Case 1. Modern Management of Diabetes Mellitus. Case 3. Case 2. What should be done now? What should be done now? What should be done now?

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1 Case 1 Modern Management of Diabetes Mellitus Type 2 Non-Insulin Medication UCSF Primary Care Update San Francisco October 24, 2014 Elizabeth J. Murphy, MD, DPhil Professor of Clinical Medicine University of California, San Francisco Chief, Division of Endocrinology San Francisco General Hospital 54 yow BMI 28 and family history of diabetes recently diagnosed with DM2 based on an A1C of 6.9%. What should be done now? 2 Case 2 60 yom with BMI 32, DM2 for 5 years. On metformin for several years but A1C in past year has increased to 8.2%. What should be done now? Case 3 72 yom BMI 32 with a 10 year history of DM2, CVD s/p CABG, CRI (Cr 2, GFR 35) with worsening proliferative diabetic retinopathy. On basal insulin, A1C 8.2%. What should be done now? 3 4 1

2 GOALS Become better informed about the different oral medication treatment options Become better informed about data on tight control Be able to make appropriate treatment decisions and determine appropriate A1C goals for you and your patients Diabetes in the Stone Age 1940s and 1950s o Goals Prevent hospitalization and death - DKA - Hyperosmolar Coma - Severe hypoglycemia 1960s and 1970s o Discovery of relationship between Hemogloblin A1C and blood glucose o Invention of the urine and then blood test strip 5 6 Urine Dip Stick s The Queen of Pee Made at home monitoring of glucose control possible for the first time First Glucose meter - Ames Reflectance Meter Introduced 1971 For use in doctors office only $500 Used a Dextrostix strip Wash the strip, put a drop of blood on it, wait 60s, wash it off with water, blot it 7 8 2

3 Tight Control Trials Start of UKPDS - DM Start of the DCCT - DM1 DCCT - Conventional Therapy Young (<40) DM1 patients without complications Conventional therapy o Insulin QD or BID (lente, ultralente, NPH, R) o Daily urine or blood glucose monitoring o Diet and exercise education Goals o Absence of symptoms of glycosuria or hyperglycemia o Absence of ketonuria o Maintenance of normal growth, development and ideal body weight o Avoidance of severe or frequent hypoglycemia 9 New England Journal of Medicine, 329(14), September 30, UKPDS - Treatment Goals Patients newly diagnosed with T2DM Conventional Therapy o FPG < 270 mg/dl (in lab, no SMBG available) o No symptoms of hyperglycemia o Diet instruction from a dietician Therapeutic Options o Sulphonylureas o Metformin o Insulin Age-Adjusted Prevalence of Diagnosed Diabetes Among U.S. Adults 1996 Missing data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% 9.0% Lancet, 1998; 352: CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at 3

4 Age-Adjusted Prevalence of Diagnosed Diabetes Among U.S. Adults 2010 Estimated lifetime risk of developing diabetes for individuals born in the United States in 2000 Missing data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% 9.0% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at Narayan et al, JAMA, 2003 Economic Costs of Diabetes, 2012 Case 1 Total cost of diabetes excess medical expenditures to treat diabetes directly to treat diabetes-related chronic complications attributed to diabetes excess medical costs reduced national productivity: $245 billion $176 billion $27 billion $58 billion $31 billion $69 billion 54 yow BMI 28 and family history of diabetes recently diagnosed with DM2 based on an A1C of 6.9%. What should be done now? a) Explain to the patient they are at goal but provide DM education (lifestyle modification) as well b) DM education, stress the need for aggressive control, start metformin and titrate up to maximum tolerated dose c) DM education, stress the need for aggressive control, start metformin and titrate up to maximum tolerated dose, provide glucose meter teaching with recommended daily BS checks. American Diabetes Association website. Diabetes Care. 2013; 16 4

5 Case 2 60 yom with BMI 32, DM2 for 5 years. On metformin for several years but A1C in past year A1C has increased to 8.2%. a) Encourage improved diet and exercise, add SMBG b) Start a sulphonylurea, add SMBG c) Start a DPPIV-inhibitor d) Start an SLGT-2 inhibitor e) Start a TZD f) Start a GLP-1 analogue g) Start insulin, add SMBG h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam Case 3 72 yom BMI 32 with CVD s/p CABG, 10 year history of DM2, CRI with worsening PDR. On basal insulin but A1C still at 8.2%. What should be done now? a) Explain to the patient the need for aggressive control to reduce complications, add meal time insulin, goal A1C 7%, SMBG QID b) Explain to the patient the need to improve his glucose control, goal A1C 7%, emphasize improved adherence, diet and exercise c) Explain to the patient the need to improve his glucose control, goal A1C 8%, emphasize improved adherence, diet and exercise d) Tell the patient it would be good to improve his glucose but he has lots of other medical problems and he s close to goal. Just don t let it get worse Tight Control Trials DCCT UKPDS ACCORD ADVANCE VADT DCCT - Outcomes, 6.5 y f/u 7.2 v 9.1 % A1C 76% reduction in risk for development of retinopathy 39% reduction in risk of new microalbuminuria 60% reduction in neuropathy No significant reduction in macrovascular disease (41% reduction, NS) 19 New England Journal of Medicine, 329(14), September 30,

