1. Type 2 Diabetes Mellitus (T2DM) Treatment
IM Residents, CUMC

2. Disclosure
I am a full-time employee of Daiichi Sankyo Pharma with part of my compensation in the form of their stock (I do not plan to discuss any Daiichi Sankyo products)
Steven E. Cohen, MD
Assistant Clinical Professor of Medicine,
Division of Endocrinology
Assistant Attending,
Columbia University Medical Center

3. Contents
Introduction: Approach to a patient with T2D even before considering the type of treatment
T2DM Treatment Paradigm: Evidence-based treatments to not only lower A1c but also decrease cardiovascular disease (CVD) & thus, morbidity & mortality
Sample Recommendations:
In what order & dose
Not meant to endorse a specific drug, just an example of what type of treatment you may want to consider based on published studies showing decreased CV events & mortality
Conclusions

4. Introduction
~40% of patients still do not meet targets for glycemic, blood pressure, or cholesterol control, & only 14% meet targets for all three measures & nonsmoking status
At each visit:
Determine bp
Examine feet: inspection, circulation, sensation (consider referral to a Podiatrist)
Ascertain results of last retina exam, A1c, lipids (TSH), & urinary albumin & eGFR
For insulin-requiring:
Capillary glucose w/ respect to insulin dose qac/qhs/0300, as necessary to improve control
Glucagon
Hypoglycemic symptoms & etiology (Rx, fasting, exercise)
Ensure vaccination status
Smoking cessation, if applicable
Always emphasize exercise & low-carbohydrate diet (consider referral to a Nutritionist)
Simplifying a complex treatment regimen may improve adherence: Can you achieve similar or better glucose control w/ less or different Rx?
Ensure close follow-up with Educator

6. Metformin Lowers CVD
UKPDS showed that metformin usage as monotherapy was associated with decreased risk of all-cause death or myocardial infarction compared with sulfonylureas or insulin
17 observational studies comparing DM regimens +/- metformin, metformin use was associated with:
Lower all-cause mortality among patients with heart failure, renal impairment, or chronic liver disease with hepatic impairment
Fewer CHF readmissions in patients with CHF or kidney disease
Ref:
Johnson JA, et al: Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care 25:2244–2248, 2002 Abstract/FREE Full Text
U.K. Prospective Diabetes Study Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865, 1998 CrossRefMedlineWeb of Science
Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease: A Systematic Review. Ann Intern Med 2017)

7. CV Outcome trial: EMPA-REG
>7k patients w/ T2D & established CVD were randomized to: pbo, empagliflozin 10 or 25 mg; followed for 3y
Results w/ either dose of empagliflozin, within the 1st months:
38% reduction in CV mortality
32% reduction in overall mortality
35% reduction in hospitalization for CHF
39% reduction in worsening nephropathy primarily driven by a reduction in new-onset macroalbuminuria
Given these impressive results that parallel some of the statin trials in terms of reducing CV risk & mortality, the FDA added a new indication for empagliflozin - to reduce CV death in patients with T2D & known CVD - the first CV indication for a diabetes drug
References:
Zinman B, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:
FDA news release. FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. December 2, 2016. 

8. SGLT inhibitor Adverse Events
Mycotic infections
DKA:
Affects 1/1000 patients, w/i 180d, which is twice the rate c/w DPP4i (4.9 events per 1000 person-years vs. 2.3 events per 1000 person-years) (hazard ratio, 2.1; 95% confidence interval [CI], 1.5 to 2.9) (NEJM 6/7/2017)
FDA & EMA has updated the labels of the whole class to indicate this risk
Amputation:
Canagliflozin:
2x >amputations than pbo (5.9 vs. 2.8 on pbo/1k patients) x1y
Toe & middle of the foot most common; however, amputations involving the leg, below & above the knee, also occurred
Some suffered more than one amputation, with a portion of those patients needing amputations on both limbs
Regulators: Consider factors that may predispose patients, e.g., h/of prior amputation, PVD, neuropathy, & foot ulcers
Warnings:
European Medicines Agency (EMA):
A warning included in the prescribing information stating that all drugs in this class may increase the risk for lower-limb amputation
"An increased risk has not been seen in studies with other medicines in the same class, dapagliflozin and empagliflozin. However, data available to date are limited & the risk may also apply to these other medicines”
FDA black boxed warning only for canagliflozin
Bone fracture & decreased BMD: FDA ( ) added a new Warning & Precaution and revised the Adverse Reactions for canagliflozin
Acute kidney injury: FDA strengthened warnings for dapagliflozin & canagliflozin
Stroke: Slight, insignificant risk found in EMPA-REG

