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Case 1

54 yow BMI 28 and family history of diabetes recently diagnosed with DM2 based on an A1C of 6.9%. Non-

Modern Management of What should be done now? Mellitus 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

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Case 2 Case 3

60 yom with BMI 32, DM2 for 5 years. On 72 yom BMI 32 with a 10 year history of DM2, CVD for several years but A1C in past s/p CABG, CRI (Cr 2, GFR 35) with worsening year has increased to 8.2%. proliferative diabetic retinopathy. On basal insulin, A1C 8.2%. What should be done now? What should be done now?

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1 GOALS Diabetes in the Stone Age

. Become better informed about the different . 1940s and 1950s oral medication treatment options o Goals . Become better informed about data on tight • Prevent hospitalization and death control -DKA . Be able to make appropriate treatment - Hyperosmolar Coma decisions and determine appropriate A1C - Severe hypoglycemia goals for you and your patients . 1960s and 1970s

o Discovery of relationship between Hemogloblin A1C and blood glucose

o Invention of the urine and then blood test strip

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First Glucose meter - Urine Dip Stick - 1960s Ames Reflectance Meter . Introduced 1971 . Made at home . For use in doctors monitoring of glucose office only control possible for the first time . $500 . Used a Dextrostix strip . Wash the strip, put a drop of blood on it, wait 60s, wash it off with water, blot it The Queen of Pee

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2 Tight Control Trials DCCT - Conventional Therapy

. Young (<40) DM1 patients without complications . 1977 - Start of UKPDS - DM2 . Conventional therapy . 1983 - Start of the DCCT - DM1 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, 1993. 10

UKPDS - Treatment Goals Age-Adjusted Prevalence of Diagnosed Diabetes Among U.S. Adults . Patients newly diagnosed with T2DM 1996 . 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 Missing data <4.5% o Insulin 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 http://www.cdc.gov/diabetes/statistics Lancet, 1998; 352:837-853. 11

3 Age-Adjusted Prevalence of Diagnosed Diabetes Estimated lifetime risk of developing diabetes for Among U.S. Adults individuals born in the United States in 2000 2010

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 http://www.cdc.gov/diabetes/statistics Narayan et al, JAMA, 2003

Economic Costs of Diabetes, 2012 Case 1

54 yow BMI 28 and family history of diabetes Total cost of diabetes $245 billion recently diagnosed with DM2 based on an A1C of 6.9%. excess medical expenditures $176 billion

to treat diabetes directly $27 billion What should be done now? to treat diabetes-related $58 billion a) Explain to the patient they are at goal but provide DM education chronic complications (lifestyle modification) as well attributed to diabetes b) DM education, stress the need for aggressive control, start metformin and titrate up to maximum tolerated dose excess medical costs $31 billion c) DM education, stress the need for aggressive control, start reduced national productivity: $69 billion 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 Case 2 Case 3

60 yom with BMI 32, DM2 for 5 years. On 72 yom BMI 32 with CVD s/p CABG, 10 year metformin for several years but A1C in past history of DM2, CRI with worsening PDR. year A1C has increased to 8.2%. On basal insulin but A1C still at 8.2%. a) Encourage improved diet and exercise, add SMBG What should be done now? b) Start a sulphonylurea, add SMBG a) Explain to the patient the need for aggressive control to reduce complications, c) Start a DPPIV-inhibitor add meal time insulin, goal A1C 7%, SMBG QID d) Start an SLGT-2 inhibitor b) Explain to the patient the need to improve his glucose control, goal A1C 7%, emphasize improved adherence, diet and exercise e) Start a TZD c) Explain to the patient the need to improve his glucose control, goal A1C 8%, f) Start a GLP-1 analogue emphasize improved adherence, diet and exercise g) Start insulin, add SMBG 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. h) Start an α-glucosidase inhibitor, or colesevelam

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Tight Control Trials DCCT - Outcomes, 6.5 y f/u 7.2 v 9.1 % A1C

