Management of Type 2 Diabetes: Should We Change Our Algorithm?

Management of Type 2 Diabetes: Should We Change Our Algorithm? Estimated lifetime risk of developing diabetes for individuals born in the United States in 2000 60 50 Total Non-Hispanic Black Non-Hispanic White Hispanic Robert J. Rushakoff, MD Professor of Medicine University of California, San Francisco Percent 40 30 20 10 0 Men Women robert.rushakoff@ucsf.edu Narayan et al, JAMA, 2003 IDF Regions and global projections for the number of people with diabetes (20-79 years), 2010-2030 Number of people with diabetes (20-79 years), 2010 and 2030 http://www.idf.org/diabetesatlas http://www.idf.org/diabetesatlas 1

Economic Costs of Diabetes, 2007 Economic Costs of Diabetes, 2012 Medical Expenditures Attributed to Diabetes, 2007 Medical Expenditures Attributed to Diabetes, 2012 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: $174 billion $245 billion $116 billion $176 billion $27 billion $58 billion $31 billion $58 billion $69 billion Hospital Inpatient Care 50% 43% DM Medications and Supplies Retail prescriptions to treat complications 12% 12% 12% 18% Physician Office Visits 11% 9% American Diabetes Association. Diabetes Care. 2008;31:596-615 American Diabetes Association. Diabetes Care. 2013; published online March 6 American Diabetes Association. Diabetes Care. 2008;31:596-615 American American Diabetes Diabetes Association. Association. Diabetes Diabetes Care. Care. 2013; 2008;31:596-615 published online March 6 The Prevalence of Meeting A1C, Blood Pressure, and LDL Goals Among People With Diabetes, 1988 2010 Diabetes Care Publish Ahead of Print, published online February 15, 2013 2

Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS DCCT / EDIC* ACCORD ADVANCE VADT Kendall DM, Bergenstal RM. International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024) Initial Trial Long Term Follow up * in T1DM ACCORD: Action to Control Cardiovascular Risk in Diabetes 10,251 Enrollees 60% male 40% female Mean age 62.2 Baseline HgA1c 8.1% BMI - 32 30% macrovascular dx Duration DM: 10 years Majority of intensive group on 3-5 oral agents plus insulin Hypoglycemia 3 times greater in intensive group Primary and Secondary Outcomes ACCORD: Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559 The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559 3

Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial Diabetes Care May 2010 vol. 33 no. 5 983-990 Diabetes Care May 2010 vol. 33 no. 5 983-990 Sustained 3-Step Change in Secondary Cohort Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes Conventional P<0.001 Intensive Kaplan-Meier Estimates of the Risk of Death from Any Cause and from Cardiovascular Causes and the Number of Cardiovascular Events, According to Treatment Group Gaede P et al. N Engl J Med 2008;358:580-591 4

Personalizing A1c targets for individuals with type 2 diabetes Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554) Diabetes Care June 2013 vol. 36 no. 6 1779-1788 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM ANTI HYPERGLYCEMIC THERAPY Glycemic targets PG = plasma glucose - HbA1c < 7.0% (mean PG 150 160 mg/dl [8.3 8.9 mmol/l]) - Pre prandial PG <130 mg/dl (7.2 mmol/l) - Post prandial PG <180 mg/dl (10.0 mmol/l) - Individualization is key: Tighter targets (6.0 6.5%) younger, healthier Looser targets (7.5 8.0%+ ) older, comorbidities, hypoglycemia prone, etc. - Avoidance of hypoglycemia 2009 ADA Type 2 Consensus Statement Diabetes Treatment Algorithm 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, Diabetologia. 19 April 2012 [Epub ahead of print] Diabetes Care. Published online Oct 22, 2008 5

Case: Routine 66 y/o female. 5 6 270 lbs Patient with DM for 3 years +FH Type 2 DM On Metformin 1000 bid No HGM Has been to DM education program HgA1c 7.8 Case: Routine What do you do?. 1. No medication change, start HGM 2. Add insulin 3. Add sulfonylurea 4. Add DPP4 inhibitor 5. Add GLP-1 agonist 6. Add TZD 7. Add SGLT-2 inhibitor Overview on self-monitoring of blood glucose In patients with type 2 diabetes, SMBG can help to achieve a better glycemic control, especially at the beginning of therapy or following adjustments, although there are not sufficient lines of evidence to attest that strict monitoring in these patients is associated with an improved outcome on the long term. The role of SMBG in patients with type 2 diabetes managed by diet control alone is still unknown. Overview on self-monitoring of blood glucose The SMBG is recommended in patients on insulin therapy. For type 1 diabetes, SMBG should be performed at least 3 times daily. SMBG is also recommended in patients treated with oral hypoglycemic agents and in all the patients not fulfilling the optimal therapeutic target. 2 Glucose Checks per day 4 Time 1 Time 2 high HgA 1c low 6

