What to add after metformin: primary care conference 2016

Transcription

1 objectives What to add after metformin: primary care conference 216 Dr. Tsang Man Wo Specialist in Endocrinology, Diabetes & Metabolism Medical Director, United Medical Practice. Consultant (P), M+G department, UCH MBBS(HK),MRCP(UK), FHKCP. FHKAM,FRCP(Lond.),FRCP(Edin),FRCP(Glasg) Hon Associated Prof. Department of Medicine, HKU Natural course of T2DM: limitation of current treatment Bridging the gap:treatment based on pathophysiology and beyond New agents Conclusion 2 Central Adiposity Asian phenotype. Unnikrishnan R et al. Diabetes 214;63:53-55 Progressive nature of type 2 diabetes: insulin deficiency due to beta-cell failure Plasma levels Normal insulin IGT Diabetes resistance Endogenous insulin Postprandial plasma glucose Fasting plasma glucose Normal blood glucose Microvascular complications Macrovascular complications Average 6.5 years Modified from graphic developed by the International Diabetes Center

2 7 Major Pathophysiologic Defects in Diabetes Hepatic glucose output Liver GI tract GLP Islet-Cell Dysfunction Glucagon (α cell) Pancreas (β cell) Hyperglycaemia resistance at muscle and liver Glucose uptake Muscle Adipose tissue Benefit of metformin Body weight Lipid CVD ( UKPDS) Low cost Safety Cancer protection Lipotoxicity Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 25: Macrovascular outcomes in Metformin-treated patients in UKPDS and 1 year follow-up study UKPDS 1 year follow up. And this benefit continues to be seen in the 1 year follow up.. Mean HOMA estimates of beta-cell function (%B) over the first 6 years from diagnosis of type 2 diabetes mellitus in nonoverweight and overweight patients allocated to, and remaining on, conventional (diet alone) or intensive (sulfonylurea or metformin [overweight subjects only]) monotherapies.

3 Declining Beta-Cell Function Was Associated with Increasing Hyperglycemia Beta-cell function (%) 5 25 Diet/conventional therapy (n=11) Metformin (n=159) Sulfonylurea (n=511) Years HbA 1c (%) Diet/conventional therapy (n=297) Metformin (n=251) or sulfonylurea (n=695) Years Beta-cell function assessed by HOMA HbA 1c results shown from obese patients UKPDS=United Kingdom Prospective Diabetes Study; HbA 1c =glycosylated hemoglobin Adapted from UKPDS Group Diabetes 1995;44: Choosing Antidiabetic Agents: Efficacy ANTIDIABETIC AGENTS EFFICACY secretagogues Metformin α-glucosidase inhibitors TZDs* GLP* analogues DPP IV* inhibitors Effect on FPG/HbA 1c 1,5 Effect on plasma insulin 1,2,5 Effect on insulin resistance 3 Effect on insulin secretion 4,5 *TZDs = thiazolidinediones; GLP = glucagon-like peptide; DPP = dipeptidyl peptidase 15 1 DeFronzo RA. Ann Intern Med 1999; 131: Lebovitz HE. Endocrinol Metab Clin North Am 21; 3: Matthaei S, et al. Endocrine Rev 2; 21: Raptis SA & Dimitriadis GD. J Exp Clin Endocrinol 21; 19 (Suppl 2): S265 S Amori RE, et al. JAMA 27; 298: Change in HbA1c (%) DURABILITY OF GLYCEMIC CONTROL WITH SULFONYLUREAS Glyburide Glimepiride SU Glyburide GLY SU Gliclazide Glyburide Gliclazide Glyburide Alvarsson (n=39) Alvarsson (n=48) RECORD (n=272) Hanefeld (n=25) Charbonnel (n=313) UKPDS (n=1,573) Chicago (n=23) ADOPT (n=1,441) PERISCOPE (n=181) Tan (n=297) TIME (years)

4 Met SU Con vs Met Control vs SU 22 TZDs: Mode of Action TZD Metabolic Control in Type 2 Diabetes by TZDs Muscle Glucose uptake and diposal Receptor Metabolic effects Increased stimulation CYTOPLASM TZDs Adipose tissue Glucose uptake and disposal Free fatty acid uptake Alteration of other adipocyte factors Improvement in metabolic imbalances PPARγ NUCLEUS CELL MEMBRANE Liver Glucose uptake VLDL cholesterol Adapted from Debril et al. J Mol Med 21;79:3 47; Kersten & Wahli. Endocr Rev 2;89: ; Escher & Wahli. Mutat Res 2;448: ; Takeda UK Ltd. Pioglitazone SmPC Feb 29; GSK UK. Rosiglitazone SmPC Jan 25 DeFronzo R. Diabetes 1988;37: ; Reginato & Lazar,.Trends Endocrinol Metab,1999;1:9 13; Saltiel & Olefsky. Diabetes 1996;45:

5 Change in HbA1c (%) DURABILITY OF GLYCEMIC CONTROL WITH THIAZOLIDINEDIONES Hanefeld (n=25) Charbonnel (n=317) PERISCOPE (n=178) RECORD (n=31) PIO PIO ROSI PIO PIO PIO Chicago (n=232) ADOPT (n=1,456) Rosenstock (n=115) Tan (n=249) Rosiglitazone TIME (years) Pioglitazone vs Gliclazide Monotherapy: Glycemic Control After 14 weeks HbA 1c FPG HbA 1c (%) FPG (mmol/l) * Pioglitazone 11.5 Pioglitazone Gliclazide 11. Gliclazide * 8. * 1.5 * * * Weeks of treatment Weeks of treatment *p<.1, p<.1, p<.5 vs gliclazide HbA 1c levels significantly lower with pioglitazone after 14 weeks: between-group difference: -.45% (95% CI: -.66, -.23) FPG levels significantly lower with pioglitazone after 14 weeks: between-group difference: -.83 mmol/l (95% CI: -1.26, -.39) Tan M et al. Diabetes Care 25;28: Pioglitazone vs Gliclazide as Add-on to Metformin: HbA 1c Results Change from baseline in HbA 1c (%) HbA 1c Weeks Pioglitazone + metformin Gliclazide + metformin Change from baseline in FPG (mmol/l) FPG Weeks p :<.1 Pioglitazone + metformin Gliclazide + metformin Charbonnel B et al. Diabetologia 25;48: Thiazolidinediones Thiazolidinediones decrease insulin resistance by making muscle and adipose cells more sensitive to insulin. They also suppress hepatic glucose production. Efficacy Decrease fasting plasma glucose ~35-4 mg/dl ( mmol/l) Reduce A1C ~.5-1.% 6 weeks for maximum effect Other Effects Weight gain, edema Hypoglycemia (if taken with insulin or agents that stimulate insulin release) Contraindicated in patients with abnormal liver function or CHF Improves HDL cholesterol and plasma triglycerides; usually LDL neutral THIAZOLIDINEDIONES AND PREVENTION OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

6 PROACTIVE In high risk type 2 diabetics: To examine whether pioglitazone reduces total mortality and macrovascular morbidity 19 European Countries 5238 Type 2 Diabetics PIOGLITAZONE REDUCES CARDIOVASCULAR EVENTS Kaplan-Meier Event Rate PROACTIVE (n=5238): TIME TO DEATH, MI, OR STROKE Plc 358 PIO 31 LANCET 366: ,25 # Events 3 Year Estimate 14.4% 12.3% Placebo P=.27 HR =.84 Pioglitazone TIME (months) CARDIOVASCULAR OUTCOMES FROM PIOGLITAZONE META- ANALYSIS OF CLINICAL TRIALS FDA and Center for Drug Evaluation & Research; July 3,27 (n = 5,23) Comparator CI = Pioglitazone (n = 5,944) TIME (weeks) HR=.75 Protection of multiple Organs by Pioglitazone Adverse Events associated with Pioglitazone: Water Retention, CHF, Bone Fractures and Bladder Cancer? 47% of SecondaryStroke in Patients with previous Stroke (PROactive) Reduction of CIMT (Carotid artery Intima- Media Thickness) CHICAGO 28% of Re-Infarction in Patients with previous MI (PROactive) 37% of Acute Coronary Syndrome after previous MI (PROactive) Stop of Progression of Coronary Atherosclerosis (PERISCOPE) of MI, Stroke & Death in Patients with CKD (PROactive) Microalbuminuria (QUARTET) 51% Mortality in Patients on Hemodialysis (USA) Reduction of Inflammation & Necrosis in NASH (Nonalcoholic Steatohepatitis) 5% Risk for Hepatocellular Ca 5% in oral Mono- or Combi Therapy 1% in combination with Peripheral Bone Fractures (Toe Fracture) Bladder CHF: HR 1.41, but no increase in mortality.9% Increase in Women, no increase in Men HR 1.2 (.9-1.5) Cancer Effect of Rosiglitazone, Metformin, and Glyburide on Bone Biomarkers in Patients with Type 2 Diabetes JAMA. 215;314(3): participants from ADOPT study 1 year Results Women: osteoclast activity marker C-terminal telopeptide for type 1 collagen (CTX) osteoblast activity markers : Procollagen type 1 N- propeptide (P1NP) and bone AP Men: No change in osteoclast activity marker but osteoblast activity markers Zinman B et al, 21 J Clin Endocrinol Metab 95(1):134-42

