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Management of : Should We Change CDC Funding Medicare Funding! Our Algorithm? • Begins 1/1/2018 • The American Association • 12 month intervention for Diabetes Educators – At least 16 weekly core 1 hour Drugs for Type 2 Diabetes • America’s Health sessions Insurance Plans – Medicare Part B • Black Women’s Health – BMI >24 (Asian >22) Imperative • National Association of – HbA1c 5.7 to 6.4 or FBS 110- 125 Chronic Disease Directors – No dx of type 1 or type 2 DM Robert J. Rushakoff, MD • YMCA of the USA (can have hx gestational DM) Professor of Medicine – No ESRD University of California, San Francisco • Payment structure - - TBD • Must be recognized CDC Diabetes Prevention [email protected] Recognition Program

ADA‐EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Approach to the management of hyperglycemia more HbA1c less stringent 7% stringent 3. ANTI‐HYPERGLYCEMIC THERAPY PATIENT / DISEASE FEATURES Risks potentially associated • Glycemic targets with hypoglycemia and low high other drug adverse effects

Disease duration - HbA1c < 7.0% (mean PG 150‐160 mg/dl [8.3‐8.9 mmol/l]) newly diagnosed long-standing

mg/dl mmol/l Usually not - Pre‐prandial PG <130 (7.2 ) Life expectancy modifiable long short - Post‐prandial PG <180 mg/dl (10.0 mmol/l) Important comorbidities absent few / mild severe - Individualization is key:  Established vascular Tighter targets (6.0 ‐ 6.5%) ‐ younger, healthier complications absent few / mild severe  Looser targets (7.5 ‐ 8.0%+) ‐ older, comorbidities,

hypoglycemia prone, etc. Patient attitude and expected treatment efforts highly motivated, adherent, less motivated, non-adherent, Potentially excellent self-care capacities poor self-care capacities - Avoidance of hypoglycemia modifiable Resources and support system Readily available limited PG = plasma glucose Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

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Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline Update From the and Lactic Acidosis American College of Physicians

Recommendation 1: •“Metformin may provoke lactic Acidosis which is ACP recommends that clinicians prescribe most likely to occur in patients with renal metformin to patients with type 2 diabetes impairment. It should not be used with even mild renal impairment” 1 when pharmacologic therapy is needed to • Metformin probably not as unsafe as previously improve glycemic control. thought. – 25% users have relative contraindication 2 (Grade: strong recommendation; moderate- – Patient’s with lactic acidosis usually have quality evidence) acute renal failure 3

1. Joint Formulary Committee British National Formulary. 2006:353 2. Diabet Med 2001; 18:483-488 Ann Intern Med. 2017;166(4):279-290. 3. Diabet Med 2007; 24:494-497

Metformin: The Safest Hypoglycaemic Agent in Chronic FDA and Metformin: 2016 Kidney Disease? • Eliminated the heart failure warning in response to 2 large observational studies that suggested that • There is no evidence from prospective metformin is safe and may be beneficial in patients comparative trials or from observational with compensated heart failure. cohort studies that metformin is associated with an increased risk of lactic acidosis, or • As a result of 2 citizen petitions, Metformin allowed with increased levels of lactate, compared in patients with: with other oral hypoglycaemic treatments. – mild to moderate kidney dysfunction, defined as an estimated glomerular filtration rate (eGFR) of 30 to 60 Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes. mL/min/1.73 m2, Cochrane Database Syst Rev 2010;4: CD002967. – but not in those with severe kidney dysfunction (eGFR <30 mL/min/1.73 m2). Nephron Clin Pract 2011;118:c380-c383

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The Effect of Intravenous Contrast on Renal 2015 American College of Radiology Function in Diabetic Patients on Metformin Manual on Contrast Media SF VA - - retrospective UCSF - - Prospective Iodinated Contrast • 130 patients • 40 patients • precontrast renal function did not • no significant change in serum Category I. (eGFR ≥30 mL/min/1.73m2) predict a decline in postcontrast creatinine was observed renal function (baseline range from 0.7 to 1.2 In patients with no evidence of AKI and with eGFR ≥30 • patients with precontrast eGFR mg/dL). Notably, an additional >60 mL/min/1.73 m2 did not have 15 patients were recruited, but any deterioration in renal function. mL/min/1.73m2, there is no need to discontinue metformin either they did not obtain a • no significant deterioration in renal postcontrast creatinine function in patients with a prior to or following the intravenous administration of iodinated precontrast eGFR <60 measurement despite mL/min/1.73 m2. receiving reminders. contrast media, nor is there an obligatory need to reassess the

patient’s renal function following the test or procedure.

