1. Diabetes Medication Update for Healthcare Professionals
21 May 2016
Joyce M. Vergili, EdD, RD, CDN, CDE, FAND
Doctor of Education (Nutrition Education)
Registered Dietitian | Certified Dietitian-Nutritionist
Certified Diabetes Educator
Fellow of the Academy of Nutrition and Dietetics

2. Overarching Objective
This session will
increase your knowledge of 8 of the 12 classes of FDA-approved diabetes medications, with an emphasis on those approved since 2012
enhance your confidence when
assessing and educating patients
discussing patients who take these medications with physicians and other healthcare professionals

3. Specific Objectives At the end of the program, you should be able to ...
explain the underlying metabolic defects of Type 2 diabetes for which medications have been developed:
insulin resistance
progressive decrease in insulin production
blunted incretin response
increased renal threshold for glucose

4. Objectives At the end of the program, you should be able to ...
identify the metabolic defect(s) that each of the following classes of diabetes medications address:
biguanides (metformin)
insulin sensitizers (TZD)
insulin secretagogues (sulfonylureas & meglitinides)
incretin-based therapies (DPP-4i & GLP-1 RA)
sodium-glucose co-transporter-2 (SGLT2) inhibitors
insulin

5. Objectives At the end of the program, you should be able to ...
accurately describe the mechanisms of action, safety, efficacy, contra-indications, and major patient-education teaching points for medications receiving FDA approval since 2012
GLP-1 Receptor Agonists
Bydureon (Exenatide Extended-Release) (2012)
Tanzeum (Albiglutide) (April 2014)
Trulicity (Dulaglutide) (Sept 2014)
Dipeptidyl Peptidase 4 (DPP-4) Inhibitors
Nesina (Alogliptin) (2013)
Kazano (Alogliptin + Metformin)
Oseni (Alogliptin + Pioglitazone)

6. … cont’d … Medications receiving FDA approval since 2012
SGLT-2 Inhibitors
Invokana (Canagliflozin) (2013)
Invokamet: Canagliflozin / Metformin (Aug 2014)
Farxiga (Dapagliflozin) (Jan 2014)
Xigduo XR (Dapagliflozin + Metformin XR) (Oct 2014)
Jardiance (Empagliflozin) (Aug 2014)
Glyxambi (Empagliflozin + Linagliptin) (Feb 2015)
Synjardy (Empagliflozin + Metformin HCl) (Aug 2015)
Insulin
Afrezza – insulin inhalation powder (June 2014)
Toujeo (Glargine) SoloSTAR pen U-300 (Feb 2015)
Humalog U-200 KwikPen (May 2015)
Tresiba (Degludec) FlexTouch U-100 & U-200 (Sept 2015)
Humulin R U-500 KwikPen (Jan 2016)

7. Objectives At the end of the program, you should be able to ...
identify reliable resources for more information

8. A Short History of Medication options for Type 2 Diabetes
From the 1950’s until 1994, there were only 2 classes of diabetes medications:
Sulfonylureas
Insulin
1994: Metformin
1999: Thiazolidinediones (Rosiglitazone [Avandia] & Pioglitazone [Actos])
. . . Fast forward . . .

9. March 2013: Invokana (Canagliflozin) – an SGLT2 inhibitor  12 Classes of Meds
Oral
Injectable
Biguanides (Metformin)
Sulfonylureas
Meglitinides
Thiazolidinediones (TZD)
-glucosidase inhibitors*
DPP-4 Inhibitors
Bromocriptine (Cycloset)*
Colesevalam (Welchol)*
Sodium-glucose co-transporter-2 (SGLT2) inhibitors
GLP-1 Receptor Agonists
Pramlintide (Symlin)*
12 (a). Insulin
Insulin
secretagogues
Inhalable
12 (b). Insulin
* α-glucosidase inhibitors, colesevalam, bromocriptine, pramlintide – generally not recommended due to modest efficacy, frequency of administration and/or limiting side effects.

10. Type 2 Diabetes (T2DM)
Type 2 diabetes is due to a progressive loss of insulin secretion on the
background of insulin resistance
There are 4 different types of diabetes, all of which are characterized by chronically elevated blood glucose.
In patients with type 1 diabetes, production of insulin by the pancreas is completely absent.
Patients with type 2 diabetes have elevated blood glucose because of a defect in the ability of the pancreas to secrete insulin and/or a defect in the body’s ability to use insulin (ie, insulin resistance).
A less common type of diabetes that is diagnosed during pregnancy and is not clearly overt diabetes is called gestational diabetes.
The fourth category of diabetes is a catch-all that includes diabetes that is caused by specific events, such as pancreatic diseases (eg, cystic fibrosis) and exposure to certain drugs or chemicals (eg, steroids).
Reference
ADA. Standards of medical care in diabetes – Diabetes Care ;34(Suppl 1):S11-S61.
ADA. Diabetes Care. 2016;39 (Suppl 1), pg S13

11. Metabolic Defect #1 in T2DM:
Insulin Resistance
Decreased glucose uptake by muscles & adipose tissue
Increased hepatic glucose output
Following an overnight fast, the liver of nondiabetic individuals produces glucose at the rate of ~2 mg/kg per min. In type 2 diabetes, the rate of basal HGP is increased, averaging ~2.5 mg/kg per min. This overproduction of glucose by the liver occurs in the presence of fasting plasma insulin levels that are increased fold, indicating severe resistance to the suppressive effects of insulin on HGP. The increase in basal HGP is explained entirely by an increase in hepatic gluconeogenesis. DeFronzo, From the Triumvirate to the Ominous Octect: A New Paradigm for the Treatment of T2 DM, Diabetes, vol 58, April 2009, pp

12. Metabolic Defect #2 in T2DM: Progressive Loss of Insulin Secretion
By the time T2 diabetes is diagnosed, -cell function may have declined by 50% or more
There are 4 different types of diabetes, all of which are characterized by chronically elevated blood glucose.
In patients with type 1 diabetes, production of insulin by the pancreas is completely absent.
Patients with type 2 diabetes have elevated blood glucose because of a defect in the ability of the pancreas to secrete insulin and/or a defect in the body’s ability to use insulin (ie, insulin resistance).
A less common type of diabetes that is diagnosed during pregnancy and is not clearly overt diabetes is called gestational diabetes.
The fourth category of diabetes is a catch-all that includes diabetes that is caused by specific events, such as pancreatic diseases (eg, cystic fibrosis) and exposure to certain drugs or chemicals (eg, steroids).
Reference
ADA. Standards of medical care in diabetes – Diabetes Care ;34(Suppl 1):S11-S61.

