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1 10:50-11:35am Cases in Type 2 Diabetes Management Disclosures The following relationships exist related to this presentation: Martin J. Abrahamson, MD, FACP: Advisory Board member for Novo Nordisk and Web MD Health Services. SPEAKER Martin J. Abrahamson, MD, FACP Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Learning objectives Understand the pathophysiology and natural history of type 2 DM (T2DM) Understand cardiovascular risk associated with T2DM and the cardiovascular outcomes studies using drugs to treat T2DM Understand the importance of individualizing goals of treatment Develop an approach to intensifying treatment of people with T2DM using medications that have weight benefit, reduce risk for hypoglycemia and are simpler and safer to use Total 425 million Total 629 million

2 Prevalence of diabetes Epidemiology in the US 30.3 million people have diabetes just over 9% of the population 23.1 million diagnosed 25% undiagnosed 95% have type 2 DM Approximately 1.5 million new cases diagnosed per year 84.1 million adults have prediabetes Minority populations are at much higher risk for Diabetes (Native Americans, Hispanics, Asian Americans and African Americans) IDF Atlas 8 th edition CDC Report Diabetes Report Card 2017 Statistics about Diabetes ADA 2018 Case 1 Mr. RL Mr. RL - examination 69 year old hotel manager Type 2 diabetes (T2DM) for 5 years Known coronary artery disease (CAD), hypertension and hyperlipidemia Active at work from early morning to late evening walks about 10,000 steps per day Tries to limit calories but has difficulty losing weight Medications Metformin 1000 mg twice daily Lisinopril 20 mg daily Atorvastatin 40 mg daily Aspirin 81 mg daily Weight 222 lb Height 70 inches BMI 32 kg/m 2 Blood pressure 140/90 mmhg No evidence of any microvascular complications HbA1c 8.3% Fasting glucose 155 mg/dl Total cholesterol 190 mg/dl LDL cholesterol 105 mg/dl LFTs normal Creatinine 1.2 mg/dl, egfr (CKD-EPI) 61 ml/min/1.73m 2

3 Pathogenesis of T2D: The Ominous Octet Islet α-cells Increased glucagon secretion GI tract Decreased incretin effect Skeletal muscle Decreased glucose uptake Sites of action of non insulin therapeutic agents GLP 1 RA DPP4i SU and meglitinides GLP 1 RA DPP4i β cells Insulin release Incretin effect GLP 1 RA AGi colesevelam Lipolysis TZD Pancreas Impaired insulin secretion (β-cell decline) Kidneys Increased glucose reabsorption Hyperglycemia Energy homeostasis GI, gastrointestinal; HGP, hepatic glucose production; SU, sulphonylurea; T2D, type 2 diabetes DeFronzo RA. Diabetes 2009;58: Brain Neurotransmitter dysfunction Liver Insulin resistance Increased HGP Adipose tissue Increased lipolysis α cells TZD MET GLP 1 RA DPP4i Glucagon secretion HGP AGi, α-glucosidase inhibitors; DPP4i, DPP-4 inhibitors; GLP-1Ra, GLP-1 receptor agonists; HGP, hepatic glucose production; SU, sulphonylureas; TZDs, thiazolidinediones Hyperglycemia Neurotransmitter dysfunction GLP 1 RA bromocriptine Glucose uptake TZD Glucose reabsorption SGLT2i Ferrannini E, DeFronzo RA. Eur Heart J 2015;36: Impact of intensive vs. conventional glucoselowering therapy in diabetes Diabetes reduces life expectancy by many years Study (HbA 1c intensive vs. conventional) UKPDS 33 1,2 (7.0% vs. 7.9%; T2D) DCCT/EDIC 3 5 (7.2% vs. 9.1%; T1D) ACCORD 6,7 (6.4% vs. 7.5%; T2D) Microvascular complications Cardiovascular complications Mortality no diabetes diabetes 60years end of life -6 yrs ADVANCE 8,9 (6.3% vs. 7.0%; T2D) VADT 10,11 (6.9% vs. 8.4%; T2D) diabetes + MI -12 yrs 1. UKPDS Lancet 1998;352:837 53; 2. Holman et al. N Engl J Med 2008;359: ; 3. DCCT. N Engl J Med 1993;329:977 86; 4. Nathan et al. N Engl J Med 2005;353: ; 5. Orchard et al. JAMA 2015;313:45 53; 6. Gerstein et al. N Engl J Med 2008;358: ; 7. ACCORDION CV Mortality Drops, Eye Benefits Remain in Follow-up. Medscape. Dec 09, 2015; 8. Patel et al. N Engl J Med 2008;358: ; 9. Zoungas et al. N Engl J Med 2014;371: ; 10. Duckworth et al. N Engl J Med 2009;360:129 39; 11. Hayward et al. N Engl J Med 2015;372: Initial trial Long-term follow-up End of life due to MI or stroke MI, myocardial infarction The Emerging Risk Factors Collaboration. JAMA 2015;314:52 60