9. CV Outcome trial: LEADER
>9k patients w/ T2D & high-risk CVD were randomly assigned to receive either liraglutide 1.8 mg qd or pbo; followed for 3.8y
Results:
13% reduction in MACE* driven by a 22% reduction in CV death
15% reduction in overall mortality
22% reduction in time to 1st renal event
Nonsignificant:
13% reduction in hospitalization for CHF
12% reduction in nonfatal MI
11% lower rate of nonfatal stroke 
Reference:
Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results — A Long Term Evaluation (LEADER), ): 9340 T2D followed for y, those randomized to liraglutide had a significant 13%  in major adverse cardiac events (MACE), driven by 22% CV death
*MACE = 3-point Major Adverse Cardiac Event components: CV death, nonfatal MI, or nonfatal stroke

10. CV Outcome Trial: Semaglutide (Ozempic, SUSTAIN)
>3k patients w/ T2D & high-risk CVD were randomly assigned to receive either once-weekly semaglutide 0.5 mg or 1.0 mg or pbo, sc, for 2 y
Methods: Hypothesized that semaglutide would be noninferior to pbo for MACE 
Results:
1 mg dose: A1c lowering of 1%; weight loss of 4.3 kg
26% reduction in MACE* driven by a significant (39%) decrease in nonfatal stroke & a nonsignificant (26%) decrease in nonfatal MI, with no significant difference in CV death
Lower risk of new or worsening nephropathy, according to differences in macroalbuminuria
Higher risk of retinopathy with an unexpected higher rate of retinopathy complications (vitreous hemorrhage, blindness, or the need for treatment with an intravitreal agent or photocoagulation): 5 patients developed diabetes related blindness c/w 1 in pbo (possibly due to improvement in glucose: it is known from the DCCT that retinopathy worsens when blood glucose is better controlled)
FDA approval ( )
Reference:
*MACE = 3-point Major Adverse Cardiac Event components: CV death, nonfatal MI, or nonfatal stroke

12. AWP = Average Wholesale Price; NADAC = National Average Drug Acquisition Cost

13. Sample Recommendations
Tailor Rx to not only safely achieve an A1c goal of <7%, but also to decrease CVD
Beginning monotherapy: Metformin po 500 mg bid w/ meals then 1 g bid w/ meals
If does not reach goal in 3 mo or starting A1c ≥9%, add one of the following:
GLP-1 agonists: e.g., liraglutide (Victoza) sc 0.6 mg qd x 1w then 1.2 to 1.8 mg qd
SGLT inhibitors: e.g., empagliflozin (Jardiance) po 10 mg qAM then 25 mg qAM
If does not reach goal in another 3 mo:
Consider triple therapy or beginning basal insulin (e.g., glargine 10 U)
Will a GLP-1 agonist + an SGLT inhibitor have incremental beneficial effects on CVD?
If starting A1c ≥10% or symptomatic: Consider basal insulin (e.g., glargine 10 U)

14. Remaining Questions
Given these impressive results with these newer agents, should metformin continue to be our 1st line agent?
Are the positive effects seen with liraglutide & empagliflozin class effects or do only these specific compounds have these effects?
Conversely, are the adverse events seen with some SGLT inhibitors specific to those drugs or are they a class effect?
Is the CV improvement with these drugs only in patients with established CVD?
Combinations of a GLP-1 agonist + an SGLT inhibitor have been shown to incrementally decrease A1c & body weight, however, will this translate into additional beneficial effects on CV morbidity & mortality?
What are the mechanisms for both the beneficial effects & adverse events that may help us proactively identify which patients should, or should not, be treated with these agents?
Clearly, more work is required to address these questions & is the focus of both ongoing molecular & clinical studies

15. Conclusions Make sure you ascertain at each visit:
Bp, foot exam, results of recent retina exam
A1c, lipids (TSH), & urinary albumin & eGFR; capillary glucose readings
Hypoglycemic symptoms & etiology; vaccinations; smoking cessation, if applicable
Attempt to tailor Rx to not only safely achieve an A1c goal of <7%, but also consider how you may achieve this biomarker with decreased CVD that may include, in addition to metformin, GLP-1 agonists &/or SGLT inhibitors
Close follow-up with an Educator to ensure optimal therapy

16. Back-up

17. Negative CV Outcome Studies
DPP4i’s:
Sitagliptin (TECOS trial = Trial Evaluating Cardiovascular Outcomes with Sitagliptin)
SAVOR (= Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with DM) study with saxagliptin (Onglyza, BMS/AZ) & EXAMINE trial of alogliptin (Nesina, Takeda) both carry warnings about heart failure on their US labels: especially in patients with preexisting kidney or CVD
Glargine (ORIGIN trial)
Acarbose (ACE study, STOP-NIDDM)
Canagliflozin (CANVAS):
Lixisenatide; Exenatide XR
Note: Pioglitazone (Insulin Resistance Intervention after Stroke = IRIS study) was in non-diabetic patients