13. Metabolic Defect #2 in T2DM: Progressive Loss of Insulin Secretion
Decreased insulin secretion from -cells of the pancreas
Following an overnight fast, the liver of nondiabetic individuals produces glucose at the rate of ~2 mg/kg per min. In type 2 diabetes, the rate of basal HGP is increased, averaging ~2.5 mg/kg per min. This overproduction of glucose by the liver occurs in the presence of fasting plasma insulin levels that are increased fold, indicating severe resistance to the suppressive effects of insulin on HGP. The increase in basal HGP is explained entirely by an increase in hepatic gluconeogenesis. DeFronzo, From the Triumvirate to the Ominous Octect: A New Paradigm for the Treatment of T2 DM, Diabetes, vol 58, April 2009, pp

14. Metabolic Defect #3 in T2DM: Blunted Incretin Effect
Progressive deficiency of GLP-1 (glucagon-like peptide-1)
Progressive β-cell resistance to the action of GIP (glucose-dependent insulinotropic polypeptide )
This conceptual diagram shows the effects of type 2 diabetes, which is begins years before it is diagnosed, and is progressive.1
Insulin resistance rises during disease development and continues to rise during pre-diabetes (impaired glucose tolerance [IGT] and impaired fasting glucose [IFG]), eventually stabilizing in type 2 diabetes.1 Initially, the rate of insulin secretion by beta cells increases to compensate for the decrease in insulin effectiveness due to insulin resistance.2 However, when beta cells fail to compensate (where lines diverge), patients become symptomatic, which is the point in the natural history when patients are usually diagnosed with type 2 diabetes. The initial increase in insulin secretion is often misperceived as an increase in beta-cell function.
In fact, we have seen that beta-cell function progressively declines long before diabetes is diagnosed.3 Therefore, beta-cell function is decreasing even with an increase in insulin secretion because of the ability of healthy beta cells to compensate for the increased metabolic load that accompanies insulin resistance. Over time, beta-cell compensatory function deteriorates causing insulin secretion to decrease.
Abnormalities in the incretin axis have been shown to have an important role in the progression of type 2 diabetes.4 Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) account for 90% of the incretin effect. In type 2 diabetes, there is both a deficiency of GLP-1 and resistance to the stimulatory effect of GLP-1 on insulin secretion. In addition, there is resistance to the action of GIP. The deficiency of GLP-1 can be observed in individuals with IGT and worsens progressively with progression to type 2 diabetes.
“Islet cell function is not necessarily irreversible. Enhancing insulin action relieves B-cell secretory burden, and any intervention that improves glycemia – from energy restriction to bariatric surgery – can ameliorate B-cell dysfunction to an extent.” Inzucchi, Mgt of Hyperglycemia in T2DM: A Pt-Centered Approach (Position Statement) Diab Care 2012
References
1Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Am J Med. 2009;122:S37-S50.
2DeFronzo RA. The triumvirate: β-cell function, muscle, liver. A collusion responsible for NIDDM. Diabetes ;37:
3Lebovitz HE. Insulin secretagogues: old and new. Diabetes Rev. 1999;7: DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:
Kendall DM et al. Am J Med. 2009;122:S37-S50.

15. Incretins: GLP-1 (glucagon-like peptide-1) & GIP (glucose-dependent insulinotropic polypeptide)
Proteins that are secreted by the small intestine when food is ingested
Stimulate β-cells to secrete insulin
Inhibit glucagon secretion from α-cells
Rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4)
In T2DM, incretin effect is blunted

16. Metabolic Defect #4 in T2DM
Kidneys:
Renal glucose threshold is increased to ~ mg/dL from normal threshold of ~180 mg/dL

17. Medications that Address Each of these Metabolic Defects
Insulin resistance
Liver
Muscle and adipose tissue
Decreased insulin secretion
Blunted incretin effect
Increased renal glucose threshold

18. Medication to Address:
Metabolic Defect:
Insulin resistance: Increased hepatic glucose output
Medication to Address:
Biguanides – ↓ hepatic glucose output
Metformin (Glucophage, Glumetza, Fortamet)
“First line therapy,” if not contraindicated
Contraindicated in hepatic impairment and HF
Until April, contraindicated in all patients with renal impairment . . .
Following an overnight fast, the liver of nondiabetic individuals produces glucose at the rate of ~2 mg/kg per min. In type 2 diabetes, the rate of basal HGP is increased, averaging ~2.5 mg/kg per min. This overproduction of glucose by the liver occurs in the presence of fasting plasma insulin levels that are increased fold, indicating severe resistance to the suppressive effects of insulin on HGP. The increase in basal HGP is explained entirely by an increase in hepatic gluconeogenesis.
DeFronzo, From the Triumvirate to the Ominous Octect: A New Paradigm for the Treatment of T2 DM, Diabetes, vol 58, April 2009, pp

19. Drug Safety Communication – Revised Warnings for Certain Patients with Reduced Kidney Function
After reviewing medical literature, FDA concluded that metformin can be used safely in some patients with mild or moderate kidney impairment
FDA is requiring changes to metformin labeling:
Metformin is contraindicated if eGFR <30 mL/min
Starting metformin if eGFR is between 30 and 45 mL/min is not recommended
Obtain an eGFR at least annually
In pts on metformin whose eGFR later falls <45, assess benefits and risks  

20. First-line therapy: Metformin
This is in your hand-out packet (pg 1)
ADA, Diabetes Care, 2016;39 (Suppl 1), pg S54
Diabetes Care 2012;35:1364–1379

21. This is in your hand-out packet (pg 2)
Few adverse events
and/or possible benefits
Use with caution
Order of medications represents a suggested hierarchy of usage; length of line reflects strength of recommendation
Garber et al, AACE comprehensive diabetes management algorithm, Endocrine Practice 2016;22(1):84-113

22. Medications to Address:
Metabolic Defect:
Insulin resistance (decreased glucose uptake by muscles & adipose tissue)
Medications to Address:
Thiazolidinediones (TZD):
 insulin sensitivity in muscle & adipose tissue by increasing the production of glucose transporters (GLUT-4)
Rosiglitazone (Avandia)
Pioglitazone (Actos)
Disadvantages:
Weight gain
Edema / heart failure
Bone fx (limbs, not hip)
Bladder cancer (?)

23. A Tale of Two TZDs Rosiglitazone (Avandia)
The FDA had restricted the distribution of Avandia in 2010 and ordered that the following boxed warning be placed on the package insert: “Taking rosiglitazone may increase the risk that you will experience a heart attack.”
In 2013, the FDA lifted prescribing restrictions on the basis of a re-analysis of the data from the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) trial, determining that there is insufficient evidence to conclude that Rosiglitazone increases the risk for CV outcomes.
“The independent readjudication of RECORD was conducted by the Duke Clinical Research Institute (DCRI) at the request of the FDA. The analysis included follow-up for mortality for 25,833 person-years, including an additional 328 person-years identified during a re-evaluation. Overall, researchers reported 184 CV or unknown-cause deaths (88 rosiglitazone, 96 metformin/sulfonylurea) and 113 patients with stroke (50 rosi, 63 met/sulf). The HR for rosi vs met/sulf for the endpoint of CV death/MI/stroke was 0.95 (95% CI, ) vs (95% CI, ) for the original RECORD. Treatment comparisons for MI (HR=1.13; 95% CI, ) and mortality (HR=0.86; 95% CI, ) also were the same compared with the original results. [Ref for RECORD: Home PD, Pocock SJ, Beck-Nielsen H et al, Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial, Lancet 2009; 373(9681): ]
During the advisory panel meeting, most members agreed that the HRs and CIs from the analyses were consistent and the drug did NOT increase risk for all-cause or CV mortality. Even so, the RECORD trial design, reliability of CV endpoints, the drug’s contraindication with statins and the absence of data on major adverse CV events came under fire. …
“The statin issue is very much up in the air, and given the number of diabetic patients that will end up on statins, I have lingering concerns about toxicity,” panel member T. Mark Woods, ParhmD.
“With 13 years since the FDA approval, the drug is still lacking conclusive evidence. Rehashing clinical trial data only goes so far. Improved real-time surveillance is critical,” Ralph G. Brindis, president-elect of the American College of Cardiology.
The European Medicines Agency (EMA) chose to ban rosiglitazone in Europe.
Only about 4600 pts in the US are currently using Rosi.
Home PD, Pocock SJ, Beck-Nielsen H et al, Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial, Lancet 2009; 373(9681):
Costa C. Resurrecting rosiglitazone: FDA panel recommendation could affect its use. Endocrine Today 2013;12(7):1,10-12.