4 Diabetes reduces life expectancy by many years no diabetes diabetes diabetes + MI 60years end of life -12 yrs -6 yrs T2D management considerations for individualized treatment More stringent Hypoglycemia and AE risks Low Disease duration Life expectancy Important comorbidities Newly diagnosed Long HbA 1c 7% Hyperglycaemia management approach Less stringent Long-standing Absent Few/mild Severe Established vascular complications Absent Few/mild Severe Patient attitude and expectations Highly motivated Less motivated Resources and support system Readily available Limited High Short Usually not modifiable Potentially modifiable End of life due to MI or stroke MI, myocardial infarction The Emerging Risk Factors Collaboration. JAMA 2015;314:52 60 American Diabetes Association. Diabetes Care 2018; 41 (Suppl 1):S55-64 Choice of therapy after metformin: what we know Hypoglycemic risk with antihyperglycemic agents added to metformin SU TZD DPP-4i GLP-1RA SGLT2i Insulin (basal) 20 Increased risk vs. placebo Efficacy ( HbA 1c ) Hypoglycemia risk Weight effect Major side effects High High Intermediate High Intermediate Highest Moderate Low Low Low Low High Hypoglycemia Edema Heart failure Bone fractures Rare GI GU Dehydration Ketoacidosis Fractures? Hypoglycemia Odds ratio vs. placebo No increased risk vs. placebo 0 Biphasic insulin Glinides SU Basal insulin DPP-4i GLP-1RA TZD AGI SGLT2-i, weight gain;, weight loss;, weight-neutral Inzucchi et al. Diabetes Care 2015;38:140 9; Inzucchi et al. Diabetologia 2015;58: AGI, alpha-glucosidase inhibitor; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; SGLT2i, sodium glucose cotransporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione Liu et al. Diabetes Obes Metab 2012;14:810 20; Liu et al. J Diabetes Complications 2015;29:

5 Impact of different treatments on body weight Range of weight change (kg) SUs Glinides TZDs Insulin Insulin DPP-4 detemir inhibitor Metformin GLP-1 analogue SGLT2i Cardiovascular outcomes trials (CVOT) in diabetes Diabetes medication DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1, glucagon-like peptide-1; SGLT2i, sodium glucose co-transporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione Adapted from Mitri & Hamdy. Expert Opin Drug Saf 2009;8:573 84; Liu et al. J Diabetes Complications 2015;29: Results of CVOT for Newer Diabetes Therapies *MACE DPP-4 Is GLP-1 RAs SGLT2-Is Saxa Alo Sita Lixi Lira Exena QW Sema Dula Alba Empa Cana Neutral Neutral Neutral Neutral (13%) Neutral (26%) (22%) (14%) (14%) CV Death (22%) (38%) (13%) Death (Any Cause) (15%) Neutral Non- Fatal Stroke (39%) Hosp for HF NS Neutral (35%) (33%) *MACE = Death From CV Causes, Nonfatal MI, or Nonfatal Stroke (+/- hospitalization for unstable angina) NS = non-statistically significant Cefalu W, et al. Diabetes Care. 2018;41(1):14-31; Hernandez AF, et al. Lancet. 2018;392(10157): ; Diabetes Care 2018;41(Suppl. 1):S73 S85

6 Drugs with proven CV benefit: Empagliflozin Canagliflozin Liraglutide Semaglutide Diabetes Care 2018;41(Suppl. 1):S73 S85 Diabetes Care 2018;41(Suppl. 1):S73 S85 Case study number 2: Mrs. JG 66 year old female Type 2 diabetes for 6 years Co morbid conditions Hypertension Hyperlipidemia Medications Glimepiride 4 mg daily Metformin 1 g twice daily Rosuvastatin 10 mg daily Lisinopril 20 mg daily HCTZ 12.5 mg qd Amlodipine 5 mg qd Aspirin 81 mg daily Mrs. JG Family history of type 2 diabetes, hypertension and coronary artery disease Non proliferative retinopathy No known neuropathy or nephropathy No known CAD or PVD HbA1c 8.2% HbA1c 7% a year ago HA1c 6.5% soon after 2 agents started (2 years ago) Fairly consistent carbohydrate intake Walks 4 times per week for 30 mins each time Tests fasting glucose only