Shah et al. ENDOCRINE PRACTICE Vol 22 No. 4 April 2016

Long term treatment with metformin in patients with type 2 2015 American College of Radiology diabetes and risk of vitamin B-12 deficiency: randomized Manual on Contrast Media placebo controlled trial

Iodinated Contrast Category II. (eGFR <30 mL/min/1.73m2) In patients taking metformin who are known to have acute kidney injury or severe chronic kidney disease (stage IV or stage V; i.e., eGFR <30 mL/min/1.73m2), or are undergoing arterial catheter studies that might result in emboli (atheromatous or other) to the renal arteries, metformin should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

Gadolinium-based contrast material It is not necessary to discontinue metformin prior to contrast medium administration when the amount of gadolinium-based contrast material administered is in the usual dose range of 0.1 to 0.3 mmol per kg of body weight.

BMJ 2010;340:c2181

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Long-term Metformin Therapy and Monitoring for Vitamin B12 Deficiency Among Older Veterans Metformin and B12

• Veterans 50 years or older with either type 2 diabetes and long-term metformin therapy (n = 3,687) or without diabetes and no prescription • Anemia may be for metformin (n = 13,258) minimal to severe

• 37% of older adults with diabetes receiving metformin were tested for vitamin B12 status • may present only as a peripheral neuropathy, • mean B12 concentration was significantly lower in the metformin- exposed group (439.2 pg/dL) compared to those without diabetes possibly (522.4 pg/dL) (P = .0015). being misdiagnosed as diabetic • About 7% of persons with diabetes receiving metformin were vitamin B12 deficient (<170 pg/dL) compared to 3% of persons without neuropathy. diabetes or metformin use (P = .0001)

J Am Geriatr Soc 2017.

Metformin: Possible Benefits

VA longitudinal Study (Wian et al - ADA 2016) • metformin exposure longer than 2 years • significant reduction in neurodegenerative disease.(reduced cognitive decline, Parkinson's, Alzheimer's) • Metformin may be neuroprotective

Targeting Aging with Metformin (TAME) study. • Demonstrated to slow the aging process in certain microbes and mammals • The researchers will give Metformin to about 3,000 elderly people, who either suffer from or have a high risk of developing diseases like cancer, heart disease, or cognitive problems.

Cancer • Studies on lung cancer; head and neck cancers, esophageal cancer • Affect multiple key processes related to cell growth, proliferation, and survival. both metabolic and intracellular-signaling activity. downregulation of the Ras/Raf/MEK/ ERK and PI3K/AKT/mTOR signaling pathways. One or both of these pathways are often activated in many types of cancer cells

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Asymptomatic Episodes of Hypoglycemia Efficacy May Go Unreported

100 Patient Hypoglycemia 75 • Hypoglycemia: Acceptance 62.5 glucose <60 mg/dl 55.7 • In a cohort of 50 46.6 patients with diabetes, more than Patients, % Adverse 50% had Weight Gain 25 asymptomatic Effects (unrecognized) n=70 n=40 n=30 hypoglycemia, as 0 identified by 3 day All patients Type 1 diabetes Type 2 with diabetes diabetes continuous glucose monitoring Insurance Patients With ≥1 Unrecognized • HgA1c 8 (T1) 7.4 (T2) Cost Hypoglycemic Event, % coverage

. Chico A et al. Diabetes Care. 2003;26(4):1153–1157.