24. A Tale of Two TZDs Pioglitazone (Actos)
Possible association with bladder cancer
“largely refuted” (AACE Consensus Statement, Garber 2016)
“…pioglitazone is associated with an increased risk of bladder cancer” (145,806 pts followed between 2000 & 2014; 63% higher risk of bladder cancer)
(Dormandy 2009; Lewis 2011; Lewis 2015;
Inzucchi 2015; Garber 2016; Tuccori 2016)
In 10,000 patient-years, there were
10 cases of bladder cancer in pt on Pio > 12 mo
7 cases of bladder cancer in pt not on Pio
10/7 = Relative Risk (RR) of 1.4
Correct translation: There is a 40% increased relative risk of developing bladder cancer for T2DM pt taking pio as compared to T2DM pt NOT taking pio.
Incorrect translation: 40% of people on Pio will get bladder cancer.

25. Medications to Address:
Metabolic Defect:
Decreased insulin secretion from -cells of the pancreas
Medications to Address:
Insulin Secretagogues -  insulin secretion
Sulfonylureas (SFU)
Glipizide (Glucotrol)
Glyburide (Micronase)
Glimepiride (Amaryl)
Meglitinides (“glinides”)
Nateglinide (Starlix)
Repaglinide (Prandin)
Disadvantages:
Weight gain
Hypoglycemia
Low durability

26. Sulfonylureas – low durability
DeFronzo 2009

27. Incretin-Based Therapies
Medications that Address the Metabolic Defect of the
“Blunted Incretin Effect” –
Incretin-Based Therapies

28. Levels of Incretin Hormones Decrease as Diabetes Progresses
Incretins (GLP-1 & GIP)
Byetta (Exenatide) – a GLP-1 Receptor Agonist – FDA-approved in 2005
injectable
Januvia (Sitagliptin) – a DPP-4 inhibitor – FDA- approved in 2006
oral

29. Today, we have 9 FDA-approved Incretin-Based Therapies
DPP-4 Inhibitors (oral)
Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Linagliptin (Tradjenta)
Alogliptin (Nesina) (Jan 2013)
GLP-1 Receptor Agonists (injectable)
Exenatide (Byetta)
Liraglutide (Victoza)
Exenatide extended-release (Bydureon) (Jan 2012)
Albiglutide (Tanzeum) (April 2014)
Dulaglutide (Trulicity) (Sept 2014)

30. Role of Incretin Hormones in Glucose Metabolism
When food is ingested, the intestines secrete the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide)
 Insulin
 Glucagon
 Glucose
How Incretins Work
Eating a meal causes the intestines to release incretin hormones, GLP-1 and GIP, into the blood. These incretins stimulate insulin release from the pancreas, resulting in lowered blood sugar. GLP-1 also decreases blood glucose by reducing the secretion by the pancreas of the hormone glucagon, a hormone that increases the production of glucose by the liver and raises the blood level of glucose. Thus, GLP-1 and GIP lower blood glucose
The body also produces an enzyme called DPP-4 that breaks down incretin hormones
1. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:
2. Aroda VR, Henry RR. Incretin hormones in diabetes and metabolism. cme.medscape.com/viewarticle/474380_3. Accessed 24 June 2010.
3. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
Incretin hormones stimulate insulin secretion in a glucose-dependent manner 30

31. Incretin Hormones are then Degraded by DPP-4
DPP-4 is an enzyme that rapidly breaks down the incretins
(half-life of incretins is only ~2 minutes) 31

32. Incretin-Based Therapies: DPP-4 Inhibitors (oral)
 Insulin
 Glucagon
DPP-4
 Glucose
DPP-4 inhibitors slow down the inactivation of incretin hormones, thereby prolonging their survival.
The resulting higher concentration of active incretins
increases insulin secretion in a glucose-dependent manner
suppresses glucagon secretion.
“Smart secretagogues” 32

33. S/Sx pancreatitis and Sx of hypersensitivity/allergic reactions
DPP-4 inhibitors (see hand-out packet, pg 3)
In general
Sitagliptin
Saxagliptin
Linagliptin
Alogliptin
Efficacy
↓ A1C by ~0.75 percentage points
↓ A1C by ~0.7 to 0.8 percentage points
↓ A1C by ~0.5 to 0.9 percentage points
↓ A1C by ~0.4 to 0.7 percentage points
↓ A1C by ~0.4 to 0.6 percentage points
Advantages
Low risk of hypoglycemia
Weight neutral
No dose change needed for ↓ renal function
High selectivity for DPP-4 enzyme
Dosing
Once daily, without regard to time of day, without regard to food (take same time everyday)
100 mg in normal renal
50 mg / 25 mg in moderate / severe renal impairment
5 mg in normal renal function
2.5 in renal impairment
5 mg/day for all – no dose adjustment needed in renal disease
25 mg in normal renal
12.5 mg / 6.25 mg in moderate / severe renal impairment
Common side effects
“Cold” symptoms
URI, nasopharyngitis, headache
URI, UTI,
headache
Nasopharyngitis
Most serious potential side effects
Ac. pancreatitis, hypersensitivity reactions, joint pain, heart failure[?]
Ac. pancreatitis, ac. renal failure, allergic & hyper-sensitivity rxns (eg, anaphylaxis)
Acute pancreatitis & serious hypersensitivity reactions
Pancreatitis
Ac. Pancreatitis; hypersensitivity reactions; hepatic failure, sometimes fatal
Patient Ed
S/Sx pancreatitis and Sx of hypersensitivity/allergic reactions
Acute pancreatits – no causality established (more on that later!)
Joint pain – Aug 2015 FDA issued warning that DPP4i may cause joint pain that can be severe and disabling.
Heart failure – to be discussed!