. DCCT . 76% reduction in risk for development of retinopathy . UKPDS . ACCORD . 39% reduction in risk of new microalbuminuria . ADVANCE . VADT . 60% reduction in neuropathy . No significant reduction in macrovascular disease (41% reduction, NS)

New England Journal of Medicine, 329(14), September 30, 1993. 19 20

5 Median HbA1c concentrations during DCCT, the “training” period DCCT/EDIC - Prevalence and between DCCT and EDIC, and EDIC Incidence of Albuminuria

Nathan D M, and for the DCCT/EDIC Research Group Diabetes Care 2014;37:9-1614 JAMA 2003;290:2159-2167. 22

DCCT/EDIC - Cumulative Incidence CVD Outcomes Tight Glucose vs Tight Blood 42% reduction in CVD risk Pressure Control in the UKPDS 57% reduction in risk of nonfatal MI, stroke or CVD death 7% v 7.9% A1C Any Diabetic DM Microvascular Stroke Endpoint Deaths Complications 0 5%

10% -10 12% + -20 24% +* -30 32% 32% +* + 37% -40 +* 44% Tight Glucose Control Tight BP Control

% Reduction In Relative Risk Relative In Reduction % +* +-50 P < 0.05 compared to conventional rx *P <0.05 compared to glucose control

N Engl J Med 2005;353:2643-2653 Turner RC, et al. BMJ. 1998;317:703-713. 24

6 UKPDS Diabetes Goals, Treatment and Outcomes Over 30 Years 10 y follow-up Intensive Glucose Control

0.76* NS

9%

Before 8% DCCT, UKPDS 7% After DCCT 0.87* 0.73* After ? 6% DCCT, UKPDS

Sulfonylurea Insulin + Metformin + TZD + Incretin 1980s 1990s 1997 2006 NEJM, 2008; 359:1577-89.

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;358:2545-2559

7 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) 54 66 62 60

BMI 28 28 32 31

CVD 7.5% 32% 35% 40%

Dx (y) New 8 10 12

A1C % 7.1 7.5 8.3 9.4

30 The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559

T2DM Trial A1C Lowering Comparison Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials UKPDS ADVANCE ACCORD VADT Study Microvasc CVD Mortality UKPDS   Starting 7.1 7.5 8.3 9.4    A1C% DCCT /    Goal A1C% - ≤ 6.5 < 6.0 -1.5 EDIC*   Int. A1C% 7.0 6.4 6.4 6.9 ACCORD    Ctrl A1C% 7.9 7.0 7.5 8.4 ADVANCE   Duration of 10+10= 5.0 3.4 5.6  Follow-up 20 VADT    Initial Trial

Long Term Follow‐up Kendall DM, Bergenstal RM. © International Diabetes Center 2009 31 * in T1DM

8 Case 1 What I know About Glucose Lowering 54 yow BMI 28 and family history of diabetes recently diagnosed with DM2 based on an A1C 1. Lowering A1C prevents microvascular of 6.9%. complications. The lower the better. The earlier in the disease the better. What should be done now? a) Explain to the patient they are at goal but provide DM education (lifestyle modification) as well 2. Lowering A1C early in the disease prevents b) DM education, stress the need for aggressive control, start macrovascular complications many years later. 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.

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Five things Physicians and Self-Monitoring of Blood Glucose Patients Should Question . 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

1 35 Franciosi et al, Diabetes Care 24:1870, 2001. 36

9 Metformin . Advantages: Metformin and B12 o Lowers A1C 1.5-2% • Metformin consistently o Weight loss (0-2 kg) decreases B12 levels in a dose o Lowers TG, LDLc; Increases HDLc and duration dependent o No hypoglycemia when used alone manner o Inexpensive . Disadvantages o Majority of patients with GI SE o Risk of lactic acidosis (MINIMAL) o Impairs B12 absorption

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Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomized Metformin and B12 placebo controlled trial • 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:c2181

10 Case 1 Case 2

54 yow BMI 28 and family history of diabetes 60 or 82 yom with BMI 32, DM2 for 5 years. On recently diagnosed with DM2 based on an A1C metformin for several years but in past year of 6.9%. A1C has increased to 8.2% or 9.2%.

