Sommer Memorial Advancements in the Management of Diabetes Mellitus. Lectures. Jessica Castle, MD Harold Schnitzer Diabetes Health Center

Transcription

1 Advancements in the Management of Diabetes Mellitus Jessica Castle, MD Harold Schnitzer Diabetes Health Center

2 Presenter Disclosure Information 2/44 Consultant: Novo Nordisk, Zealand, Dexcom Stockholder: Pacific Diabetes Technologies

3 Impact of Chronic Hyperglycemia 3/44 Leading cause 2-fold to 4-fold of blindness increase in in working age Diabetic cardiovascular adults Retinopathy Stroke events and mortality Diabetic Cardiovascular Nephropathy Disease Leading cause of end-stage renal disease Diabetic Neuropathy Leading cause of nontraumatic lower extremity amputations National Diabetes Information Clearinghouse. At:

4 American College of Physicians Guidance Statement 4/44 Aim to achieve an A1C 7-8% in most patients with type 2 diabetes Personalize goals for glycemic control Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA. Hemoglobin A1c Targets for Glycemic Control With Pharmacologic Therapy for Nonpregnant Adults With Type 2 Diabetes Mellitus: A Guidance Statement Update From the America College of Physicians. Annals of internal medicine Mar 6.

5 Glycemic Control & Complications 5/44 Type 1 Studies Type 2 Studies Microvascular Macrovascular Mortality DCCT/EDIC 1 UKPDS 2,3 ACCORD 4,5 ADVANCE 6,7 VADT 8 Observational Follow-up Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352: Holman RR, et al. N Engl J Med. 2008;359: Gerstein, et al. NEJM. 2008;358: ACCORD Study Group. NEJM. 2010; 363: Patel, et al. NEJM. 2008;358: Zoungas S, et al. N Engl J Med. 2014;371: Duckworth, et al, NEJM 2009;360:

6 Keep in Mind. 6/44 A1C threshold of 6.5% is strongly correlated with retinopathy ~33% of newly diagnosed patients already have complications Complications (particularly macrovascular) are present even in patients with pre-diabetes Diabetes Care 2009;32:

7 Also Keep in Mind. 7/44 Intensive group vs less intensive: % vs % The therapy options for type 2 diabetes have drastically changed over the past 10 years Sulfonylureas and insulin have a high risk of hypoglycemia

8 Lessons from ACCORD: Severe Hypoglycemia and Mortality Risk ACCORD Severe Hypo Intensive Standard (% / year) 3.1% 1.1% 8/44 Annual Mortality (%) Pts with 1 HMA event 4.0 Pts with no HMA event Intensive Standard HMA = symptomatic, severe hypoglycemic event requiring medical assistance. Bonds DE, et al. BMJ. 2010;340:b4909.

9 American College of Physicians Guidance Statement 9/44 Consider deintensifying pharmacologic control in patients with A1C<6.5% Treat to minimize symptoms related to hyperglycemia and avoid targeting an A1C in patients with a life expectancy <10 yrs Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA. Hemoglobin A1c Targets for Glycemic Control With Pharmacologic Therapy for Nonpregnant Adults With Type 2 Diabetes Mellitus: A Guidance Statement Update From the America College of Physicians. Annals of internal medicine Mar 6.

10 10/44 A1C and Mean Glucose Data from 3 A1C, % randomized clinical trials in people with type 1 or 2 diabetes (N = 387) yrs of age % white 81% type 1 diabetes Estimated Mean Glucose, mg/dl Beck RW, et al. Diabetes Care. 2017;40:

11 Median Glucose (mg/dl) A1C Represents a Wide Range of Glucose Values Different glucose excursions in people with A1C of 8% Glucose Exposure Subject Lab A1c Average Glucose Estimated A1c Low Glucose Ranges In Target Range Subject A Subject B High A 8.0% 195 mg/dl 8.4%.5% 42.2% 57.3% B 8.0% 156 mg/dl 7.0% 10.1% 54.5% 35.4% Target Glucose Range 12AM2AM 4AM 6AM 8AM10AM12PM2PM 4PM 6PM 8PM10PM12AM12AM2AM 4AM 6AM 8AM10AM12PM2PM 4PM 6PM 8PM10PM12AM Beck RW, et al. Diabetes Care. 2017;40: Time of Day 11/44