34. S/Sx pancreatitis and Sx of hypersensitivity/allergic reactions
DPP-4 inhibitors
In general
Sitagliptin
Saxagliptin
Linagliptin
Alogliptin
Efficacy
↓ A1C by ~0.75 percentage points
↓ A1C by ~0.7 to 0.8 percentage points
↓ A1C by ~0.5 to 0.9 percentage points
↓ A1C by ~0.4 to 0.7 percentage points
↓ A1C by ~0.4 to 0.6 percentage points
Advantages
Low risk of hypoglycemia
Weight neutral
No dose change needed for ↓ renal function
High selectivity for DPP-4 enzyme
Dosing
Once daily, without regard to time of day, without regard to food (take same time everyday)
100 mg in normal renal
50 mg / 25 mg in moderate (GFR ml/min) / severe (GFR <30) renal impairment
5 mg in normal renal function
2.5 in renal impairment
5 mg/day for all – no dose adjustment needed in renal disease
25 mg in normal renal
12.5 mg / 6.25 mg in moderate / severe renal impairment
Common side effects
“Cold” symptoms
URI, nasopharyngitis, headache
URI, UTI,
headache
Nasopharyngitis
Most serious potential side effects
Ac. pancreatitis, hypersensitivity reactions, joint pain, heart failure [?]
Ac. pancreatitis, ac. renal failure, allergic & hyper-sensitivity rxns (eg, anaphylaxis)
Acute pancreatitis & serious hypersensitivity reactions
Pancreatitis
Ac. Pancreatitis; hypersensitivity reactions; hepatic failure, sometimes fatal
Patient Ed
S/Sx pancreatitis and Sx of hypersensitivity/allergic reactions

35. S/Sx pancreatitis and Sx of hypersensitivity/allergic reactions
DPP-4 inhibitors
In general
Sitagliptin
Saxagliptin
Linagliptin
Alogliptin
Efficacy
↓ A1C by ~0.75 percentage points
↓ A1C by ~0.7 to 0.8 percentage points
↓ A1C by ~0.5 to 0.9 percentage points
↓ A1C by ~0.4 to 0.7 percentage points
↓ A1C by ~0.4 to 0.6 percentage points
Advantages
Low risk of hypoglycemia
Weight neutral
No dose change needed for ↓ renal function
High selectivity for DPP-4 enzyme
Dosing
Once daily, without regard to time of day, without regard to food (take same time everyday)
100 mg in normal renal
50 mg / 25 mg in moderate (GFR ml/min) / severe (GFR <30) renal impairment
5 mg in normal renal function
2.5 in renal impairment
5 mg/day for all – no dose adjustment needed in renal disease
25 mg in normal renal
12.5 mg / 6.25 mg in moderate / severe renal impairment
Common side effects
“Cold” symptoms
URI, nasopharyngitis, headache
URI, UTI,
headache
Nasopharyngitis
Most serious potential side effects
Ac. pancreatitis, hypersensitivity reactions, joint pain, heart failure[?]
Ac. pancreatitis, ac. renal failure, allergic & hyper-sensitivity rxns (eg, anaphylaxis)
Ac. pancreatitis, serious hypersensitivity reactions, heart failure [?]
Pancreatitis
Ac. Pancreatitis; hypersensitivity reactions; hepatic failure, sometimes fatal
Patient Ed
S/Sx pancreatitis and Sx of hypersensitivity/allergic reactions

36. S/Sx pancreatitis and Sx of hypersensitivity/allergic reactions
DPP-4 inhibitors
In general
Sitagliptin
Saxagliptin
Linagliptin
Alogliptin
Efficacy
↓ A1C by ~0.75 percentage points
↓ A1C by ~0.7 to 0.8 percentage points
↓ A1C by ~0.5 to 0.9 percentage points
↓ A1C by ~0.4 to 0.7 percentage points
↓ A1C by ~0.4 to 0.6 percentage points
Advantages
Low risk of hypoglycemia
Weight neutral
No dose change needed for ↓ renal function
High selectivity for DPP-4 enzyme
Dosing
Once daily, without regard to time of day, without regard to food (take same time everyday)
100 mg in normal renal
50 mg / 25 mg in moderate / severe renal impairment
5 mg in normal renal function
2.5 in renal impairment
5 mg/day for all – no dose adjustment needed in renal disease
25 mg in normal renal
12.5 mg / 6.25 mg in moderate / severe renal impairment
Common side effects
“Cold” symptoms
URI, nasopharyngitis, headache
URI, UTI,
headache
Nasopharyngitis
Most serious potential side effects
Acute pancreatitis & hypersensitivity reactions, joint pain, heart failure[?]
Ac. pancreatitis, ac. renal failure, allergic & hyper-sensitivity rxns (eg, anaphylaxis)
Ac. pancreatitis, serious hypersensitivity reactions, heart failure [?]
Pancreatitis
Ac. Pancreatitis; hypersensitivity reactions; hepatic failure, sometimes fatal
Patient Ed
S/Sx pancreatitis and Sx of hypersensitivity/allergic reactions

37. S/Sx pancreatitis and Sx of hypersensitivity/allergic reactions
DPP-4 inhibitors
Newest DPP-4 inhibitor (2013)
In general
Sitagliptin
Saxagliptin
Linagliptin
Alogliptin
Efficacy
↓ A1C by percentage points
↓ A1C by ~0.7 to 0.8 percentage points
↓ A1C by ~0.5 to 0.9 percentage points
↓ A1C by ~0.4 to 0.7 percentage points
↓ A1C by ~0.4 to 0.6 percentage points
Advantages
Low risk of hypoglycemia
Weight neutral
No dose change needed for ↓ renal function
Only DPP-4 avail in combination with a TZD (pio) (Oseni)
Dosing
Once daily, without regard to time of day, without regard to food (take same time everyday)
100 mg in normal renal
50 mg / 25 mg in moderate / severe renal impairment
5 mg in normal renal function
2.5 in renal impairment
5 mg/day for all – no dose adjustment needed in renal disease
25 mg in normal renal
12.5 mg / 6.25 mg in moderate / severe renal impairment
Common side effects
“Cold” symptoms
URI, nasopharyngitis, headache
URI, UTI,
headache
Nasopharyngitis
Most serious potential side effects
Ac. pancreatitis, hypersensitivity reactions, joint pain, heart failure[?]
Ac. pancreatitis, ac. renal failure, allergic & hyper-sensitivity rxns (eg, anaphylaxis)
Ac. pancreatitis, serious hypersensitivity reactions, heart failure [?]
Pancreatitis
Ac. pancreatitis; hypersensitivity reactions; hepatic failure, sometimes fatal
Patient Ed
S/Sx pancreatitis and Sx of hypersensitivity/allergic reactions
Alogliptin (Nesina): Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly discontinue Nesina . . .
Alogliptin is a highly selective inhibitor of DPP-4, demonstrating > 10,000 times more selectivity for DPP-4 than for other related proteases. After oral administration of alogliptin in a range of doses from 25 to 800 mg, mean DPP-4 inhibition ranged from 93 to 99%, with mean inhibition at 24 hours after dosing ranging from 74 to 97%. (Levien 2009)
The clinical significance of this remains uncertain. (Tanzi 2013)