7 It is not the drug for everyone. In an epidemiological analysis of 66,696 type 2 diabetic subjects followed from 1994 to 25 in the UK, 6% used TZDs, with a dose effect on total, hip, and wrist fractures.38 It is certainly the relatively best drug in patients already presenting with cardiovascular disease such as stroke, myocardial infarction, and acute coronary syndrome. Pioglitazone: the benefits/risks balance The clinical question: in which patients will benefits exceed the risks? Adapted from Bertrand Cariou, Bernard Charbonnel and Bart Staels : Trends in Endocrinology 212 Decreased Secretion OMINOUS OCTET Decreased Incretin Effect Increased Lipolysis Increased Glucagon Secretion Islet α cell Increased HGP MET HYPERGLYCEMI A Neurotransmitter Dysfunction Increased Glucose Reabsorption 4 Oral Anti-Diabetic Medications Less Weight Gain/Hypoglycemia DPP-IV Inhibitor Mechanism of action Food intake Pancreas Increases glucose utilisation by muscle and adipose Intestine Active GLP-1 (7-36) DPP-4 Decreases hepatic glucose release Improving overall glucose control Inactive GLP-1 (9-36) amide DPP-IV Inhibitor His-Ala cleaved from amino terminus Adapted from Drucker DJ. Expert Opin Invest Drugs. 23;12(1):87 1 Ahrén B. Curr Diab Rep. 23;3:

8 DPP4 inhibitors impair deactivation of incretins lead to improved glycemic control Benefits Glucose-dependent action Weight neutral Low rate of hypoglycemia Complement action of other antidiabetic agents Neutral effects on cardiovascular outcomes Indicated for renal impairment, dosage adjustment required Elderly patients Side effects Skin rash URI Nasopharyngitis Headache Cautions Hypersensitivity reaction such as urticaria, angioedema?heart failure in high risk patient In normal renal glucose handling, 9% of glucose is reabsorbed by SGLT2 1 4 SGLT2 Glucose SGLT, sodium-glucose co-transporter. Glucose filtration Proximal tubule Majority of glucose is reabsorbed by SGLT2 (9%) Remaining glucose is reabsorbed by SGLT1 (1%) Adapted from: 1. Wright EM. Am J Physiol Renal Physiol 21;28:F1 18; 2. Lee YJ, et al. Kidney Int Suppl 27;16:S27 35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 211;3:C14 21; 4. Marsenic O. Am J Kidney Dis 29;53: Minimal to no glucose excretion SGLT2 inhibitor inhibits SGLT2 and removes excess glucose in the urine independently of insulin SGLT2 Glucose SGLT2i Glucose filtration Reduced glucose reabsorption SGLT2i Proximal tubule By inhibiting SGLT2, FORXIGA removes glucose and associated calories SGLT2i is >14-times more selective for SGLT2 versus SGLT1 SGLT2 Increased urinary Increased urinary excretion of excess glucose (~7 g/day, corresponding to to 28 kcal/day*) 1 ) SGLT2 Inhibitors block reabsorption of glucose in kidneys lead to glucosuria, improved glycemic control Benefits independent action Weight loss Lower BP Low rate of hypoglycemia Complement action of other antidiabetic agents Can be used regardless of diabetes duration or pancreatic beta-cell function Secondary cardiovascular protection Side effects Genital infection Urinary tract infection Dehydration Increased hematocrit Drop in blood pressure Euglycemic ketoacidosis Cautions Elderly Renal impairment Poly-pharmacy - Anti-BP medications/diuretics Euglycaemia DKA Bone fracture/ Toe amputtion Conclusion 47 48

9 The Best Combination with Metformin: Considerations Low risk of hypoglycemia No weight gain CV safety Low risk of adverse events Physicians clinical experience Clinical data in wide range of patients (renal, elderly) Patient Preference (daily dosing, oral vs injection) Simplicity & ease of treatment Cost 5 Risk of All-cause Mortality for Different Comparisons of Drug Groups: Follow up of 91,521 Patients for 7.1 Years HR (95 % CI) (Log Scale) HR 1.43 HR 1.4 (UK GPRD) HR.8 HR.6 HR 1.37 *Any therapy (monotherapy and combinations). **Other drugs and combinations of any oral antidiabetes drugs excluding rosiglitazone and pioglitazone. Tzoulaki I, et al. BMJ. 21 J Clin Endocrinol Metab, December 212, 97(12): The apparent differences in the risk of serious adverse events warrants investigation by the regulatory authorities. 53 J Clin Endocrinol Metab, December 212, 97(12):

10 randomly assigned to 1 of 4 commonly-used glucose-lowering drugs (glimepiride, sitagliptin, liraglutide, and basal insulin glargine), plus metformin, and will be followed for up to 7 years J Clin Endocrinol Metab, December 212, 97(12): Sponsored by the U.S. National Institutes of Health, Thank You Tsang MW.ISRN Endocrinology Volume 212, Article ID 47812, 9 pages 58