What should be recommended now? a) Encourage improved diet and exercise, add SMBG a) Explain to the patient they are at goal but provide DM education (lifestyle modification) as well b) Start a sulphonylurea, add SMBG b) DM education, stress the need for aggressive control, start c) Start a TZD metformin and titrate up to maximum tolerated dose d) Start a DPPIV-inhibitor c) DM education, stress the need for aggressive control, start e) Start an SLGT-2 inhibitor metformin and titrate up to maximum tolerated dose, provide glucose meter teaching with recommended daily BS checks. f) Start a GLP-1 analogue g) Start insulin, add SMBG h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam

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Case 2 Hypoglycemia in the Elderly 60 or 82 yom with BMI 32, DM2 for 5 years. On metformin for several years but in past year • 2007-2011 adverse drug reporting and a A1C has increased to 8.2% or 9.2%. national household survey of insulin use • 97,648 ED visits annually for insulin-related a) Encourage improved diet and exercise, add SMBG hypoglycemia and errors b) Start a sulphonylurea, add SMBG – 29% hospitalized c) Start a TZD • Over 80 years old versus age 45-64 d) Start a DPPIV-inhibitor – Double the rate of ED visits e) Start an SLGT-2 inhibitor – 5 fold increase in hospitalization f) Start a GLP-1 analogue g) Start insulin, add SMBG • Most common causes were decreased food h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam intake and using the wrong insulin

43 Geller et al., JAMA Internal Medicine, 174:678, 2014

11 1 in 7 US Households are Food Insecure

21 million adults 8.3 million kids

12 million adults 977,000 kids

Case 2 TZDs (PPAR-γ Agonists)

60 or 82 yom with BMI 32, DM2 for 5 years. On . Lower A1C 0.4-1.5% no hypoglycemia when used alone metformin for several years but in past year . November, 2013 FDA lifted its earlier restrictions on prescribing A1C has increased to 8.2% or 9.2%. . CVD risk?, if so more likely in folks with CHF at baseline . More concerning risks a) Encourage improved diet and exercise, add SMBG o Osteoporosis and increased fracture (dose and duration b) Start a sulphonylurea, add SMBG dependent) c) Start a TZD o Bladder cancer with ? (dose and duration dependent) d) Start a DPPIV-inhibitor o Weight gain, edema e) Start an SLGT-2 inhibitor . Good for significant A1C lowering when there is a major concern for hypoglycemia f) Start a GLP-1 analogue . Should be stopped when insulin is started g) Start insulin, add SMBG . Preference for pioglitazone h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam

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12 Case 2 Plasma Insulin Responses to Oral and Intravenous Glucose 60 or 82 yom with BMI 32, DM2 for 5 years. On metformin for several years but in past year Non-Diabetic Diabetic A1C has increased to 8.2% or 9.2%. 90 Oral 90 Oral Intravenous Intravenous U/mL) a) Encourage improved diet and exercise, add SMBG U/mL) 60 60  b) Start a sulphonylurea, add SMBG  c) Start a TZD 30 30 d) Start a DPPIV-inhibitor Insulin ( Insulin ( e) Start an SLGT-2 inhibitor 0 0 f) Start a GLP-1 analogue 030 60 90 120 150 180 030 60 90 120 150 180 g) Start insulin, add SMBG Minutes Minutes h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam GIP, GLP-1, CCK T 2-5 minutes 49 1/2 J Clin Invest 1967; 46:1954-1962