38. Sx pancreatitis and hypersensitivity/allergic reactions
DPP-4 inhibitors
In general
Sitagliptin
Saxagliptin
Linagliptin
Alogliptin
Efficacy
↓ A1C by percentage points
↓ A1C by ~0.7 to 0.8 percentage points
↓ A1C by ~0.5 to 0.9 percentage points
↓ A1C by ~0.4 to 0.7 percentage points
↓ A1C by ~0.4 to 0.6 percentage points
Advantages
Low risk of hypoglycemia
Weight neutral
No dose change needed for ↓ renal function
Only DPP-4 avail in combination with a TZD (pio);
No ↑ CV risk
Dosing
Once daily, without regard to time of day, without regard to food (take same time everyday)
100 mg in normal renal
50 mg / 25 mg in moderate / severe renal impairment
5 mg in normal renal function
2.5 in renal impairment
5 mg/day for all – no dose adjustment needed in renal disease
25 mg in normal renal
12.5 mg / 6.25 mg in moderate / severe renal impairment
Common side effects
“Cold” symptoms
URI, nasopharyngitis, headache
URI, UTI,
headache
Nasopharyngitis
Most serious potential side effects
Acute pancreatitis & hypersensitivity reactions, joint pain, heart failure[?]
Ac. pancreatitis, ac. renal failure, allergic & hyper-sensitivity rxns (eg, anaphylaxis)
Ac. pancreatitis, serious hypersensitivity reactions, heart failure [?]
Pancreatitis
Ac. pancreatitis; hypersensitivity reactions; hepatic failure, sometimes fatal
Patient Ed
Sx pancreatitis and hypersensitivity/allergic reactions

39. Patient Education: DPP-4 Inhibitors
Sx of acute pancreatitis:
persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting
Sx of hypersensitiInvity / allergic reactions:
skin rash or itching, flaking or peeling of skin; hives; swelling of the face, lips, tongue and throat that may cause difficulty in breathing or swallowing
Pt should stop taking DPP-4 inhibitor and seek medical advice immediately.

40. Use cautiously, if at all, in pts with heart failure
DPP-4 Inhibitors & Cardiovascular Outcomes
No risk or benefit for all-cause mortality, CV mortality, MI or stroke among patients treated with DPP-4 inhibitors compared with placebo.
RCTs that examined relationship b/t DPP-4i and heart failure (HF) have yielded mixed results
SAVOR-TIMI 53 (2013): Pts treated with saxagliptin (Onglyza) were sig more likely to be hospitalized for HF than were those given placebo (3.5% vs. 2.8%)
EXAMINE – alogliptin (Nesina) (2015) and TECOS – sitagliptin (Januvia) (2015): No signif diff in rates of HF hospitalizations for DPP-4i group compared to placebo
Observational, cohort study 1.5 million pts, incretin-based drugs were not associated with increased risk of HF hospitalization (Fillion 2016)
Use cautiously, if at all, in pts with heart failure
(ADA Standards of Care in Diabetes – 2016; Inzucchi, 2015)

41. Injectable Incretin-based Therapies
GLP-1 Receptor Agonists:
Exenatide (Byetta), Liraglutide (Victoza),
Exenatide extended-release (Bydureon), Albiglutide (Tanzeum), Dulaglutide (Trulicity)
[Note: Approved ONLY for adults with Type 2]
Incretins (GLP-1 & GIP)
This conceptual diagram shows the effects of type 2 diabetes, which is begins years before it is diagnosed, and is progressive.1
Insulin resistance rises during disease development and continues to rise during pre-diabetes (impaired glucose tolerance [IGT] and impaired fasting glucose [IFG]), eventually stabilizing in type 2 diabetes.1 Initially, the rate of insulin secretion by beta cells increases to compensate for the decrease in insulin effectiveness due to insulin resistance.2 However, when beta cells fail to compensate (where lines diverge), patients become symptomatic, which is the point in the natural history when patients are usually diagnosed with type 2 diabetes. The initial increase in insulin secretion is often misperceived as an increase in beta-cell function.
In fact, we have seen that beta-cell function progressively declines long before diabetes is diagnosed.3 Therefore, beta-cell function is decreasing even with an increase in insulin secretion because of the ability of healthy beta cells to compensate for the increased metabolic load that accompanies insulin resistance. Over time, beta-cell compensatory function deteriorates causing insulin secretion to decrease.
Abnormalities in the incretin axis have been shown to have an important role in the progression of type 2 diabetes.4 Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) account for 90% of the incretin effect. In type 2 diabetes, there is both a deficiency of GLP-1 and resistance to the stimulatory effect of GLP-1 on insulin secretion. In addition, there is resistance to the action of GIP. The deficiency of GLP-1 can be observed in individuals with IGT and worsens progressively with progression to type 2 diabetes.
References
1Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Am J Med. 2009;122:S37-S50. 2DeFronzo RA. The triumvirate: β-cell function, muscle, liver. A collusion responsible for NIDDM. Diabetes ;37: Lebovitz HE. Insulin secretagogues: old and new. Diabetes Rev. 1999;7: DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:
Kendall DM et al. Am J Med. 2009;122:S37-S50.

42. 42
GLP-1 Receptor Agonists (Exenatide, Liraglutide, Exenatide ER, Albiglutide, Dulaglutide)
Directly activate the GLP-1 receptors but are resistant to breakdown by DPP-4. 4
Brain
Promotes insulin secretion in a glucose-dependent manner
Decreases hepatic glucose production by decreasing glucagon secretion
Slows gastric emptying
Promotes satiety 3 2
Mechanism of GLP-1 Receptor Agonists1,2
Incretin mimetic therapies, such as GLP-1 receptor agonists, directly activate the GLP-1 receptor and have glucoregulatory effects similar to the effects of endogenous GLP-1, but are resistant to breakdown by DPP-41,2
Actions of GLP-1 agonists include appetite reduction; delayed gastric emptying and promotion of the feeling of satiety; improved pancreatic insulin production in response to elevated blood glucose; and reduced release of glucose from the liver2,3
1. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;10:
NO GLP-1 RA has been approved for use with meal-time insulin. Exenatide (Byetta), Liraglutide (Victoza), Albiglutide (Tanzeum) have been approved for use with basal insulin 1

43. GLP-1 Receptor Agonists43
GLP-1 Receptor Agonists
Exenatide = Byetta
2x/day
Liraglutide = Victoza
1x/day
Exenatide ER = Bydureon
1x/week
Albuglutide = Tanzeum
Dulaglutide = Trulicity 3 2
Mechanism of GLP-1 Receptor Agonists1,2
Incretin mimetic therapies, such as GLP-1 receptor agonists, directly activate the GLP-1 receptor and have glucoregulatory effects similar to the effects of endogenous GLP-1, but are resistant to breakdown by DPP-41,2
Actions of GLP-1 agonists include appetite reduction; delayed gastric emptying and promotion of the feeling of satiety; improved pancreatic insulin production in response to elevated blood glucose; and reduced release of glucose from the liver2,3
1. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;10: 1