18. GLP-1 agonists
Po qd:
TTP-273 (Vtv): Ph2; +metformin: mean pbo subtracted HbA1c -0.86% w/o N/V (ADA )
Semaglutide (NN): Ph3; mg where higher dose: lowers A1c 9% & weight 7 kg, but N 33%, V 20%
Sc: Qd
Liraglutide (Victoza, NN): FDA approved 2010
Lixisenatide (Lyxumia, Sanofi): T1/2 ~3h; failed to show CV outcome benefits
Once-weekly:
Exenatide XR (Bydureon, AZ): 14% reduction in the risk of death from any cause but failed to significantly decrease combined risk of heart attack, stroke & CV death - possibly b/c the population was too broad (EASD )
Albiglutide (Tanzeum, GSK)
Semaglutide (Ozempic, NN) 0.5 mg or 1.0 mg: vs. pbo for 104 weeks (NEJM 2016)
Dulaglutide (Trulicity, Lilly): Not yet posted CV Outcome data
Sc GLP-1 + basal insulin: FDA approved iGlarLixi =LixiLan = Soliqua (100/33, Sanofi) = glargine (15-60) + lixisenatide (5-20, Adlyxin, Zealand); $20/d 2. Xultophy (100/3.6, Novo) = degludec (Tresiba) + liraglutide: better b/c liraglutide improves CVO; $16/d
Exenatide XR 2 mg/w (Bydureon, AZ) + dapagliflozin 10 mg/d (Farxiga/Forxiga, AZ) x28w: dec: A1c 2%, BW 3.4 kg, SBP 4 mm Hg

19. SGLT-2 inhibitors
empagliflozin (Jardiance, Boehringer Ingelheim & Lilly):
+ metformin = Synjardy XR
SGLT2i + DPP4i: - Qtern (AZ) = saxagliptin (Onglyza) 5 mg + dapagliflozin (Farxiga) 10 mg (FDA ) - Glyxambi (Lilly/BI) = linagliptin (Tradjenta) + empagliflozin (Jardiance) (FDA )
Ertugliflozin (Steglatro, Merck/Pfizer): approved 12/2017 w/ two combination versions:
Steglujan: w/ sitagliptin: PBO-subtracted A1c drop 1.2%
Segluromet w/ metformin

20. Newer insulins
Degludec (Tresiba, NN): T1/2 42h; 54% <nocturnal hypo & 27% <overall hypo than glargine
Fiasp (NN)
Faster-acting, mealtime version of insulin aspart (Novolog) for the treatment of T1 & T2DM in adults
injection 100 units/mL
Niacinamide (vitamin B3) has been added to help increase the speed of the initial insulin absorption
Dosed at the beginning of a meal or within 20 minutes after starting a meal, as the insulin will appear in the blood approximately 2.5 minutes after dosing
FDA approved: will be available in a prefilled delivery device, the FlexTouch pen, and a 10-mL vial; not approved for use in insulin pumps

21. Rx: T2DM Consider dual Rx when A1C ≥9%
Consider metformin + basal insulin + mealtime insulin or GLP-1-RA if BG ≥300 mg/dL &/or A1C ≥10%, especially w/ symptomatic/catabolic features, in which case basal insulin + mealtime insulin is the preferred initial regimen
Drugs not shown in figure (S34) due to modest efficacy, frequency of administration &/or AEs:
Meglitinide:
Rapid-acting secretagogue in patients w/ irregular meal schedules or those who develop late postprandial hypoglycemia on a SU
e.g., repaglinide, nateglinide
α-glucosidase inhibitors: Acarbose, miglitol; A1c ~0.7%, tid, flatulance
Bile acid sequestrant: Colesevelam (Wellchol): LDL, no hypoglycemia; A1c 0.5%, constipation, TG
Dopamine-2 agonist: Bromocriptine (Cycloset): dizziness, syncope, fatigue, nausea
Pramlintide (See Rx - T1D)

22. Glyburide: AE of the labeling was updated to include bullous reactions, erythema multiforme, & exfoliative dermatitis

23. From Pharma to Clinic: Disease Biomarkers & Complications
Thrombosis
Hypertension
Dyslipidemia
Retinopathy
Neuropathy
T2D
Nephropathy
Heart Failure
Obesity
Stroke
ACS/AMI
PVD
VTE
“Biomarkers”
Complications
In drug development we necessarily target biomarkers, especially in preclinical & early clinical studies, however our end-game is prevention of CV morbidity & mortality
Therefore, we look for drugs that achieve a BMI of <25 kg/m2, bp <130/80 mm Hg, LDL <~70 mg/dL, & HbA1c <7.0%, in the hope that this will translate into better patient outcomes
However, there is not necessarily a correlation between which compound, for example, lowers HbA1c the most & which lowers CVD the most
VTE = Venous Thromboembolism
ACS = Acute Coronary Syndrome
AMI = Acute Myocardial Infarction
PVD = Peripheral Vascular Disease