Efficacy Patient Acceptance Hypoglycemia Weight Gain Adverse Effects Insurance coverage Cost Metformin and Lactic Acidosis Metformin may provoke lactic Acidosis which is most likely to occur in patients with renal impairment. It should not be used with even mild renal impairment 1 Metformin probably not as unsafe as previously thought. 25% users have relative contraindication 2 Patient s with lactic acidosis usually have acute renal failure 3 1. Joint Formulary Committee British National Formulary. 2006:353 2. Diabet Med 2001; 18:483-488 3. Diabet Med 2007; 24:494-497 Metformin: The Safest Hypoglycaemic Agent in Chronic Kidney Disease? There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared with other oral hypoglycaemic treatments. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes. Cochrane Database Syst Rev 2010;4: CD002967. Nephron Clin Pract 2011;118:c380-c383 7

Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomized placebo controlled trial ** egfr of 30 ml/min per 1.73m 2 **NICE Clinical Guideline CG87 (May 2009): Type 2 diabetes newer agents (a partial update of CG66). Briet et al. EASD October 2009 Decrease in vitamin B12 levels. (decreased in 4.2-47%) Metformin is thought to induce malabsorption of vitamin B12 and intrinsic factor in the ileum, an effect that can be reversed by increased calcium intake. BMJ 2010;340:c2181 Weighted prevalence of biochemical B12 deficiency and borderline deficiency adjusted for age, race, and sex in U.S. adults 50 years of age: NHANES 1999 2006. DM, Met (+) DM, Met ( ) No DM Metformin and B12 Anemia may be minimal to severe 1. Parenteral vitamin B 12 treatment (8 to 10 loading injections of 1000 μg each, followed by monthly 1000-μg injections) may present only as a peripheral neuropathy, possibly being misdiagnosed as diabetic neuropathy. 2. High-dose oral vitamin B 12 treatment (1000 to 2000 μg daily) 3. Effective vitamin replacement will correct blood counts in 2 months and correct or improve neurologic signs and symptoms within 6 months. Reinstatler L et al. Dia Care 2012;35:327-333 8

Origin Glargine Trial Origin Glargine Trial Two coprimary composite CV outcomes: CV death, nonfatal MI, or nonfatal stroke N Engl J Med 2012; 367:319-328 N Engl J Med 2012; 367:319-328 Origin Glargine Trial Secondary outcomes over median follow-up of 6.2 years : glargine group vs the standard care group Origin Glargine Trial Secondary Outcome: Cancer Incedence N Engl J Med 2012; 367:319-328 N Engl J Med 2012; 367:319-328 9

Frequency of Hypoglycemic Symptoms Among Patients With Type 2 Diabetes Asymptomatic Episodes of Hypoglycemia May Go Unreported Patients Self-Reporting Hypoglycemic Events, % 60 50 40 30 20 10 0 Frequency of Hypoglycemic Symptoms During the Preceding Month 1 Any insulin (n=133) Oral agents only (n=176) All patients (N=309) Patients, % 100 75 50 25 0 55.7 All patients with diabetes 62.5 Type 1 diabetes 46.6 n=70 n=40 n=30 Patients With 1 Unrecognized Hypoglycemic Event, % Type 2 diabetes Hypoglycemia: glucose <60 mg/dl In a cohort of patients with diabetes, more than 50% had asymptomatic (unrecognized) hypoglycemia, as identified by 3 day continuous glucose monitoring HgA1c 8 (T1) 7.4 (T2) 1. Lundkvist J et al. Eur J Health Econom. 2005;6(3):197 202. Chico A et al. Diabetes Care. 2003;26(4):1153 1157. Patients Are Worried About the Risk of Hypoglycemia: The Diabcare Asia 2003 Study Positive Side to TZDs Survey of 15,549 patients with diabetes 96% had type 2 diabetes and 4% of patients had type 1 diabetes 54% of respondents were anxious about the risk of hypoglycemia all or most of the time Reduction in glucose Reduces BP Reduces albuminuria Reduces CRP Possible DM prevention Reduces NASH Reduces LFT Reduces IMT Reduces stent failure Reduces death after CHF Increases adiponectin Increases HDL Mohamed M. Curr Med Res Opin. 2008;24(2):507 514. 10