6 Median HbA1c concentrations during DCCT, the training period between DCCT and EDIC, and EDIC DCCT/EDIC - Prevalence and Incidence of Albuminuria Nathan D M, and for the DCCT/EDIC Research Group Diabetes Care 2014;37: JAMA 2003;290: DCCT/EDIC - Cumulative Incidence CVD Outcomes 42% reduction in CVD risk 57% reduction in risk of nonfatal MI, stroke or CVD death N Engl J Med 2005;353: Tight Glucose vs Tight Blood Pressure Control in the UKPDS 7% v 7.9% A1C 0 % Reduction In Relative Risk Stroke 5% Any Diabetic Endpoint DM Deaths % 10% % +* % +* % +* Tight Glucose Control P < 0.05 compared to conventional rx *P <0.05 compared to glucose control Turner RC, et al. BMJ. 1998;317: Microvascular Complications 32% + 37% +* Tight BP Control 24 6

7 UKPDS 10 y follow-up Intensive Glucose Control Diabetes Goals, Treatment and Outcomes Over 30 Years 0.76* NS 9% 0.87* 0.73* Before DCCT, UKPDS 8% After DCCT 7% After DCCT, UKPDS? 6% NEJM, 2008; 359: Sulfonylurea Insulin + Metformin + TZD 1980s 1990s Incretin 2006 Tight Control Trials ACCORD - Primary and Secondary Outcomes DCCT UKPDS ACCORD Action to Control CardiOvacular Risk in Diabetes ADVANCE Action in Diabetes and Vascular disease: preterax and diamicron mr Controlled Evaluation VADT VA Diabetes Trial 27 The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:

8 ACCORD: Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups T2DM Trial Subject Comparison UKPDS ADVANCE ACCORD VADT # 4,209 11,140 10,251 1,791 subjects Age (y) BMI CVD 7.5% 32% 35% 40% Dx (y) New A1C % The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358: T2DM Trial A1C Lowering Comparison UKPDS ADVANCE ACCORD VADT Starting A1C% Goal A1C% < Int. A1C% Ctrl A1C% Duration of Follow-up 10+10= Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS DCCT / EDIC* ACCORD ADVANCE VADT 31 Kendall DM, Bergenstal RM. International Diabetes Center 2009 Initial Trial Long Term Follow up * in T1DM 8

9 What I know About Glucose Lowering 1. Lowering A1C prevents microvascular complications. The lower the better. The earlier in the disease the better. 2. Lowering A1C early in the disease prevents macrovascular complications many years later. Case 1 54 yow BMI 28 and family history of diabetes recently diagnosed with DM2 based on an A1C of 6.9%. What should be done now? a) Explain to the patient they are at goal but provide DM education (lifestyle modification) as well b) DM education, stress the need for aggressive control, start metformin and titrate up to maximum tolerated dose c) DM education, stress the need for aggressive control, start metformin and titrate up to maximum tolerated dose, provide glucose meter teaching with recommended daily BS checks. 34 Five things Physicians and Patients Should Question Self-Monitoring of Blood Glucose In patients not treated with insulin, self-monitory was associated with higher A1C and increased psychological burden. 1 Other studies show a modest benefit SMBG can have an important role in improving metabolic control if part of a wider educational strategy Selected monitoring may be more effective than daily monitoring 35 1 Franciosi et al, Diabetes Care 24:1870,

10 Metformin Advantages: o Lowers A1C 1.5-2% o Weight loss (0-2 kg) o Lowers TG, LDLc; Increases HDLc o No hypoglycemia when used alone o Inexpensive Disadvantages o Majority of patients with GI SE o Risk of lactic acidosis (MINIMAL) o Impairs B12 absorption Metformin and B12 Metformin consistently decreases B12 levels in a dose and duration dependent manner 37 Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomized placebo controlled trial Metformin and B 12 True B12 deficiency is associated with megaloblastic anemia, peripheral neuropathy (which could be misdiagnosed as diabetic neuropathy), depression and cognitive impairment. Classic symptoms often absent with biochemical B12 deficiency Could consider checking for megaloblastic anemia yearly, checking B12 levels every 2-3 years BMJ 2010;340:c