44. 44
GLP-1 Receptor Agonists (Exenatide, Liraglutide, Exenatide ER, Albiglutide, Dulaglutide)
In general:
↓ A1C by ~1.0 percentage point
low risk of hypoglycemia
weight loss (~2 to 3 kg)
? CV protection (↓ BP, ↓ chol)
Mar 2016 LEADER trial results – Liraglutide (Victoza) reduces the risk of major adverse CV events in people with T2DM (details to be presented at 76th Scientific Sessions of the ADA in June).  (
May preserve (possibly improve) β-cell function 3 2
Mechanism of GLP-1 Receptor Agonists1,2
Incretin mimetic therapies, such as GLP-1 receptor agonists, directly activate the GLP-1 receptor and have glucoregulatory effects similar to the effects of endogenous GLP-1, but are resistant to breakdown by DPP-41,2
Actions of GLP-1 agonists include appetite reduction; delayed gastric emptying and promotion of the feeling of satiety; improved pancreatic insulin production in response to elevated blood glucose; and reduced release of glucose from the liver2,3
1. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;10: 1

45. 45
GLP-1 Receptor Agonists (Exenatide, Liraglutide, Exenatide ER, Albiglutide, Dulaglutide)
In general:
In patients not able to achieve A1C goal with > 1 oral agent + basal insulin, GLP-1 RAs are increasingly preferred to meal-time insulin as the next “add-on” agent (Inzucchi 2015)
Common S/E
GI – Nausea, vomiting, diarrhea
Injection site reactions – Pruritus, nodule formation (more common with those that require mixing)
May need to ↓ dose of insulin / secretagogue 3 2
Mechanism of GLP-1 Receptor Agonists1,2
Incretin mimetic therapies, such as GLP-1 receptor agonists, directly activate the GLP-1 receptor and have glucoregulatory effects similar to the effects of endogenous GLP-1, but are resistant to breakdown by DPP-41,2
Actions of GLP-1 agonists include appetite reduction; delayed gastric emptying and promotion of the feeling of satiety; improved pancreatic insulin production in response to elevated blood glucose; and reduced release of glucose from the liver2,3
1. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;10: 1

46. 46
GLP-1 Receptor Agonists (Exenatide, Liraglutide, Exenatide ER, Albiglutide, Dulaglutide)
All GLP-1 RAs except Exenatide (Byetta, Bydureon) carry “boxed warning”:
Risk of thyroid C-cell tumors
Contraindicated in pts with personal or family h/o medullary thyroid cancer (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2)
MTC = 3
Cases of MTC reported during post-marketing period in pts on Liraglutide (Victoza), but causal relationship NOT established ( 2
Mechanism of GLP-1 Receptor Agonists1,2
Incretin mimetic therapies, such as GLP-1 receptor agonists, directly activate the GLP-1 receptor and have glucoregulatory effects similar to the effects of endogenous GLP-1, but are resistant to breakdown by DPP-41,2
Actions of GLP-1 agonists include appetite reduction; delayed gastric emptying and promotion of the feeling of satiety; improved pancreatic insulin production in response to elevated blood glucose; and reduced release of glucose from the liver2,3
1. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;10: 1

47. In general: Contraindications / Cautions47
GLP-1 Receptor Agonists (Exenatide, Liraglutide, Exenatide ER, Albiglutide, Dulaglutide)
In general: Contraindications / Cautions
Contraindicated in pts with h/o
Pancreatitis
GI problems (gastroparesis, IBD)
Renally impaired patients
Exenatide (Byetta & Bydureon) contraindicated if Cr Cl < 30 (renally excreted)
Use caution when initiating or increase dose in renally impaired pts (eGFR 30-50)
Closely monitor renal function in renally impaired pts reporting severe GI reactions 3 2
Mechanism of GLP-1 Receptor Agonists1,2
Incretin mimetic therapies, such as GLP-1 receptor agonists, directly activate the GLP-1 receptor and have glucoregulatory effects similar to the effects of endogenous GLP-1, but are resistant to breakdown by DPP-41,2
Actions of GLP-1 agonists include appetite reduction; delayed gastric emptying and promotion of the feeling of satiety; improved pancreatic insulin production in response to elevated blood glucose; and reduced release of glucose from the liver2,3
1. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;10: 1

48. 48
GLP-1 Receptor Agonists (Exenatide, Liraglutide, Exenatide ER, Albiglutide, Dulaglutide)
Patient Education
Self-Monitoring of Blood Glucose (SMBG) is needed to assess effects of GLP-1 and guide dose adjustments of insulin or secretagogue (SFU, glinide) to prevent hypoglycemia 3
Exenatide
Extended Release
(Bydureon)
Albiglutide
(Tanzeum)
Dulaglutide
(Trulicity)
Therapeutic concentration achieved
at week 2
within 3 to 5 days
within 1 to 3 days
Steady state concentration achieved
at about week 7
after 4 to 5 weeks
within 2 to 4 weeks 2
Mechanism of GLP-1 Receptor Agonists1,2
Incretin mimetic therapies, such as GLP-1 receptor agonists, directly activate the GLP-1 receptor and have glucoregulatory effects similar to the effects of endogenous GLP-1, but are resistant to breakdown by DPP-41,2
Actions of GLP-1 agonists include appetite reduction; delayed gastric emptying and promotion of the feeling of satiety; improved pancreatic insulin production in response to elevated blood glucose; and reduced release of glucose from the liver2,3
1. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;10: 1

49. 49
GLP-1 Receptor Agonists (Exenatide, Liraglutide, Exenatide ER, Albiglutide, Dulaglutide)
Patient Education (continued)
Sx of acute pancreatitis
Correct injection technique
How to reconstitute Exenatide ER (Bydureon) and Albiglutide (Tanzeum) prior to administration 3 2
Mechanism of GLP-1 Receptor Agonists1,2
Incretin mimetic therapies, such as GLP-1 receptor agonists, directly activate the GLP-1 receptor and have glucoregulatory effects similar to the effects of endogenous GLP-1, but are resistant to breakdown by DPP-41,2
Actions of GLP-1 agonists include appetite reduction; delayed gastric emptying and promotion of the feeling of satiety; improved pancreatic insulin production in response to elevated blood glucose; and reduced release of glucose from the liver2,3
1. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;10: 1

50. Bydureon Single Dose Tray (“kit”) – vial & syringe:
Powder (Bydureon)
Liquid microspheres
Orange connecting device
Needle
Bydureon Pen:

51. 51
GLP-1 Receptor Agonists (Exenatide, Liraglutide, Exenatide ER, Albiglutide, Dulaglutide)
Patient Education (continued)
Albiglutide (Tanzeum) must be reconstituted prior to administration 3 2
Mechanism of GLP-1 Receptor Agonists1,2
Incretin mimetic therapies, such as GLP-1 receptor agonists, directly activate the GLP-1 receptor and have glucoregulatory effects similar to the effects of endogenous GLP-1, but are resistant to breakdown by DPP-41,2
Actions of GLP-1 agonists include appetite reduction; delayed gastric emptying and promotion of the feeling of satiety; improved pancreatic insulin production in response to elevated blood glucose; and reduced release of glucose from the liver2,3
1. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;10: 1

