of hypoglycaemia Contribute to weight loss HbA1c, glycosylated haemoglobin References Inzucchi SE et al. Diabetologia 2012;55:1577–1596 Bryan J et al. Curr Pharm Des 2005;11:2699–2716 Kahn SE et al. N Engl J Med 2006;355:2427–2443 Gerich J et al. Diabetes Care 2005;28:2093–2099 Dormandy JA et al. Lancet 2005;366:1279–1289
- Byetta SPC - http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000698/WC500051845.pdf Victoza SPC - http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001026/human_med_001137.jsp&mid=WC0b01ac058001d124
- The LEAD programme: reduction in HbA1c when liraglutide is added Estimated means are obtained from an ANCOVA with treatment, country, and previous treatment as fixed effects and baseline value as a covariate; estimated mean ± 1.96 × SE (Table 14.2.13) ANCOVA, analysis of covariance; HbA1c, glycosylated haemoglobin; SE, standard error References Garber A et al. Lancet 2009;373:473–481 Nauck M et al. Diabetes Care 2009;32;84–90 Marre M et al. Diabet Med 2009;26;268–278 Zinman B et al. Diabetes Care 2009;32:1224–1230 Russell-Jones D et al. Diabetologia 2009;52:2046–2055 Buse JB et al. Lancet 2009;374:39–47
- The LEAD programme: reduction in HbA1c when liraglutide is added Estimated means are obtained from an ANCOVA with treatment, country, and previous treatment as fixed effects and baseline value as a covariate; estimated mean ± 1.96 × SE (Table 14.2.13). ANCOVA, analysis of covariance; HbA1c, glycosylated haemoglobin; SE, standard error References Garber A et al. Lancet 2009;373:473–481 (LEAD-3) Nauck M et al. Diabetes Care 2009;32;84–90 (LEAD-2) Marre M et al. Diabet Med 2009;26;268–278 (LEAD-1) Zinman B et al. Diabetes Care 2009;32:1224–1230 (LEAD-4) Russell-Jones D et al. Diabetologia 2009;52:2046–2055 (LEAD-5) Buse JB et al. Lancet 2009;374:39–47 (LEAD-6)
- Post-hoc analysis of change in body weight by weight loss quartile Wt by quartile tab_bw_exploratory_20080409_all
- The unique weight-sparing benefit of detemir emerges when all the weight data from the treat to target studies are viewed together. Study designs: Philis-Tsimikas et al. 2006 This 20-week, multicenter, randomised, open-label, three-arm, parallel-group trial was conducted at 91 centres across Europe and the United States. Men and women were eligible for participation if they were aged ≥18 years, had a BMI &lt;40 kg/m2, had a diagnosis of type 2 diabetes of at least 12 months&apos; duration, and were insulin-naϊve. Eligible patients also had an HbA1c concentration value not outside the range of 7.5–11.0% following at least 3 months&apos; treatment with one or more OADs. Patients were randomly assigned to receive an evening subcutaneous injection of detemir, a pre-breakfast injection of detemir or an evening injection of NPH insulin (1:1:1), administered at initial doses of 10 IU (U). Hermansen et al. 2006 Individuals (n=476) with HbA1c 7.5–10.0% were randomised to addition of twice-daily insulin detemir or NPH insulin in a parallel-group, multicentre trial. Over 24 weeks, insulin doses were titrated toward pre-breakfast and pre-dinner plasma glucose targets of 6.0 mmol/L (108 mg/dL). Outcomes assessed included HbA1c, percentage achieving HbA1c 7.0%, risk of hypoglycaemia and body weight. Riddle et al. 2003 In a randomised, open-label, parallel, 24-week multicentre trial, 756 overweight men and women with inadequate glycaemic control (HbA1c 7.5%) on one or two oral agents continued pre-study oral agents and received bedtime glargine or NPH once daily, titrated using a simple algorithm seeking a target FPG 100 mg/dL (5.5 mmol/L). Outcome measures were FPG, HbA1c, hypoglycaemia and percentage of patients reaching HbA1c 7% without documented nocturnal hypoglycaemia. Rosenstock et al. 2008 Insulin-naϊve adults (n=582, HbA1c 7.5–10.0%, BMI ≤40.0 kg/m2) were randomised 1:1 to receive insulin detemir or glargine once daily (evening) actively titrated to target FPG ≤6.0 mmol/L. An additional morning insulin detemir dose was permitted if pre-dinner plasma glucose (PG) was &gt;7.0 mmol/L after achieving FPG &lt;7.0 mmol/L. Due to labelling restrictions, no second glargine dose was allowed.
- Speaker notes There is growing concern that the weight gain induced by most diabetes medications diminishes their clinical benefit. Treating diabetes with medications that are weight-neutral, induce weight loss or reduce weight gain may emerge as the future direction for treating overweight and obese patients with diabetes. Insulin, in most of its forms, has been associated with weight gain, an estimated 50% of which is seen during its first 3 months of use. Evidence for insulin detemir consistently shows a weight benefit in terms of loss or reduced gain when compared to NPH or glargine in RCTs up to 12 months of intervention. Reference: Mitri and Hamdy. Expert Opin Drug Saf 2009;8:573–84
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