Patients Are Worried About the Risk of Hypoglycemia: Cardiac Effects of Related The Diabcare–Asia 2003 Study Hypoglycemia

• Survey of 15,549 patients with diabetes • 30 type 2 DM patients on • Mean HbA1c 6.9 • 96% had type 2 diabetes and 4% of • 48 hour CGM • Hypoglycemia (<63 mg/dl for >20 minutes) was detected in 9 of 30 patients had type 1 diabetes subjects • Episodes were typically nocturnal (67%) and asymptomatic (73%). • Hypoglycemia associated QTc prolongation was seen in five of nine subjects with a large variation in individual response. • 54% of respondents were anxious about • Higher QT dynamicity, a poor prognostic factor in cardiac disease, was the risk of hypoglycemia all or most of seen in subjects who experienced hypoglycemia compared with subjects who did not (0.193 vs. 0.159 for the nocturnal period; P = 0.01). This the time finding persisted after the hypoglycemic event. • The rates of ventricular and supraventricular ectopy demonstrated a nonsignificant trend toward an increase during hypoglycemia

Mohamed M. Curr Med Res Opin. 2008;24(2):507–514. Diabetes Care 2017 Feb; dc161972.

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Positive Side to TZDs Current TZD Side Effects

• Reduction in glucose • Reduces IMT • Weight Gain: 5-12 lbs in 1 year • Reduces BP • Reduces stent failure – Blunted with metformin • Reduces albuminuria • Reduces death after – Worse with • Reduces CRP CHF • Edema: 4-30% • Possible DM – Unresponsive to diuretics prevention •BUT: • Reduces NASH • Increases adiponectin – Increased Cardiac Index • Reduces LFT • Increases HDL – Increased Stroke volume – Decreased systemic resistance – Decreased Blood Pressure

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack • multicenter, double-blind trial • 3876 patients who had had a recent ischemic stroke or TIA

• No diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index • was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003).

• received either pioglitazone (target dose, 45 mg daily) or • Pioglitazone can help prevent recurrence of stroke and progression into diabetes in those patients placebo. with insulin resistance and recent cardiovascular events. • Bone mineral density should be closely monitored in patients taking pioglitazone due to high rates of bone fracture, hospitalizations, and surgeries. N Engl J Med 2016; 374:1321-1331

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Pioglitazone Bladder Cancer Negative Side to TZDs

2013 Meta Analysis (1): • hazard ratio higher in patients using pioglitazone (hazard ratio 1.23; 95% CI 1.09-1.39) • Weight Gain

2012 Meta Analysis (2): • Edema • hazard ratio higher in patients using pioglitazone (pooled RR 1.22, 95% CI 1.07-1.39) • Bone loss 2016 Population study • 145806 patients over 14 years • Bladder Cancer • Compared with other antidiabetic drugs, pioglitazone was associated with an increased risk of bladder cancer (121.0 v 88.9 per 100 000 person years; hazard ratio 1.63, 95% confidence interval 1.22 to 2.19). Conversely, was not associated with an increased risk of bladder cancer (86.2 v 88.9 per 100 000 person years; 1.10, 0.83 to 1.47). Duration-response and dose-response relations were observed for pioglitazone but not for rosiglitazone.

2016 FDA • after updating its review of published research, which had gone back and forth on the issue. • concluded pioglitazone may stull pose an increased risk for bladder cancer

(1) Diabet Med 2013 Jan 28. (2) CMAJ, 2012 Sep 4;184(12):E675-83 (3)BMJ 2016;352:i1541

Plasma Insulin Responses to Oral and INCRETINS Intravenous Glucose

Non-Diabetic Diabetic 90 Oral 90 Oral Intravenous Intravenous • Gut factors that promote insulin U/mL) U/mL) 60 60  secretion in response to nutrients 

30 30

•Major incretins: GLP-1, CCK, GIP ( Insulin Insulin ( 0 0 030 60 90 120 150 180 030 60 90 120 150 180 Minutes Minutes

J Clin Invest 1967; 46:1954-1962

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Glucose-Dependent Effects of GLP-1 on Insulin and Glucagon Levels in Patients With Type 2 Diabetes