11 Case 1 54 yow BMI 28 and family history of diabetes recently diagnosed with DM2 based on an A1C of 6.9%. What should be recommended now? a) Explain to the patient they are at goal but provide DM education (lifestyle modification) as well b) DM education, stress the need for aggressive control, start metformin and titrate up to maximum tolerated dose c) DM education, stress the need for aggressive control, start metformin and titrate up to maximum tolerated dose, provide glucose meter teaching with recommended daily BS checks. Case 2 60 or 82 yom with BMI 32, DM2 for 5 years. On metformin for several years but in past year A1C has increased to 8.2% or 9.2%. a) Encourage improved diet and exercise, add SMBG b) Start a sulphonylurea, add SMBG c) Start a TZD d) Start a DPPIV-inhibitor e) Start an SLGT-2 inhibitor f) Start a GLP-1 analogue g) Start insulin, add SMBG h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam Case 2 60 or 82 yom with BMI 32, DM2 for 5 years. On metformin for several years but in past year A1C has increased to 8.2% or 9.2%. a) Encourage improved diet and exercise, add SMBG b) Start a sulphonylurea, add SMBG c) Start a TZD d) Start a DPPIV-inhibitor e) Start an SLGT-2 inhibitor f) Start a GLP-1 analogue g) Start insulin, add SMBG h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam Hypoglycemia in the Elderly adverse drug reporting and a national household survey of insulin use 97,648 ED visits annually for insulin-related hypoglycemia and errors 29% hospitalized Over 80 years old versus age Double the rate of ED visits 5 fold increase in hospitalization Most common causes were decreased food intake and using the wrong insulin 43 Geller et al., JAMA Internal Medicine, 174:678,

12 1 in 7 US Households are Food Insecure 21 million adults 8.3 million kids 12 million adults 977,000 kids Case 2 60 or 82 yom with BMI 32, DM2 for 5 years. On metformin for several years but in past year A1C has increased to 8.2% or 9.2%. a) Encourage improved diet and exercise, add SMBG b) Start a sulphonylurea, add SMBG c) Start a TZD d) Start a DPPIV-inhibitor e) Start an SLGT-2 inhibitor f) Start a GLP-1 analogue g) Start insulin, add SMBG h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam TZDs (PPAR-γ Agonists) Lower A1C % no hypoglycemia when used alone November, 2013 FDA lifted its earlier restrictions on rosiglitazone prescribing CVD risk?, if so more likely in folks with CHF at baseline More concerning risks o Osteoporosis and increased fracture (dose and duration dependent) o Bladder cancer with pioglitazone? (dose and duration dependent) o Weight gain, edema Good for significant A1C lowering when there is a major concern for hypoglycemia Should be stopped when insulin is started Preference for pioglitazone

13 Case 2 60 or 82 yom with BMI 32, DM2 for 5 years. On metformin for several years but in past year A1C has increased to 8.2% or 9.2%. a) Encourage improved diet and exercise, add SMBG b) Start a sulphonylurea, add SMBG c) Start a TZD d) Start a DPPIV-inhibitor e) Start an SLGT-2 inhibitor f) Start a GLP-1 analogue g) Start insulin, add SMBG h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam 49 Plasma Insulin Responses to Oral and Intravenous Glucose Non-Diabetic Insulin ( U/mL) Oral Intravenous Insulin ( U/mL) Diabetic Oral Intravenous Minutes GIP, GLP-1, CCK T 1/2 2-5 minutes Minutes J Clin Invest 1967; 46: GLP-1 as a Therapeutic Target Long Acting GLP-1 Analogues Longer Acting GLP-1 Heloderma suspectum Gila Monster Prevent GLP-1 Breakdown DPPIV- Inhibition (also increases GIP) Exenatide o BID SC injection (Byetta) o Qweek SC Injection, LAR (Bydureon) Liraglutide (Victoza) QD SC injection Albiglutide (Tanzeum) approved 2014 o Qweek SC injection Dulaglutide (Trulicity) approved 9/2014 o Qweek SC injection Lixisenatide (Lyxumia) EU only Semaglutide Lixsenatide