52. 52
GLP-1 Receptor Agonists (Exenatide, Liraglutide, Exenatide ER, Albiglutide, Dulaglutide)
Patient Education (continued)
Trulicity (Dulaglutide) pen
no reconstitution necessary
pen must be unlocked to release “no-see” needle
pt places pen against skin; presses & holds the injection button (hear a click)
continues holding against skin until hear a 2nd click or “pop” (5-10 seconds); can then remove pen from skin 3 2
Mechanism of GLP-1 Receptor Agonists1,2
Incretin mimetic therapies, such as GLP-1 receptor agonists, directly activate the GLP-1 receptor and have glucoregulatory effects similar to the effects of endogenous GLP-1, but are resistant to breakdown by DPP-41,2
Actions of GLP-1 agonists include appetite reduction; delayed gastric emptying and promotion of the feeling of satiety; improved pancreatic insulin production in response to elevated blood glucose; and reduced release of glucose from the liver2,3
1. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;10: 1

53. GLP-1 Receptor Agonists (hand-out pg 4)53
GLP-1 Receptor Agonists (hand-out pg 4)
In general
Exenatide
(Byetta)
Liraglutide
(Victoza) ER
(Bydureon)
Albiglutide
(Tanzeum)
Dulaglutide
(Trulicity)
Efficacy
↓ A1C by ~1
percentage point
0.7 to 1.0
0.9 to 1.5
1.0 (3-year data);
1.0 to 1.9 in clinical trials
0.6 to 1.0
0.7 to 1.6
Dosing
Variable; all by Byetta can be given without regard to meals
2x/day (1 hr ac b’fast; 1 hr ac dinner); ↑ from 5 mcg to 10 mcg if needed (after 1 mo)
1x/day;
↑ from 0.6 to 1.2 mg after 1 week; max dose is 1.8 mg
1x/wk;
2 mg
Start with 30 mg, ↑ to 50 mg if needed
Start with 0.75 mg, ↑ to 1.5 mg if needed
Common S/E
GI (nausea, vomiting, diarrhea)
Nausea: 8-44%
Vomiting: 3- 18%
Nausea: 8-35%
Vomiting: 6-12%
Nausea: 9-27%
Vomiting: 11%
Nausea: 11%
Vomiting: 4%
Diarrhea: 13%
Nausea: 12-21%
Vomit: 6-13%
Diarrhea: 9-13%
Abd pain: 7-9%
Patient Educa-tion
SMBG;
how to reconstitute Bydureon & Tanzeum;
S/Sx pancreatitis
How to use Byetta pen
How to use Victoza pen
How to assemble components of single dose tray (“kit”); how to use pen (reconstitution required for both)
How to reconstitute lyophilized powder in pen
Available as a pen (no reconstitution necessary but some training still needed) 3 2
Mechanism of GLP-1 Receptor Agonists1,2
Incretin mimetic therapies, such as GLP-1 receptor agonists, directly activate the GLP-1 receptor and have glucoregulatory effects similar to the effects of endogenous GLP-1, but are resistant to breakdown by DPP-41,2
Actions of GLP-1 agonists include appetite reduction; delayed gastric emptying and promotion of the feeling of satiety; improved pancreatic insulin production in response to elevated blood glucose; and reduced release of glucose from the liver2,3
1. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;10: 1

54. GLP-1 Receptor Agonists (hand-out pg 4)54
GLP-1 Receptor Agonists (hand-out pg 4)
In general
Exenatide
(Byetta)
Liraglutide
(Victoza) ER
(Bydureon)
Albiglutide
(Tanzeum)
Dulaglutide
(Trulicity)
Efficacy
↓ A1C by ~1
percentage point
0.7 to 1.0
0.9 to 1.5
1.0 (3-year data);
1.0 to 1.9 in clinical trials
0.6 to 1.0
0.7 to 1.6
Dosing
Variable; all by Byetta can be given without regard to meals
2x/day (1 hr ac b’fast; 1 hr ac dinner); ↑ from 5 mcg to 10 mcg if needed (after 1 mo)
1x/day;
↑ from 0.6 to 1.2 mg after 1 week; max dose is 1.8 mg
1x/wk;
2 mg
Start with 30 mg, ↑ to 50 mg if needed
Start with 0.75 mg, ↑ to 1.5 mg if needed
Common S/E
GI (nausea, vomiting, diarrhea)
Nausea: 8-44%
Vomiting: 3- 18%
Nausea: 8-35%
Vomiting: 6-12%
Nausea: 9-27%
Vomiting: 11%
Nausea: 11%
Vomiting: 4%
Diarrhea: 13%
Nausea: 12-21%
Vomit: 6-13%
Diarrhea: 9-13%
Abd pain: 7-9%
Patient Educa-tion
SMBG;
how to reconstitute Bydureon & Tanzeum;
S/Sx pancreatitis
How to use Byetta pen
How to use Victoza pen
How to assemble components of single dose tray (“kit”); how to use pen (reconstitution required for both)
How to reconstitute lyophilized powder in pen
Available as a pen (no reconstitution necessary but some training still needed) 3 2
Mechanism of GLP-1 Receptor Agonists1,2
Incretin mimetic therapies, such as GLP-1 receptor agonists, directly activate the GLP-1 receptor and have glucoregulatory effects similar to the effects of endogenous GLP-1, but are resistant to breakdown by DPP-41,2
Actions of GLP-1 agonists include appetite reduction; delayed gastric emptying and promotion of the feeling of satiety; improved pancreatic insulin production in response to elevated blood glucose; and reduced release of glucose from the liver2,3
1. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;10: 1

55. GLP-1 Receptor Agonists (hand-out pg 4)55
GLP-1 Receptor Agonists (hand-out pg 4)
In general
Exenatide
(Byetta)
Liraglutide
(Victoza) ER
(Bydureon)
Albiglutide
(Tanzeum)
Dulaglutide
(Trulicity)
Efficacy
↓ A1C by ~1
percentage point
0.7 to 1.0
0.9 to 1.5
1.0 (3-year data);
1.0 to 1.9 in clinical trials
0.6 to 1.0
0.7 to 1.6
Dosing
Variable; all by Byetta can be given without regard to meals
2x/day (1 hr ac b’fast; 1 hr ac dinner); ↑ from 5 mcg to 10 mcg if needed (after 1 mo)
1x/day;
↑ from 0.6 to 1.2 mg after 1 week; max dose is 1.8 mg
1x/wk;
2 mg
Start with 30 mg, ↑ to 50 mg if needed
Start with 0.75 mg, ↑ to 1.5 mg if needed
Common S/E
GI (nausea, vomiting, diarrhea)
Nausea: 8-44%
Vomiting: 3- 18%
Nausea: 8-35%
Vomiting: 6-12%
Nausea: 9-27%
Vomiting: 11%
Nausea: 11%
Vomiting: 4%
Diarrhea: 13%
Nausea: 12-21%
Vomit: 6-13%
Diarrhea: 9-13%
Abd pain: 7-9%
Patient Educa-tion
SMBG;
how to reconstitute Bydureon & Tanzeum;
S/Sx pancreatitis
How to use Byetta pen
How to use Victoza pen
How to assemble components of single dose tray (“kit”); how to use pen (reconstitution required for both)
How to reconstitute lyophilized powder in pen
Available as a pen (no reconstitution necessary but some training still needed)
Lower rates of N/V with QW than BID/QD 3 2
Mechanism of GLP-1 Receptor Agonists1,2
Incretin mimetic therapies, such as GLP-1 receptor agonists, directly activate the GLP-1 receptor and have glucoregulatory effects similar to the effects of endogenous GLP-1, but are resistant to breakdown by DPP-41,2
Actions of GLP-1 agonists include appetite reduction; delayed gastric emptying and promotion of the feeling of satiety; improved pancreatic insulin production in response to elevated blood glucose; and reduced release of glucose from the liver2,3
1. Hinnen D, Nielsen LL, Waninger A, Kushner P. Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. J Am Board Fam Med. 2006;19:
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.
3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;10: 1