Pioglitazone Bladder Cancer 2013 Meta Analysis (1): hazard ratio higher in patients using pioglitazone (hazard ratio 1.23; 95% CI 1.09-1.39) INCRETINS Gut factors that promote insulin secretion in response to nutrients 2012 Meta Analysis (2): hazard ratio higher in patients using pioglitazone (pooled RR 1.22, 95% CI 1.07-1.39) Major incretins: GLP-1, CCK, GIP (1) Diabet Med 2013 Jan 28. [Epub ahead of print] (2) CMAJ, 2012 Sep 4;184(12):E675-83 Incretin Drugs GLP Agonists Exenatide Liraglutide Semaglutide Albiglutide Taspoglutide Exenatide Lar Lixsenatide DPP 4 Inhibitors Vildagliptin Sitagliptin Saxagliptin Alogliptin Linagliptin Dutogliptin metogliptin 11

Use of Twice-Daily Exenatide in Basal Insulin Treated Patients With Type 2 Diabetes Glycemic outcome.change from baseline in hemoglobin A1c level. Buse J B et al. Ann Intern Med 2011;154:103-112 Use of Twice-Daily Exenatide in Basal Insulin Treated Patients With Type 2 Diabetes Changes in body weight and glucose levels over 30 weeks. Data are least-squares means estimated from a mixed model, in which the postbaseline response variable = treatment + pooled investigator + visit + baseline + baseline hemoglobin A1c stratum ( 8.0% or >8.0%) +(treatment visit), and the participant is treated as a random effect with an unstructured covariance matrix. Efficacy and Safety of Switching From the DPP-4 Inhibitor Sitagliptin to the Human GLP-1 Analog Liraglutide After 52 Weeks in Metformin-Treated Patients With Type 2 Diabetes Liraglutide 1.2mg Liraglutide 1.8mg Sitagliptin to Liraglutide 1.2 Sitagliptin to Liraglutide 1.8 Buse J B et al. Ann Intern Med 2011;154:103-112 Pratley R E et al. Dia Care 2012;35:1986-1993 12

Incretin Drugs: Pancreatitis Incretin Drugs: Pancreatitis Patients without Diabetes General Population in US 0.33-0.44 events per 1000 adults per year (1) Severe disease in 15-20% of these cases (2) Death in 2-4% of cases (2) Type 2 Diabetes Patients Epidemiology study shows 3 times risk compared to subjects without diabetes (3) Rate of pancreatitis in exenatide patients 0.39 events per 1000 patient years Initial Studies: Exenatide: 1.7/1000 subject-years Placebo: 3.0/1000 subject-years Insulin: 2.0/1000 subject-years 1. Frey et al Pancreas. 2006. 33:336-344 2. Forsmark et al Gastroenterology 2007 132:2022-2044 3. Noel et al Diabetes Care 2009 May;32(5):834-8 Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin A retrospective observational pharmacy claims analysis Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin A retrospective observational pharmacy claims analysis Diabetes Care 33:2349 2354, 2010 Diabetes Care 33:2349 2354, 2010 13

Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials Fifty-three trials enrolling 20,312 and 13,569 patients for DPP4i and comparators, respectively 22 pancreatitis risk of cancer (MH-OR 1.020 [0.742 1.402]; p = 0.90) risk of pancreatitis (0.786 [0.357 1.734], p = 0.55 Glucagonlike Peptide 1 Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus Current Medical Research and Opinion, November 2011, Vol. 27, No. S3 : Pages 57-64 JAMA Intern Med. Published online February 25, 2013 Incretins and CHF retrospective study 4,400 patients taking diabetes medications between 2000 and 2012. About 1,500 were taking GLP-1 medications and nearly 3,000 were not. Over an average nine-month follow-up period, patients taking GLP-1 medications were 41 percent less likely than others to be hospitalized with heart failure. Additionally, these patients were 44 percent less likely to be hospitalized for any reason, and 80 percent less likely to die of any cause. Presented at ACC 3/13 San Francisco Renal Glucose Reabsorption in Type 2 Diabetes Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule Renal glucose reabsorption is increased in type 2 diabetes Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose J Intern Med. 2007;261:32-43. 14

Renal Handling of Glucose (180 L/day) (900 mg/l)=162 g/day Rationale for SGLT2 Inhibitors Glucose SGLT2 S1 SGLT1 90% S3 10% No Glucose Inhibit glucose reabsorption in the renal proximal tubule Resultant glucosuria leads to a decline in plasma glucose and reversal of glucotoxicity This therapy is simple and nonspecific Even patients with refractory type 2 diabetes are likely to respond SGLT2 Inhibitors Potential Advantages Weight loss Low risk of hypoglycemia Possible BP lowering effect Effect independent of insulin Concerns Polyuria Electrolyte disturbances Bacterial UTIs Fungal genital infections? Mean Change (mg/dl) Fasting Plasma glucose: Mean Change From Baseline 40 20 0-20 -40-60 -80 0 7 14 21 28 Weeks Diabetes 452:146, 1993 Continued glyburide (n=209) Switched to metformin (n=210) Metformin + glyburide (n+213) 15