12 12/44 Individualizing A1C Targets Most Intensive Less Intensive Least Intensive 6.0% 7.0% 8.0% Psychosocioeconomic Considerations Highly Motivated, Adherent, Knowledgeable, Less motivated, Nonadherent, Limited Insight, Excellent Self-Care Capacities, & Comprehensive Support Systems Low Hypoglycemia Risk Moderate High Person s Age, yrs Disease Duration, yrs Other Comorbidities Established Vascular Complications None Few/Mild Multiple/Severe Non e Ismail-Beigi F, et al. Ann Intern Med. 2011;154: Poor Self-Care Capacities, & Weak Support Systems Cardiovascular Disease Early MicrovascularAdvanced Microvascular

13 Multiple Outcomes to Consider When Treating Diabetes 13/44 Cardiovascular Glycemic protection control No severe or No symptomatic weight gain hypoglycemia

14 Parameter SGLT-2 Inhibitors GLP-1 Agonists DPP-4 Inhibitors TZDs SUs Insulin Efficacy Intermediate High Intermediate High High Highest Hypoglycemia No No No No Yes Yes Weight Loss Loss Neutral Gain Gain Gain effect ASCVD benefit Potential risks Canagliflozin Liraglutide Potential Neutral Neutral Neutral Empagliflozin Semaglutide (pioglitazone) DKA, Fluid amputation, Thyroid C- retention, CV GU infection, cell tumor, Joint pain, mortality fracture, volume GI issues, acute (based ISRs depletion, ISRs, acute pancreatitis bladder on older hypotension, pancreatitis cancer, SU) LDL LDL American Diabetes Association. Diabetes Care. 2018;41:S73-S85. ISR = injections site reactions.

15 Sodium/Glucose Co-transporter 2 (SGLT-2) Inhibitors 15/44

16 16/44 SGLT-2 Inhibitors FDA-approved agents: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin Benefits Limitations Cardioprotective Genitourinary (canagliflozin, infections empagliflozin) Dehydration Low risk of hypoglycemia Risk of diabetic ketoacidosis Weight loss Increased risk of Decreased blood amputation in highrisk pts (with pressure canagliflozin) American Diabetes Association. Diabetes Care. 2018;41:S73-S85. Heerspink HJ, et al. Circulation. 2016;134:

17 Cardiovascular Outcomes in Diabetes: Empagliflozin EMPA-REG: randomized, double-blind, multicenter phase III trial in pts with type 2 diabetes and CVD (N = 7020) Primary Outcome: CV Mortality, Nonfatal MI, or Nonfatal Stroke 2 0 Placebo 1 HR: 0.86 (95.02% CI: ) 5 P =.04 for superiority Empagliflozin Months Patients With Event (%) Zinman B, et al. N Engl J Med. 2015;373: /44

18 Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes Patients with type 2 diabetes randomly assigned to empagliflozin (n=4124) or placebo (n=2061) Criteria included estimated GFR >30 ml/min/1.73 m 2 18/44 Kaplan Meier Analysis of Two Key Renal Outcomes. Wanner C et al. N Engl J Med 2016;375:

19 19/44 Empagliflozin Reduced Risk of New or Worsening Nephropathy Wanner C et al. N Engl J Med 2016;375:

20 20/44 Empagliflozin Reduced Risk of Composite of Doubling of Serum Creatinine, Need for Dialysis, or Death from Renal Disease Wanner C et al. N Engl J Med 2016;375:

21 Cardiovascular Outcomes in Diabetes: Canagliflozin CANVAS/CANVAS-R: randomized, double-blind, multicenter phase III/IV trials in pts with type 2 diabetes and high CV risk (N = 10,142) Primary Outcome: CV Mortality, Nonfatal MI, or Patients With an Event (%) Nonfatal Stroke 20 Placebo Neal B, et al. N Engl J Med. 2017;377: Canagliflozin also associated with increased amputation risk, primarily at toe or 10 HR: 0.86 (95% CI: ) 0 P <.001 for noninferiority P =.02 for superiority 12 Canagliflozin 60 8 metatarsal Weeks since Randomization 21/44

22 Glucagon-like Peptide-1 (GLP-1) Agonists 22/44 GLP-1 Neuroprotection Appetite Cardiac output Gastric emptying Glucagon secretion Insulin secretion Insulin biosynthesis Glucose production Glucose disposal Sodium excretion Campbell RK, et al. J Family Pract. 2009;59(suppl 1):S5-S9. DeFronzo RA. Med Clin N Am.2004;88: Gallwitz B. Rev Diabet Stud. 2009;6:

23 23/44 GLP-1 Agonists FDA-approved agents: albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide Benefits Limitations Cardioprotective Potential side effects (liraglutide, (eg, nausea, vomiting, semaglutide) diarrhea) Low risk of Injectable (although hypoglycemia pain is minimal) Weight loss common Minimal/no titration American Diabetes Association. Diabetes Care. 2018;41:S73-S85. Madsbad S. Diabetes Obes Metab. 2016;18: Zaccardi F, et al. Ann Int Med. 2016;164:

24 24/44 GLP-1 Receptor Agonists 24/45 GLP-1 receptor agonists Short-acting Long-acting Exenatide BID Lixisenatide OD Liraglutide Dulaglutide Albiglutide Semaglutide OD OW OW OW Exenatide OW BID, twice daily; GLP-1, glucagon-like peptide-1; OD, once daily; OW, once weekly.

25 Cardiovascular Outcomes in Diabetes: Liraglutide LEADER: randomized, double-blind, multicenter phase III trial in pts with type 2 diabetes and high CV risk (N = 9340) Primary Outcome: CV Mortality, Nonfatal MI, or Nonfatal Stroke HR: 0.87 (95% CI: ) Placebo 0 P <.001 for noninferiority P =.01 for superiority Liraglutide Patients With an Event (%) Months since Randomization Marso SP, et al. N Engl J Med. 2016;375: /44

26 26/44 Mann JF et al. N Engl J Med 2017;377: The primary composite renal outcome in the time-to-event analysis was a composite (Panel A) of the first occurrence of persistent macroalbuminuria (Panel B), persistent doubling of the serum creatinine level and an estimated glomerular filtration rate of 45 ml or less per minute per 1.73 m 2 of body-surface area (referred to as persistent doubling of the serum creatinine level; Panel C), the need for continuous renal-replacement therapy (for end-stage renal disease; Panel D), or death due to renal disease (data not shown). Liraglutide Reduced New Onset Macroalbuminuria

27 27/44 Semaglutide vs Exenatide ER Randomisation (1:1) 813 patients with T2D Age 18 years HbA 1c % Semaglutide 1.0 mg Stable treatment with 1 2 OADs (metformin, thiazolidinediones, sulphonylurea) Exenatide ER 2.0 mg egfr >60 ml/min/1.73 m 2 Dose escalation* Treatment maintenance Follow-up 8 weeks 48 weeks 5 weeks Treatment duration 56 weeks Trial information Open-label, active-controlled, parallel-group, multi-centre, multi-national, two-armed trial Conducted at 141 sites in 12 countries in Europe, South America and USA Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, Holst AG, Annett MP, Aroda VR. Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes care Feb 1;41(2):

28 28/44 HbA 1c ESTIMATED MEAN BY WEEK AND CHANGE FROM BASELINE AT WEEK 56 Overall mean at baseline: 8.35% Semaglutide mg 0.0 Exenatide ER 2.0 mg HbA 1c (%) ETD: 0.62* [ 0.79; 0.44] Time since randomisation (week) Semaglutide 1.0 mg Exenatide ER Change from baseline (%) -0.9 Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, Holst AG, Annett MP, Aroda VR. Efficacy and Safety of Once- Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes care Feb 1;41(2):

29 29/44 Body weight Body weight (kg) ESTIMATED MEAN BY WEEK AND CHANGE FROM BASELINE AT WEEK 56 Overall mean at baseline: kg Change from baseline (kg) -6 Semaglutide 1.0 mg Exenatide ER 2.0 mg Time since randomisation (week) ETD: 3.73* [ 4.53; 2.93] Semaglutide 1.0 mg Exenatide ER 2.0 mg Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, Holst AG, Annett MP, Aroda VR. Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes care Feb 1;41(2):258-66

30 30/44 Adverse Events Semaglutide 1.0 mg Exenatide ER 2.0 mg Subjects (%) Nausea Diarrhea Increased Nasopharyngitis appetite site Headache Decreased Vomiting Dyspepsia Constipation Injection lipase nodule BGconfirmed hypo* Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, Holst AG, Annett MP, Aroda VR. Efficacy and Safety of Once- Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes care Feb 1;41(2):