14 GLP-1 Analogue Actions Lower A1C % Advantages: o Weight loss (2-3 kg), less hypo Disadvantages: o Injectable o GI Side Effects (nausea, vomiting) o Expensive o Pancreatitis? o Pancreatic cancer? o Medullary thyroid cancer? DPPIV Inhibitors Sitagliptin (Januvia) Vidagliptin (Galvus Europe only) Saxagliptin (Onglyza) Linagliptin (Trajenta) Alogliptin (Nesina-US; Vipidia-Europe) Anagliptin (Japan only) Teneligliptin (Japan only) Dutogliptin Gemigliptin Improvements in HbA 1C With Initial Coadministration of Sitagliptin and Metformin HbA 1C (%)* Mean Baseline HbA 1C = 8.8% N= * Placebo-subtracted LS mean change form baseline at Week 24. Sita=sitagliptin; Met=metformin. Aschner P, et al. Oral presentation at the EASD 42 nd Annual Meeting; September 2006; Copenhagen. Sita 100 mg QD Met 500 mg BID Met 1000 mg BID Sita 50 mg BID + Met 500 mg BID Sita 50 mg BID + Met 1000 mg BID DPPIV Inhibitors Lowers A1C % (mean diff from baseline) Advantages: o Oral, weight neutral, less hypo Disadvantages: o Expensive o Nausea o Increased URI Potential AE o Pancreatitis? o Cancer? o Immune modulating effects (T cell effects)? 56 14

15 CD26/DPPIV Case 2 Expressed on the surface of most cell types T-cell activation marker 62 known substrates Tumor suppressor role Inhibitors inhibit T-cell proliferation Good or evil: CD26 and HIV infection. J Derm Sci. 2000; 22: Role of CD26/dipeptidyl peptidase IV in human T cell activation and function. Front Biosci. 2008;13: Dipeptidyl peptidase IV (DPPIV), a candidate tumor suppressor gene in melanomas is silenced by promoter methylation. Front Biosci : or 82 yom with BMI 32, DM for 5 years. On metformin for several years but A1C in past year has increased to 8.2% or 9.2% a) Encourage improved diet and exercise, add SMBG b) Start a sulphonylurea, add SMBG c) Start a TZD d) Start a DPPIV-inhibitor e) Start an SLGT-2 inhibitor f) Start a GLP-1 analogue g) Start insulin, add SMBG h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam Renal Handling of Glucose SLGT2 Inhibitors (180 L/day) (900 mg/l)=162 g/day Glucose SGLT2 S1 SGLT1 90% S3 10% No Glucose Lowers A1C about 1% at max dose No hypoglycemia when used alone or with MF Advantages Weight loss kg Decrease in SBP 5 mmhg Disadvantages Increased mycotic genital infections in men and women (10% of women get yeast infections) Increased UTIs and fracture Polyuria, presyncope, sycope Increases Cr, decreases egfr, can cause hyperkalemia Expensive 15

16 SGL2 Inhibitors Canagliflozin (Invokana) Dapagliflozin (Fraxiga) initially rejected by FDA for safety concerns, resubmission approved 1/2014 Empagliflozin (Jardiance) approved 8/2014 Ipragliflozin Tofogliflozin Remogliflozin etabonate Ertugliflozin Mean difference from placebo The between-group change in HbA1c, which reflects long-term glycemic control, was 1.7% units. Repaglinide (Prandin) vs. Placebo HbA1c (%) Placebo Repaglinide Baseline 8.1% 8.5% 3 months 9.2% 7.9% Change from Baseline 1.1% -0.6%* *: p< 0.05 for between group difference Source: Package insert Prandin 62 A1C Goal?? Hypoglycemia Efficacy Cost Comorbidities Contraindications Adverse Effects and Risks Patient Acceptance 16

17 What I know About Glucose Lowering 1. Lowering A1C prevents microvascular complications. The lower the better. The earlier in the disease the better. 2. Lowering A1C early in the disease prevents macrovascular complications many years later. 3. Aggressive A1C lowering results in more hypoglycemia and the elderly are more prone to severe hypoglycemia. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM ANTI HYPERGLYCEMIC THERAPY Glycemic targets - HbA1c < 7.0% - Individualization is key: Tighter targets ( %) younger, healthier Looser targets ( %+ ) older, comorbidities, hypoglycemia prone, etc. - Avoidance of hypoglycemia Diabetes Care, Diabetologia. 19 April 2012 Good Rx.com 10/2014 A1C Cost/mth Sulfonylurea 1-2% $5 Metformin 1-2% $4 Pioglitazone % $20 Exenatide % $450 Canagliflozin 0.5-1% $330 Sitagliptin % $320 Acarbose % $30 Colesevelam % $80 Bromocriptine 0.4%? $ Test strips 0.4%? $20-60 Good Rx.com 10/2014 A1C Cost/mth Sulfonylurea 1-2% $5 Metformin 1-2% $4 Pioglitazone % $20 Exenatide % $450 Canagliflozin 0.5-1% $330 Sitagliptin % $320 Acarbose % $30 Colesevelam % $80 Bromocriptine 0.4%? $ Test strips 0.4%? $