7 Mrs. JG Physical Examination Height 68 Weight 203 lbs BMI 30 kg/m 2 Acanthosis nigricans BP 120/70 Pulse 66 Background retinopathy but no other evidence of any micro or macrovascular complications 3 Laboratory Data Fasting glucose 155 mg/dl HbA1c 8.2% Lipids TC 175 mg/dl Triglycerides 142 mg/dl HDL 44 mg/dl LDL 103 mg/dl Urine albumin:creat 2.1 mcg/mg LFTs normal Creatinine 0.9 mg/dl - egfr=67 ml/min/1.73m 2 Decline of -Cell Function in the UKPDS Illustrates Progressive Nature of Type 2 Diabetes -cell function (% of normal by HOMA) Time of diagnosis Let s get more data Mrs. JG is testing sugars in the morning before breakfast only We ask her to test sugars twice daily, fasting and 2 hours after meals, on a grid system One week later she is seen in the office with the following glucose readings: HOMA=homeostasis model assessment Years Adapted from Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25

8 Fasting 2 hrs post breakfast Monday hrs post lunch 2 hrs post dinner Tuesday Wednesday Thursday * Friday Saturday 156 & 238 # Sunday 152 * ate out; had fish with rice (a cup) and small ice cream & went for an hour walk after lunch # ate out pasta! BG in mg/dl Case 3 - Mr E 56 years old Diagnosed with T2DM 10 years ago Initially well controlled with metformin, but 2 years after diagnosis required addition of sulfonylurea to improve glycemic control (HbA1c was 8.0%) Further intensification of treatment with basal insulin required 3 years ago (A1c had risen again to 8.1%) He has gained 3 lbs since starting insulin He exercises regularly and tries to limit carbohydrate intake He is a non-smoker and non-drinker Current medications Metformin 1000 mg twice daily Glipizide 10 mg twice daily U100 Glargine 16 units at night Losartan 100 mg daily HCTZ 12.5 mg daily Aspirin 81 mg daily Atorvastatin 20 mg daily Mr E: Examination Laboratory data Height 68 inches Weight 190lb BMI 29.7 kg/m2 BP 125/80 Non proliferative retinopathy Mild decrease in vibration sensation in toes but foot exam otherwise normal with palpable pulses 2+ No evidence of macrovascular disease Fasting glucose 165 mg/dl HbA1c 8.1% Total cholesterol 167 mg/dl LDL-C 97 mg/dl HDL - C 35 mg/dl Triglycerides 175 mg/dl Urine albumin:creatinine 15 mg/g Serum creatinine 1.6 mg/dl - egfr=48 ml/min/1.73m 2 LFTs normal

9 46 Next steps You decide to titrate the basal insulin to achieve fasting glucoses between 80 and 130 mg/dl 3 months later he is taking 36 units of U100 glargine at night in addition to his other diabetes medications The A1c is 7.5% His weight has increased by 4lbs Other findings on examination are unchanged He has measured fasting and postprandial sugars after some meals on a grid system BG monitoring data (mg/dl) Fasting Post breakfast Post lunch Monday Tuesday Wednesday Thursday Friday Saturday Post dinner 47 Clinical trial design and results template 48 What would you do next? Case 4 Mrs. AK 1. Reduce the dose of the sulfonylurea (SU) and add a GLP 1 RA 2. Reduce the dose of the SU and add a SGLT2i 3. Stop the SU and add prandial insulin 4. Stop the SU and change the insulin regimen to premixed insulin twice daily 85 year old female Type 2 diabetes for 25 years Known CAD for many years Also has hypertension, hyperlipidemia Has no retinopathy but mild peripheral neuropathy Has been on basal bolus treatment for almost 10 years Currently taking 25 units of U 100 glargine at night Sliding scale of rapid acting insulin analogue with each meal, ranging from 4 to 8 units per meal Checks glucose 3 to 4 times daily ( my fingers are hard and sore )