15.0 250 12.5 mg/dL Placebo Glucose 200 Incretin Drugs 10.0 * * GLP-1

mmol/L 150 7.5 * * * 5.0 * * 100 *P <0.05 2.5 50 Patients with type 2  GLP Agonists  DPP 4 Inhibitors diabetes (N=10) 0 0  250 40 200 mU/L  30 When glucose levels Insulin 150

pmol/L approach normal values, 100 20   Trelagliptin * * * insulin levels decreases. 50 * * * * * 10 0 0 

20 20  pmol/L Glucagon 15 15 When glucose levels (1/week)  Exenatide Lar  Dutogliptin

pmol/L approach normal values, 10 * * 10 * * glucagon levels rebound. 5 5  Lixsenatide  Metogliptin Infusion 0 0 –30 0 60 120 180 240  Minutes

Adapted with permission from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag.

Use of Twice-Daily Exenatide in Basal Insulin–Treated Use of Twice-Daily Exenatide in Patients With Type 2 Diabetes 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. Glycemic outcome.Change from baseline in hemoglobin A1c level.

Buse J B et al. Ann Intern Med 2011;154:103-112 Buse J B et al. Ann Intern Med 2011;154:103-112

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Incretin Agents: Safety Concerns Incretin Drugs: Pancreatitis

• Thyroid Cancer and Neoplasia: • Patients without Diabetes – Thyroid C-cell tumors in rodent models – General Population in US – Not recommended for use in patients with a • 0.33-0.44 events per 1000 adults per year (1) personal or family history of MTC or MEN 2A • Severe disease in 15-20% of these cases (2) or 2B • Death in 2-4% of cases (2) • Type 2 Diabetes Patients • Pancreatitis – Epidemiology study shows 3 times risk compared to subjects without diabetes (3) • Pancreatic Cancer 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 Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin Exenatide or Sitagliptin A retrospective observational pharmacy claims analysis A retrospective observational pharmacy claims analysis

Diabetes Care 33:2349–2354, 2010 Diabetes Care 33:2349–2354, 2010

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Risks of Pancreatitis and Pancreatic DPP-4 Inhibitor–Related Cancer with Incretin therapies Pancreatitis: Rare but Real!

• Large-scale CVOTs have now been reported for three DPP-4 inhibitors: saxagliptin, alogliptin, and sitagliptin • FDA and EMA independent reviews of patient data and

animal studies have identified no evidence for causal • There were clear numerical imbalances, with more cases of acute pancreatitis relationship but maintain that the risks should be occurring with each of the three DPP-4 inhibitors than in the control groups, which failed to reach statistical significance in each of the individual trials disclosed and further investigated (Egan et al NEJM 2014; EMA Report 2013). • The estimated odds ratio for an increased risk of acute pancreatitis with DPP-4 inhibitors was 1.79 with an absolute increased risk of 0.13% • No prospective studies have identified a causal • translates to one to two additional cases of acute pancreatitis for every 1,000 relationship thus far patients treated for 2 years.

• Represents an area of ongoing investigation • Translated to 1 million users in the U.S., a very conservative estimate, this would result in ∼750 additional cases of acute pancreatitis per year.

Diabetes Care 2017 Feb; 40(2): 284-286. Diabetes Care 2017;40:161–163

Meta-analysis of the cardiovascular outcome trials reporting the risk of HF with DPP-4 inhibitors. Incretins (dpp-4): CVD

SAVOR-TIMI 53: Saxagliptin • unexpected excess rate of hospitalization for heart failure in the saxagliptin group (hazard ratio, 1.27; 95% CI, 1.07 to 1.51)

EXAMINE: Alogliptin • nonsignificant numerical imbalance in hospitalization for heart failure in the alogliptin group as compared with placebo (hazard ratio, 1.19; 95% CI, 0.90 to 1.58)

TECOS: Sitagliptin, • rates of hospitalization for heart failure was no different from placebo

Retrospective (Diabetes Care 2016): • In patients with type 2 diabetes, there was no association between HF, or other selected cardiovascular outcomes, and treatment with a DPP-4i relative to SU or treatment with saxagliptin relative to sitagliptin.