GLP-1 as a Therapeutic Target Long Acting GLP-1 Analogues

. Longer Acting GLP-1 Prevent GLP-1 Breakdown o BID SC injection (Byetta)

o Qweek SC Injection, LAR (Bydureon) . (Victoza) QD SC injection DPPIV- Inhibition . (Tanzeum) – approved 2014 o Qweek SC injection (also increases GIP) . (Trulicity) – approved 9/2014

o Qweek SC injection . (Lyxumia) – EU only Heloderma suspectum . Gila Monster . Lixsenatide

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13 GLP-1 Analogue Actions DPPIV Inhibitors

. Lower A1C 0.5-1.5% . (Januvia) . Advantages: . Vidagliptin (Galvus – Europe only) o Weight loss (2-3 kg), less hypo . (Onglyza) . Disadvantages: . (Trajenta) o Injectable . (Nesina-US; Vipidia-Europe) o GI Side Effects (nausea, vomiting)

o Expensive . (Japan only) o Pancreatitis? . (Japan only) o Pancreatic cancer? . Dutogliptin o Medullary thyroid cancer? .

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Improvements in HbA1C With Initial Co- DPPIV Inhibitors administration of Sitagliptin and Metformin . Lowers A1C 0.5-0.8% (mean diff from baseline) . Advantages: Mean Baseline HbA1C = 8.8% N=1091 o Oral, weight neutral, less hypo . Disadvantages:

-0.5 Sita 100 mg QD o Expensive

Met 500 mg BID -1.0 o Nausea -0.8 Met 1000 mg BID (%)* -1.0 o Increased URI

1C -1.5 Sita 50 mg BID + -1.3 Met 500 mg BID . Potential AE

HbA Sita 50 mg BID + -2.0 -1.6 Met 1000 mg BID o Pancreatitis? -2.1 -2.5 o Cancer?

* Placebo-subtracted LS mean change form baseline at Week 24. o Immune modulating effects (T cell effects)? Sita=sitagliptin; Met=metformin. Aschner P, et al. Oral presentation at the EASD 42nd Annual Meeting; 14-17 September 2006; Copenhagen. 56

14 CD26/DPPIV Case 2

. Expressed on the surface of most cell types 60 or 82 yom with BMI 32, DM for 5 years. On . T-cell activation marker metformin for several years but A1C in past . 62 known substrates year has increased to 8.2% or 9.2% . Tumor suppressor role . Inhibitors inhibit T-cell proliferation a) Encourage improved diet and exercise, add SMBG b) Start a sulphonylurea, add SMBG . Good or evil: CD26 and HIV infection. c) Start a TZD J Derm Sci. 2000; 22:152-60. d) Start a DPPIV-inhibitor . Role of CD26/dipeptidyl peptidase IV in human T cell activation and function. Front Biosci. 2008;13:2299-310. e) Start an SLGT-2 inhibitor . Dipeptidyl peptidase IV (DPPIV), a candidate tumor suppressor gene in f) Start a GLP-1 analogue melanomas is silenced by promoter methylation. Front Biosci. 2008 g) Start insulin, add SMBG 13:2435-43. h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam

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Renal Handling of Glucose SLGT2 Inhibitors

(180 L/day) (900 mg/L)=162 g/day • Lowers A1C about 1% at max dose • No hypoglycemia when used alone or with MF Glucose SGLT2 • Advantages – Weight loss 2.5-4 kg S1 – Decrease in SBP 5 mmHg

SGLT1 • Disadvantages 90% S3 – Increased mycotic genital infections in men and women (10% of women get yeast infections) 10% – Increased UTIs and fracture – Polyuria, presyncope, sycope – Increases Cr, decreases eGFR, can cause hyperkalemia No Glucose – Expensive

15 SGL2 Inhibitors Mean difference from placebo

“The between-group change in HbA1c, which reflects • (Invokana) long-term glycemic control, was 1.7% units.” • (Fraxiga) initially rejected by FDA for safety concerns, resubmission approved (Prandin) vs. Placebo 1/2014 HbA1c (%) • (Jardiance) approved 8/2014 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