10 49 Clinical trial design and results template 50 Blood glucose log book (mg/dl). Relevant clinical and laboratory data Before Before lunch Before dinner Before bed breakfast Monday Tuesday Wednesday 76 65* Thursday Friday Saturday Forgot to test Out shopping ** Sunday 92 62*** 150 No test * Felt a little light headed and had 4 oz orange juice ** Woke during the night sweaty and had 4 oz OJ ** Did not eat breakfast but had no insulin at breakfast had no Sx at lunch Height 64 inches Weight BP 135/70 Pulse 88 Distal pulses 1+; mild peripheral neuropathy Plasma glucose 78 mg/dl (not fasting) HbA1c 6.2% Creatinine 1.3 mg/dl (egfr=41 ml/min/1.73m 2) Urine albumin 88 mg/g LFTs normal Combining a GLP-1 RA and a basal insulin in one pen improves efficacy and safety Uncontrolled on OADs LixiLan-O: IGlarLixi vs. IGlar U100 vs. lixisenatide Study design Efficacy Side effects Patients with T2D inadequately controlled on metformin ± 1 additional OAD (n=1170) IGlarLixi + metformin (n=469) IGlar U100 + metformin (n=467) Max. dose 60 U HbA 1c FPG PPG WEIGHT Basal insulin GLP-1 RA/basal insulin combined in one pen HYPOGLYCEMIA GLP-1 RA monotherapy NAUSEA Inclusion criteria T2D Insulin-naïve OADs metformin ± one additional OAD (SU, glinide, DPP-4i or SGLT-2i) HbA 1c % for patients on prior metformin alone or % for patients on prior metformin + additional OAD Age 18 years BMI >20 to 40 kg/m 2-4* 0 30 weeks *4-week run-in phase Second OAD stopped, metformin titrated to at least 2000 mg/day or maximum tolerated dose Randomised 2:2:1 (open label) with criteria HbA 1c 7.0% and 10.0% FPG 250 mg/dl (13.9 mmol/l) Metformin MTD 1500 mg/day Lixisenatide + metformin (n=234) For illustrative purposes only, not drawn to scale GLP-1 RA, glucagon-like peptide-1 receptor agonist; FPG, fasting plasma glucose; PPG, postprandial glucose 1. Inzucchi et al. Diabetes Care 2015;38:140 9; 2. Garber et al. Endocr Pract 2016;22: BMI, body mass index; DPP-4i, dipeptidyl peptidase-4 inhibitor; FPG, fasting plasma glucose; GLP-1 RA, glucagon-like peptide-1 receptor agonist; IGlar U100, insulin glargine U100; MTD, maximum tolerated dose; OAD, oral antidiabetic drug; SFLT-2i, sodium/glucose cotransporter 2; T2D, type 2 diabetes Rosenstock et al. Diabetes Care 2016;39:

11 Uncontrolled on OADs Uncontrolled on insulin LixiLan-O Key clinical findings LixiLan-L: IGlarLixi vs. IGlar U100 Study design Change in HbA 1c (%) IGlarLixi -1.6 IGlar U p< HbA 1c Lixi -0.9 p< Baseline HbA 1c 8.1% 8.1% 8.1% EOT HbA 1c 6.5% 6.8% 7.3% Change in weight (kg) IGlarLixi -0.3 Weight IGlar U100 p< Max. dose 60 U; Documented symptomatic hypoglycaemia with PG <70 mg/dl (3.9 mmol/l). Symptomatic hypoglycaemia = symptomatic hypoglycaemia 1.1 Lixi -2.3 Hypoglycaemia rate (events/patient-year) Confirmed symptomatic hypoglycemia 1.4 IGlarLixi 1.2 IGlar U Lixi Severe hypoglycaemia: 1 event with IGlar U100 Patients with T2D inadequately controlled on basal insulin ± 1 2 OADs (n=730) Inclusion criteria T2D OADs may also be on one or two of the following at a stable dose for 1 month: metformin, SU, glinide, DPP-4i, SGLT-2i) Basal insulin 6 months and on a stable regimen (time/frequency of dose [15 40 U/day], type of insulin) for 2 months HbA 1c % FPG 180 mg/dl (10.0 mmol/l) for patients on basal insulin + 2 OADs or 1 OAD other than metformin; 200 mg/dl (11.1 mmol/l) for patients on basal insulin only or basal insulin + metformin Age 18 years BMI >20 to 40 kg/m 2-6* IGlarLixi ± metformin (n=365) IGlar U100 ± metformin (n=365) 0 30 weeks *6-week run-in phase: IGlar U100 introduced and/or titrated ( 50 U), metformin was the only OAD continued Randomisation 1:1 (open-label) with criteria: HbA 1c 7% and 10% FPG 140 mg/dl (7.8 mmol/l) Daily IGlar U100 dose 20 U and 50 U Max. dose 60 U recorded on the dedicated ecrf and meeting protocol definition for severe, or documented, or probable symptomatic hypoglycaemia. ecrf, electronic Case Report Form; EOT, end of treatment; IGlar U100, insulin glargine U100; Lixi, lixisenatide; OAD, oral antidiabetic drug Rosenstock et al. Diabetes Care 2016;39: BMI, body mass index; DPP-4i, dipeptidyl peptidase-4 inhibitor; FPG, fasting plasma glucose; IGlar U100, insulin glargine U100; OAD, oral antidiabetic drug; pio, pioglitazone; SFLT-2i, sodium/glucose cotransporter 2; SU, sulfonylurea; T2D, type 2 diabetes. Aroda et al. Diabetes Care 2016;39: Uncontrolled on insulin LixiLan-L Key clinical findings HbA 1c Weight Confirmed symptomatic hypoglycemia IGlarLixi IGlar U100 (max. 60 U) IGlarLixi IGlar U100 (max. 60 U) Change in HbA 1c (%) Change in weight (kg) Hypoglycaemia rate (events/patient-year) p< p< IGlarLixi IGlar U100 (max. 60 U) Baseline HbA 1c 8.1% 8.1% EOT HbA 1c 6.9% 7.5% Severe hypoglycaemia in four IGlarLixi patients and one IGlar U100 patient Diabetes Care Publish Ahead of Print, published online February 26, 2018 Documented symptomatic hypoglycaemia with PG <70 mg/dl (3.9 mmol/l). Symptomatic hypoglycaemia = symptomatic hypoglycaemia recorded on the dedicated ecrf and meeting protocol definition for severe, documented or probable symptomatic hypoglycaemia ecrf, electronic Case Report Form; EOT, end of treatment; IGlar U100, insulin glargine U100 Aroda et al. Diabetes Care 2016;39:

12 Trial design HbA 1c over time IDegLira + metformin Subjects with (n=252) T2D (N=506) IGlar U100 + IAsp ( 4 times) + metformin (n=254) Week Screening Randomisation End of trial Randomised 1:1 Open label Inclusion criteria Age 18 yearsa 1c % HbA 1c % IGlar U U + metformin BMI 40 kg/m 2 Trial information: Non-inferiority Treat-to-target BG, blood glucose; BMI, body mass index; FU, follow-up; HbA 1c, glycosylated haemoglobin; IAsp, insulin aspart; IDegLira, insulin degludec/liraglutide combination; IGlar U100, insulin glargine 100 units/ml; T2D, type 2 diabetes; U, units. Novo Nordisk. NN Presented at 77th ADA Scientific Sessions; June 9 13, 2017; San Diego, California. 1 st FU 2 nd FU Key endpoints Primary: Change from baseline in HbA 1c after 26 weeks of treatment Secondary: Number of treatment emergent severe or BG-confirmed symptomatic hypoglycaemic episodes during 26 weeks of treatment Change from baseline in body weight after 26 weeks of treatment HbA 1c (%) ETD: 0.02% [ 0.16; 0.12] 95% CI p< for test for non-inferiority by 0.3% Time (weeks) Diabetes Care Publish Ahead of Print, published online February 26, 2018 IDegLira (n=252) IGlar U100 + IAsp (n=254) 6.7% 6.7% Change in body weight over time Change in body weight (kg) kg Time (weeks) IDegLira (n=252) IGlar U100 + IAsp (n=254) IDegLira IGlar U100 + IAsp ETD [95% CI] Weight (kg) LSMean [-4.19; -2.95], p< Diabetes Care Publish Ahead of Print, published online February 26, kg Severe or BG-confirmed symptomatic hypoglycemia over time Number of episodes per subject Time (weeks) And 92% reduction in nocturnal hypoglycemia IDegLira (n=252) IGlar U100 + IAsp (n=253) Treatment ratio: 0.11 [0.08; 0.17] 95%CI p< Diabetes Care Publish Ahead of Print, published online February 26, 2018

13 Approach to intensification of therapy Patients with T2D are diverse and complex?? Comorbidities Diabetes Care 2018;41(Suppl. 1):S73 S85 T2D, type 2 diabetes Hypoglycemia risk Key points Key points There are multiple pathophysiologic abnormalities that contribute to the development of T2DM Ominous octet T2DM is a progressive disease characterised by progressive loss of beta cell function People with T2DM are at increased risk for cardiovascular disease The goal of care is the best possible glycemic control that you can achieve safely Do no harm Goals should be individualised based on the characteristics of the patient One size does not fit all We can optimise care using therapies that are safer and associated with less risk of hypoglycemia, lower weight gain, lower cardiovascular risk and are simpler to use

14 Key points Basal insulin analogs are safer than NPH and the newer longer acting analogs are associated with less hypoglycemia than the first generation analogs There are many newer effective combination treatments including that can be utilized in people not at goal on metformin Combining basal insulin with a GLP-1 RA is as effective at lowering A1c as basal insulin plus prandial insulin with less hypoglycemia and weight gain DKA, diabetic ketoacidosis