Kristian B. Filion, and Samy Suissa Dia Care 2016;39:735- 737

©2016 by American Diabetes Association

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Incretins (GLP-1): CVD Renal Glucose Reabsorption in Type 2 Diabetes ELIXA: (N Engl J Med 2015; 373:2247-2257) • neutral effect on heart failure and other cardiovascular problems  Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule Liraglutide (N Engl J Med 2016; 375:311-322) • rate of the first occurrence of  Renal glucose reabsorption is increased in death from cardiovascular causes, nonfatal myocardial type 2 diabetes infarction, or nonfatal stroke among patients with type 2  Selective inhibition of SGLT2 increases diabetes mellitus was lower with liraglutide than with urinary glucose excretion, reducing blood placebo glucose

J Intern Med. 2007;261:32-43.

SGLT2 Inhibitors

Rationale for SGLT2 Inhibitors • Potential Advantages – Weight loss  Inhibit glucose reabsorption in the renal – Low risk of hypoglycemia proximal tubule – Possible BP lowering effect – Effect independent of insulin  Resultant glucosuria leads to a decline in plasma glucose and reversal of • Concerns glucotoxicity – Polyuria – Electrolyte disturbances  This therapy is simple and nonspecific – Bacterial UTIs  Even patients with refractory type 2 – Fungal genital infections diabetes are likely to respond – Euglycemic DKA

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Glimiperide Canagliflozin 100mg 300mg Body weight, kg LS mean (SE) change 0.70 (0.2) ‐3.7 (0.2) ‐4.0 (0.2) Systolic BP LS mean (SE) change 0.2 (0.6) ‐3.3 (0.6) ‐4.6 (0.6) Hypoglycemia (n, %) 164 (34%) 27 (6%) 24 (5%) Cefalu WT et al. Lancet 2013. Bailey CJ et al. BMC Medicine 2013

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

Primary outcome: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke

Cefalu WT et al. Lancet 2013. Zinman B et al. N Engl J Med 2015;373:2117-2128

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Possible mechanisms that could contribute to the reduction of CV mortality by in the EMPA- SGLT2 Inhibitors REG OUTCOME study Amputations

– Increased risk for lower-limb amputations (toes) • ? Mechanism • Limited data • 3.4 year interim analysis of CANVAS

rate of amputations per every 1000 patients 100 mg/day: 7 300 mg/day: 5 Placebo: 3

Diabetes Care 2016 May; 39(5): 717-725

SGLT2 Inhibitors Bone Loss Generic Oral Hypoglycemic Slide

• 714 elderly patients with type 2 diabetes (mean age, 64 years; range, 55 - 80 years). • At 2 years, – Decreases in total hip BMD were seen with canagliflozin 100 and 300 mg versus Change from Drug A to B, C, or D placebo (-1.7%, -2.1%, -0.8%; differences of -0.9% and -1.2%) – No bone loss at other sites, (normal age-related bone loss, ~0.5-1.0%/year).

• Fractures tended to occur as early as 12 weeks after initiating treatment and were Add Drug A to B, or B to A primarily located in the distal parts of the upper and lower extremities. HgA1c • Why? Add Drug C – SGLT2 inhibitors increase concentrations of phosphate in serum, probably via increased tubular reabsorption, which has the potential to adversely affect bone. Add Drug D – SGLT2 inhibitors increase concentrations of parathyroid hormone (PTH). Sustained increases in PTH concentration enhance bone resorption and increase the risk for bone fractures. Time

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ADA‐EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic 1. Patient‐Centered Approach Review and Meta-analysis “...providing care that is respectful of and responsive to individual patient preferences, needs, and values ‐ ensuring that patient values guide all clinical decisions.” 204 studies analyzed

• Gauge patient’s preferred level of involvement. 50 spanned several continents, while others were • Explore, where possible, therapeutic choices. Consider using conducted across Europe, Asia and the United States. decision aids. Most of the studies were short term, with only 22 mostly • Shared Decision Making – a collaborative process between observational studies lasting more than two years patient and clinician, using best available evidence and taking into account the patient’s preferences and values

• Final decisions regarding lifestyle choices ultimately lie with the patient.

Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Ann Intern Med. 2016;164(11):740-751.

Pooled between-group differences in the change in HbA1c for comparisons of Pooled between-group differences in the change in weight for comparisons of monotherapies and metformin-based combination therapies. monotherapies and metformin-based combination therapies.

Ann Intern Med. 2016;164(11):740-751. Ann Intern Med. 2016;164(11):740-751.

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Pooled odds ratios for GI side effects for monotherapies Pooled odds ratios for mild and moderate hypoglycemia for comparisons of monotherapies and metformin-based combination therapies. and metformin-based combination therapies.

Ann Intern Med. 2016;164(11):740-751. Ann Intern Med. 2016;164(11):740-751.

Oral Pharmacologic Treatment of Type 2 Diabetes Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: Mellitus: A Clinical Practice Guideline Update From the A Clinical Practice Guideline Update From the American American College of Physicians College of Physicians Recommendation 2: ACP recommends that clinicians consider adding either a sulfonylurea, a , an SGLT-2 inhibitor, or a DPP-4 inhibitor to metformin to improve glycemic control when a second oral therapy is considered. (Grade: weak recommendation; moderate-quality evidence.) ACP recommends that clinicians and patients select among medications after discussing benefits, adverse effects, and costs.

Ann Intern Med. 2017;166(4):279-290. Ann Intern Med. 2017;166(4):279-290.

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Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: Drug Cost Comparison A Clinical Practice Guideline Update From the American Drug and Dose Cost/month College of Physicians (2014) 2017 Glucose Strips (2 per day) $66

Sulfonylurea $4-14/$50-90 Rapaglinide 2 mg tid $38-275 120 tid $58-145 100 mg tid $30-77 Metformin 1000 bid $ 4-32 /120 Canagliflozin 300 mg/d (342) $433-535 Pioglitazone 45 mg/d (12/$480) $12/$715 Sitagliptin/Saxagliptin (300) $400-450 Dulaglutide1.5 /Liraglutide 1.2mg (L-400) $750/515-650 Glargine, 45 U/d /(pen) (236) $360 Aspart/lispro/apidra (30 U/d) vial (180) $300 Pens (225) $390

24 hour fitness center $35 YMCA $65 Cross Fit $300 Ann Intern Med. 2017;166(4):279-290. Personal Trainer $1000

Clinical Inertia in People with Type 2 Diabetes • 81000 people with Type 2 DM • Followed from 2004-2011 • Median time to add another drug

HbA1c On 1 drug On 2 drugs Adding insulin if on 1-3 oral >7 2.9 7.2 8.7 >7.5 1.9 7.2 9.1 >8 1.6 6.9 9.7

Diabetes Care. 2013. 36:3411

16 Class Mechanism of Dosage Relative Major Side Effects / Interactions Weight Cost Generic Name Action Effective- / Uses Effects (Brand Name) ness (average)

Sulfonylureas Stimulate Gain glyburide insulin release 2.5-20 mg bid 1 Hypoglycemia 2 lbs (Micronase) from beta cells $ of the pancreas 5-20 mg bid (Glucotrol) 1 0.5-4 mg bid (Amaryl) 1

Meglitinides Stimulate Hypoglycemia Gain 1 lb $ insulin release 0.5-2 mg tid 1 Useful in pts on glucocorticoids (Prandin) from beta cells (before meals) and in pts with renal failure who of the pancreas often have good FBS and high BS nateglinide 60-360 mg tid 1 over the course of the day (Starlix) (before meals) Prandin is short-acting. Starlix is very short-acting Primarily 500-2000 mg 1 Diarrhea, nausea, vomiting Loss $ metformin inhibits hepatic daily with Increased risk of lactic acidosis if 2-3 lbs (Glucophage) gluconeogenesis meals impaired renal or hepatic function or heavy EtOH use. B12 deficiency Bile Acid Sequestrants esophageal obstruction, bowel 3.75 g/d obstruction, fecal impaction, Colesevelam unknown 0.7 dysphagia pancreatitis, nausea, (Welchol) (3- 625 mg tabs constipation neutral $$$ bid)