18 2008 ADA Type 2 Consensus Statement Diabetes Treatment Algorithm Revised Consensus Algorithm - ADA and EASD Diabetes Care 31:173, An American Diabetes Association consensus statement represents the authors collective analysis, evaluation, and opinion at the time of publication and does not represent official association opinion. Diabetes Care. Published online Oct 22, 2008 Trends in New Noninsulin Antidiabetic Drug Prescription Diabetes Care, Diabetologia. 19 April 2012 Hampp, C. et al. "Use of Antidiabetic Drugs in the U.S., , Diabetes Care. 2014;

19 Case 2 60 yom with BMI 32, DM2 for 5 years. On metformin for several years but A1C in past year A1C has increased to 8.2%. GOAL A1C < 7% or lower if tolerated without hypoglycemia Case 2 60 yom with BMI 32, DM2 for 5 years. On metformin for several years but A1C in past year A1C has increased to 8.2%. a) Encourage improved diet and exercise, add SMBG b) Start a sulphonylurea, add SMBG c) Start a DPPIV-inhibitor d) Start an SLGT-2 inhibitor e) Start a TZD f) Start a GLP-1 analogue g) Start insulin, add SMBG h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam Case 2 60 yom with BMI 32, DM2 for 5 years. On metformin for several years but A1C in past year A1C has increased to 9.2%. a) Encourage improved diet and exercise, add SMBG b) Start a sulphonylurea, add SMBG c) Start a DPPIV-inhibitor d) Start an SLGT-2 inhibitor e) Start a TZD f) Start a GLP-1 analogue g) Start insulin, add SMBG h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam Case 2 82 yom with BMI 32, DM2 for 5 years. On metformin for several years but A1C in past year A1C has increased to 8.2%. GOAL: - Prevent hospitalization and symptomatic hyperglycemia - A1C < 8% or lower if tolerated without hypoglycemia

20 Case 2 82 yom with BMI 32, DM2 for 5 years. On metformin for several years but A1C in past year A1C has increased to 8.2%. Case 2 82 yom with BMI 32, DM2 for 5 years. On metformin for several years but A1C in past year A1C has increased to 9.2%. a) Encourage improved diet and exercise, add SMBG b) Start a sulphonylurea, add SMBG c) Start a DPPIV-inhibitor d) Start an SLGT-2 inhibitor e) Start a TZD f) Start a GLP-1 analogue g) Start insulin, add SMBG h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam a) Encourage improved diet and exercise, add SMBG b) Start a sulphonylurea, add SMBG c) Start a DPPIV-inhibitor d) Start an SLGT-2 inhibitor e) Start a TZD f) Start a GLP-1 analogue g) Start insulin, add SMBG h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam Case 3 72 yom BMI 32 with CVD s/p CABG, 10 year history of DM2, CRI with worsening PDR. On basal insulin but A1C still at 8.2%. Crude and Age-Adjusted Incidence of End-Stage Renal Disease Related to Diabetes Mellitus (ESRD-DM) per 100,000 Diabetic Population, United States, What should be done now? a) Explain to the patient the need for aggressive control to reduce complications, add meal time insulin, goal A1C 7%, SMBG QID b) Explain to the patient the need to improve his glucose control, goal A1C 7%, emphasize improved adherence, diet and exercise c) Explain to the patient the need to improve his glucose control, goal A1C 8%, emphasize improved adherence, diet and exercise d) Tell the patient it would be good to improve his glucose but he has lots of other medical problems and he s close to goal. Just don t let it get worse

21 Take Home Points Lowering A1C prevents microvascular complications. The lower the better. The earlier in the disease the better. Lowering A1C early in the disease prevents macrovascular complications later. Hypoglycemia, especially in the elderly, is bad. We are going to continue to have more and more new therapies which should be carefully evaluated based on: a) Efficacy (A1C lowering) b) Contraindications, adverse effects, risks c) Cost d) Hypoglycemic effects Routine daily BG monitoring is not indicated for patients well controlled on metformin or diet and exercise alone 81 21