31 Cardiovascular Outcomes in Diabetes: Semaglutide SUSTAIN-6: randomized, double-blind, multicenter phase III trial in pts with type 2 diabetes and high CV risk (N = 3297) Primary Outcome: CV Mortality, Nonfatal MI, or Nonfatal Stroke HR: 0.74 (95% CI: Placebo ) 8 80 P <.001 for noninferiority 6 P =.02 for superiority 60 Semaglutide 4 Patients With an Event (%) Weeks since Randomization Marso SP, et al. N Engl J Med. 2016;375: /44

32 32/44 Cardiovascular Protection In people with uncontrolled T2DM and established CV disease (or specifically to reduce CV risk), consider: The oral SGLT-2 inhibitors canagliflozin empagliflozin The injectable GLP-1 agonists liraglutide or semaglutide Other agents are under investigation for CVD outcomes American Diabetes Association. Diabetes Care 2018;41:S86 S104.

33 Cardiovascular Outcomes in Diabetes: Summary and Ongoing Trials Study Class Agent Results CANVAS [1] SGLT-2 Canagliflozin inhibitor Reduced CV events EMPA-REG [2] SGLT-2 Reduced CV events and Empagliflozin inhibitor CV death LEADER [3] Reduced CV events and GLP-1 agonist Liraglutide CV death SUSTAIN-6 [4] GLP-1 agonist Semaglutide Reduced CV events DECLARE- TIMI58 [5] SGLT-2 inhibitor Dapagliflozin Expected July 2018 REWIND [6] GLP-1 agonist Dulaglutide Expected July 2018 CAROLINA Canagliflozin [7] DPP-4 [1] associated inhibitor with Linagliptin increased amputation Expected risk March /44

34 34/44 Recent advances in diabetes technology 34

35 35/44 Continuous Glucose Monitoring CGM provides much more information Glucose value Trend arrow Rate of change Trend graph Know where you are by how you got there AND where its going

36 Dexcom G4 or G5 Mobile 36/44 And now the G6 which does not require calibration!

37 37/44 FreeStyle Libre No calibrations required

38 Advanced Treatments for Diabetes: Artificial Pancreas (AP) 38/44 Computerized control of insulin ± glucagon delivery based on data from a continuous glucose sensor Continuous Glucose Monitor Master Controller Speed of insulin is critical to the success of automation* Insulin/ Glucagon Pump *3 major delays: insulin absorption, insulin action, glucose sensing.

39 MiniMed 670G: Hybrid AP System First FDA-approved AP system Hybrid indicates that meal boluses still required Insulin delivery is adjusted based on a PID algorithm: Proportional error (distance from target) Integral error (area under the curve) Derivative error (rate of change) Insulin-on-board safety constraints 39/44 Garg, S.K., Weinzimer, S.A., Tamborlane, W.V., Buckingham, B.A., Bode, B.W., Bailey, T.S., Brazg, R.L., Ilany, J., Slover, R.H., Anderson, S.M. and Bergenstal, R.M., Glucose outcomes with the in-home use of a hybrid closed-loop insulin delivery system in adolescents and adults with type 1 diabetes. Diabetes Technology & Therapeutics, 19(3), pp

40 40/44 Imagine if the heat source for your home was a mile away Your house would alternate between: Artic Freeze Blazing Inferno Delays in insulin onset/offset lead to hyperglycemia and hypoglycemia

41 OHSU Artificial Pancreas Study: 4-way Randomized Cross-over 41/44 Current care Sunday Monday Tuesday Wednesday Thursday Friday Saturday In clinic Home In clinic exercise exercise exercise PLGS Insulin CL Home In clinic In clinic exercise exercise exercise Home In clinic In clinic exercise exercise exercise Insulin + Glucagon CL In clinic Home In clinic exercise exercise exercise *Current care: patient s usual regimen **PLGS: predictive low glucose suspend system ***In clinic exercise: running at 60% of VO2max for 45 min ****Home exercise: exercise of subjects choice for 45 min

42 OHSU Artificial Pancreas Systems Improved Time in Range ( mg/dl); Glucagon Reduced Hypoglycemia 42/44 Time in range: 63.1% vs 65.2% vs 74.3% vs 72.0% Castle, Jacobs et al. Diabetes Care, 2018, in press.

43 Summary 43/44 Type 2 diabetes is a progressive disease that commonly requires multiple medications Consider benefits and limitations of drug choices to determine optimal choice Individualize glycemic targets There are now multiple SGLT-2 inhibitor and GLP-1 agonist options available that reduce cardiovascular risk CGM is available and has enabled automated insulin delivery

44 Thank you!