Bromocriptine improved glucose /Cyclset tolerance (enhanced Nasal Stuffiness, Nausea, headache, stimulated insulin- constrictive pericarditis, neuroleptic ---- $$- mediated glucose 0.25– 0.5 mg/d .5 malignant syndrome, hypotension $$$ disposal). 1.6-4.8 mg/d Class Mechanism of Dosage Relative Major Side Effects / Interactions Weight Cost Generic Name Action Effective- / Uses Effects (Brand Name) ness (average)

Alpha-glucosidase Inhibits enzymes 50 mg with 1st bite Gas/ GI upset Inhibitor needed to break of each meal (start 0.7 Need to use glucose to treat Loss $ acarbose down glucose in the at 12.5 mg and hypoglycemia (not a complex CHO) 1-2 lbs (Precose) small intestine titrate up over weeks) Insulin sensitizers— Weight gain, edema which is resistant to Activate receptor 1 diuretic therapy Gain $ rosiglitazone molecules inside cell 4-8 mg daily Associated with bone loss and fractures. 12 lbs (Avandia) nuclei to decrease insulin resistance pioglitazone 15-45 mg daily (Actos) 1 Incretins Nausea, Vomiting, constipation, pancreatitis exenatide 5-10 mcg bid SQ 1 (?) Renal failure Loss $$$ (Byetta) Mimics GLP-1 (gut 2mg/week Weight loss achieved through appetite 8 lbs (Bydureon) hormone which affects suppression insulin, glucagon, gastric emptying and satiety) Liraglutide 0.6-1.8 mg qd SQ Thyroid C-cell tumors at clinically relevant (Victoza) exposures in rodents.

Albiglutide 30-50 mg SC weekly (Tanzeum)

Dulaglutide (Trulicity) 0.75/1.5 mg SQ weekly sitagliptin Side effects are rare. Occ GI side effects. Neutral $$$ (Januvia) 100, 50, or 25 mg daily 0.7-1 DPP-4 inhibitor (enzyme (dose by Cr Cl) saxagliptin that breaks down GLP-1) (Onglyza) 5, 2.5 mg (for decrease creat) linagliptin (Trajenta) 5 mg (no change for creat Alogliptin 25, 12.5, or 6.25 mg (nesia) daily (dose by Cr Cl) Class Mechanism of Dosage Relative Major Side Effects / Interactions Weight Cost Generic Name Action Effective- / Uses Effects (Brand Name) ness (average)

1 SGLT 2 Inhibitor Inhibit glucose 100/300 mg Dehydration, urinary tract Loss 4 lbs $$$ reabsorption in daily infections, genital mycotic Canagliflozin infection, bone loss (Invokana) the renal proximal tubule 5 mg daily (Farxiga) 10/25 mg Empagliflozin daily (Jardiance)

Preop management program: ucsf.logicnets.com Healthy eating, weight control, increased physical activity & diabetes education Mono- therapy Metformin Efficacy* high Hypo risk low risk Weight neutral/loss Side effects GI / lactic acidosis Costs low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin Metformin Metformin Metformin Metformin Metformin + + + + + + Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal) therapy† dione inhibitor inhibitor agonist Efficacy* high high intermediate intermediate high highest Hypo risk moderate risk low risk low risk low risk low risk high risk Weight gain gain neutral loss loss gain

Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia Costs low low high high high variable

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin Metformin Metformin Metformin Metformin Metformin + + + + + + Triple Sulfonylurea Thiazolidine- DPP-4 SGLT-2 GLP-1 receptor Insulin (basal) dione Inhibitor Inhibitor agonist therapy + + + + + +

TZD SU SU SU SU TZD

or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i

or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i

or GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

§ § or Insulin or Insulin

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin + Combination injectable Basal Insulin + Mealtime Insulin or GLP-1-RA therapy‡ Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442