Comorbidities Cost Contraindications

Adverse Effects Patient and Risks Acceptance

16 ADA-EASD Position Statement: Management of What I know About Glucose Lowering Hyperglycemia in T2DM ANTI‐HYPERGLYCEMIC THERAPY 1. Lowering A1C prevents microvascular Glycemic targets complications. The lower the better. The earlier in the disease the better. - HbA1c < 7.0% - Individualization is key: 2. Lowering A1C early in the disease prevents  Tighter targets (6.0 ‐ 6.5%) ‐ younger, healthier macrovascular complications many years later.  Looser targets (7.5 ‐ 8.0%+) ‐ older, comorbidities, hypoglycemia prone, etc. 3. Aggressive A1C lowering results in more - Avoidance of hypoglycemia hypoglycemia and the elderly are more prone to severe hypoglycemia.

Diabetes Care, Diabetologia. 19 April 2012

Good Rx.com 10/2014 A1C Cost/mth Good Rx.com 10/2014 A1C Cost/mth 1-2% $5 Sulfonylurea 1-2% $5 Metformin 1-2% $4 Metformin 1-2% $4 Pioglitazone 0.5-1.5% $20 Pioglitazone 0.5-1.5% $20 Exenatide 0.5-1.5% $450 Exenatide 0.5-1.5% $450 Canagliflozin 0.5-1% $330 Canagliflozin 0.5-1% $330 Sitagliptin 0.5-0.8% $320 Sitagliptin 0.5-0.8% $320 0.5-0.8% $30 Acarbose 0.5-0.8% $30 Colesevelam 0.5-0.8% $80 Colesevelam 0.5-0.8% $80 Bromocriptine 0.4%? $35-312 Bromocriptine 0.4%? $35-312 Test strips 0.4%? $20-60 Test strips 0.4%? $20-60

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17 2008 ADA Type 2 Consensus Statement Revised Consensus Algorithm - ADA and EASD Diabetes Treatment Algorithm Diabetes Care 31:173, 2008.

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 2003-2012

Diabetes Care, Diabetologia. 19 April 2012 Hampp, C. et al. "Use of Antidiabetic Drugs in the U.S., 2003-2012”, Diabetes Care. 2014; 38.

18 Case 2 Case 2

60 yom with BMI 32, DM2 for 5 years. On 60 yom with BMI 32, DM2 for 5 years. On metformin for several years but A1C in past metformin for several years but A1C in past year A1C has increased to 8.2%. year A1C has increased to 8.2%.

a) Encourage improved diet and exercise, add SMBG GOAL – A1C < 7% or lower b) Start a sulphonylurea, add SMBG c) Start a DPPIV-inhibitor if tolerated without d) Start an SLGT-2 inhibitor hypoglycemia e) Start a TZD f) Start a GLP-1 analogue g) Start insulin, add SMBG h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam

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Case 2 Case 2

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

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19 Case 2 Case 2

82 yom with BMI 32, DM2 for 5 years. On metformin 82 yom with BMI 32, DM2 for 5 years. On for several years but A1C in past year A1C has metformin for several years but A1C in past increased to 8.2%. year A1C has increased to 9.2%. a) Encourage improved diet and exercise, add SMBG a) Encourage improved diet and exercise, add SMBG b) Start a sulphonylurea, add SMBG b) Start a sulphonylurea, add SMBG c) Start a DPPIV-inhibitor c) Start a DPPIV-inhibitor d) Start an SLGT-2 inhibitor d) Start an SLGT-2 inhibitor e) Start a TZD e) Start a TZD f) Start a GLP-1 analogue f) Start a GLP-1 analogue g) Start insulin, add SMBG g) Start insulin, add SMBG h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam

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Case 3 Crude and Age-Adjusted Incidence of End-Stage Renal Disease Related to Diabetes Mellitus (ESRD-DM) per 100,000 Diabetic Population, United States, 1980–2008 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.

http://www.cdc.gov/diabetes/statistics/esrd/fig7.htm 79

20 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

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