Approach to management of Hyperglycemia Generic Oral Hypoglycemic Slide Change from Drug A to B, C, or D Add Drug A to B, or B to A HgA 1c Add Drug C Add Drug D Time Patient Centered Approach...providing care that is respectful of and responsive to individual patient preferences, needs, and values ensuring that patient values guide all clinical decisions. Gauge patient s preferred level of involvement. Explore, where possible, therapeutic choices. Utilize decision aids. Shared decision making final decisions re: lifestyle choices ultimately lies with the patient. Diabetes Care 2012;35:1364-1379 Future management of Hyperglycemia GRADE Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study 16

Class Generic Name (Brand Name) Mechanism of Action Dosage Relative Effectiveness Major Side Effects / Interactions / Uses Weight Effects (average) Cost Sulfonylureas glyburide (Micronase) glipizide (Glucotrol) glimepiride (Amaryl) Stimulate insulin release from beta cells of the pancreas 2.5-20 mg bid 5-20 mg bid 0.5-4 mg bid 1 1 1 Hypoglycemia Gain 2 lbs $ Meglitinides repaglinide (Prandin) nateglinide (Starlix) Biguanide metformin (Glucophage) Bile Acid Sequestrants Colesevelam (Welchol) Stimulate insulin release from beta cells of the pancreas Primarily inhibits hepatic gluconeogenesis. unknown 0.5-2 mg tid (before meals) 60-360 mg tid (before meals) 500-2000 mg daily with meals 3.75 g/d (3-625 mg tabs bid) Hypoglycemia 1 Useful in pts on glucocorticoids and in pts with renal failure who often have good FBS and high BS 1 over the course of the day Prandin is short-acting. Starlix is very short-acting 1 Diarrhea, nausea, vomiting Increased risk of lactic acidosis if impaired renal or hepatic function or heavy EtOH use. B12 deficiency 0.7 Gain 1 lb $$$ Loss 2-3 lbs esophageal obstruction, bowel obstruction, fecal impaction, dysphagia pancreatitis, nausea, constipation neutral $$$ $ Bromocriptine /Cyclset improved glucose tolerance (enhanced stimulated insulinmediated glucose disposal). 0.25 0.5 mg/d 1.6-4.8 mg/d.5 Nasal Stuffiness, Nausea, headache, constrictive pericarditis, neuroleptic malignant syndrome, hypotension ---- $$=$$ $

Relative Effectiveness Class Generic Name (Brand Name) Alphaglucosidase Inhibitor acarbose (Precose) Thiazolidinediones rosiglitazone (Avandia) pioglitazone (Actos) Incretins exenatide (Byetta) Liraglutide (Victoza) Mechanism of Action Inhibits enzymes needed to break down glucose in the small intestine Insulin sensitizers Activate receptor molecules inside cell nuclei to decrease insulin resistance Mimics GLP-1 (gut hormone which affects insulin, glucagon, gastric emptying and satiety) Dosage 50 mg with 1 st bite of each meal (start at 12.5 mg and titrate up over weeks) 4-8 mg daily 15-45 mg daily 5-10 mcg bid SQ 0.6-1.8 mg qd SQ 0.7 1 1 1 Major Side Effects / Interactions / Uses Gas/ GI upset Need to use glucose to treat hypoglycemia (not a complex CHO) Weight gain, edema which is resistant to diuretic therapy Associated with bone loss and fractures. Nausea, Vomiting, constipation, pancreatitis (?) Renal failure Weight loss achieved through appetite suppression Thyroid C-cell tumors at clinically relevant exposures in rodents. Weight Effects (average) Loss 1-2 lbs Gain 12 lbs Loss 8 lbs Cost $$$ $$$ $$$ sitagliptin (Januvia) DPP-4 inhibitor (enzyme that breaks down GLP- 1) 100, 50, or 25 mg daily (dose by Cr Cl) 0.7-1 Side effects are rare. Occ GI side effects. Neutral $$$ saxagliptin (Onglyza) 5, 2.5 mg (for decrease creat) linagliptin (Trajenta) 5 mg

Class Generic Name (Brand Name) SGLT 2 Inhibitor Canagliflozin (Invokana) Mechanism of Action Inhibit glucose reabsorption in the renal proximal tubule Dosage Relative Effectiveness 100/300 mg daily 1 Major Side Effects / Interactions / Uses Dehydration, urinary tract infections, genital mycotic infection Weight Effects (average) Loss 4 lbs Cost $$$

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]