56. Pancreatic disease and Incretin-based Therapies

57. Pancreatic disease & Incretin-based Therapies
Few years ago, epidemiologic studies, rodent studies, and a human autopsy raised concerns that these therapies may be associated with pancreatitis and/or pancreatic cancer.
ADA: “…assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer … are inconsistent with the current data.” (Egan 2014)
AACE/ACE: “No studies have confirmed that incretin agents cause pancreatitis” … however, GLP-1 RA and DPP-4 inhibitors “should be used with caution in patients with a history of pancreatitis and discontinued if pancreatitis develops” (Garber, 2016, pg 89)
(Add’l ref: Scirica 2013; White 2013; Thompsen 2015)

58. Medications that Address the Increased Renal Glucose Threshold
The kidneys filter ~ 162 g of glucose everyday. 90% of the filtered glucose is reabsorbed by the high capacity SGLT2 transporter in the convoluted segment of the proximal tubule, and the remaining 10% of the filtered glucose is reabsorbed by the SHLT1 transporter in the straight segment of the descending proximal tubule. The result is that no glucose appears in the urine.
In diabetes, the maximal renal tubular reabsorptive capacity (Tm) for glucose is increased. Instead of dumping glucose in the urine to correct hyperglycemia, the kidney chooses to hold on to the glucose.
DeFronzo, From the Triumvirate to the Ominous Octect: A New Paradigm for the Treatment of T2 DM, Diabetes, vol 58, April 2009, pp

59. Medications to Address:
Metabolic Defect:
Increased Renal Glucose Threshold
Medications to Address:
Sodium-glucose co-transporter-2
(SGLT2) inhibitors (“glucuretics”)
Canagliflozin (Can’a-glif-LOZ’-in)
Invokana – March 2013
Dapagliflozin
Farxiga – Jan 2014
Empagliflozin
Jardiance – Aug 2014
The kidneys filter ~ 162 g of glucose everyday. 90% of the filtered glucose is reabsorbed by the high capacity SGLT2 transporter in the convoluted segment of the proximal tubule, and the remaining 10% of the filtered glucose is reabsorbed by the SHLT1 transporter in the straight segment of the descending proximal tubule. The result is that no glucose appears in the urine.
In diabetes, the maximal renal tubular reabsorptive capacity (Tm) for glucose is increased. Instead of dumping glucose in the urine to correct hyperglycemia, the kidney chooses to hold on to the glucose.
DeFronzo, From the Triumvirate to the Ominous Octect: A New Paradigm for the Treatment of T2 DM, Diabetes, vol 58, April 2009, pp

60. Sodium-glucose co-transporter-2
SGLT2 actively transports glucose across the proximal convoluted tubule of the kidney so it can be reabsorbed into the blood
The kidneys filter ~ 162 g of glucose everyday. 90% of the filtered glucose is reabsorbed by the high capacity SGLT2 transporter in the convoluted segment of the proximal tubule, and the remaining 10% of the filtered glucose is reabsorbed by the SHLT1 transporter in the straight segment of the descending proximal tubule. The result is that no glucose appears in the urine.
In diabetes, the maximal renal tubular reabsorptive capacity (Tm) for glucose is increased. Instead of dumping glucose in the urine to correct hyperglycemia, the kidney chooses to hold on to the glucose.
DeFronzo, From the Triumvirate to the Ominous Octect: A New Paradigm for the Treatment of T2 DM, Diabetes, vol 58, April 2009, pp

61. Sodium-glucose co-transporter-2
The renal glucose threshold in someone without diabetes is ~180 mg/dL
In diabetes, the renal glucose threshold is increased to ~ mg/dL
When the maximum capacity of the renal tubule to reabsorb glucose is exceeded, glucose is excreted into the urine
The kidneys filter ~ 162 g of glucose everyday. 90% of the filtered glucose is reabsorbed by the high capacity SGLT2 transporter in the convoluted segment of the proximal tubule, and the remaining 10% of the filtered glucose is reabsorbed by the SHLT1 transporter in the straight segment of the descending proximal tubule. The result is that no glucose appears in the urine.
In diabetes, the maximal renal tubular reabsorptive capacity (Tm) for glucose is increased. Instead of dumping glucose in the urine to correct hyperglycemia, the kidney chooses to hold on to the glucose.
DeFronzo, From the Triumvirate to the Ominous Octect: A New Paradigm for the Treatment of T2 DM, Diabetes, vol 58, April 2009, pp

62. When SGLT2 is blocked Renal threshold is lowered
Less glucose is reabsorbed by the kidneys
More glucose is excreted into the urine
Plasma glucose decreases
The kidneys filter ~ 162 g of glucose everyday. 90% of the filtered glucose is reabsorbed by the high capacity SGLT2 transporter in the convoluted segment of the proximal tubule, and the remaining 10% of the filtered glucose is reabsorbed by the SHLT1 transporter in the straight segment of the descending proximal tubule. The result is that no glucose appears in the urine.
In diabetes, the maximal renal tubular reabsorptive capacity (Tm) for glucose is increased. Instead of dumping glucose in the urine to correct hyperglycemia, the kidney chooses to hold on to the glucose.
DeFronzo, From the Triumvirate to the Ominous Octect: A New Paradigm for the Treatment of T2 DM, Diabetes, vol 58, April 2009, pp

63. Invokana (Canagliflozin) blocking SGLT2 from reabsorbing glucose

64. SGLT2 inhibitors Efficacy Renal Function Advantages
↓ A1C by ~0.5 to 1 percentage point
Renal Function
eGFR must be > 45 mL/min (Invokana & Jardiance) and > 60 mL/min (Farxiga)
Advantages
Low risk of hypoglycemia (~3%)
↓ weight (~3 to 5 lb)
1/3 is LBM (including fluid) & 2/3 is fat loss
~50-70 g gluc (≈ kcal) “spilled” into urine/day
↓ systolic BP by ~3 to 5 mm Hg

65. SGLT2 inhibitors Disadvantages ↑ LDL by ~3 to 8% However . . .
Canagliflozin (Invokana) ↑ HDL by ~8%
Empagliflozin (Jardiance) associated with significantly lower rates of
all-cause and cardiovascular death
hospitalizations for heart failure (Garber, 2016)

66. Most common side effects
SGLT2 inhibitors
Most common side effects
Genital yeast infections
UTI
Increased urination
Dehydration  hypotension
Invokana only: Hyperkalemia
UTI rates similar in both the Invokana group and in Sitagliptin group in the “active” control studies (pts also on Met – or – Met + SU)

67. SGLT2 inhibitors Use with caution in Patients > 65-75 years old
Higher incidence of adverse reactions related to volume depletion (hypotension, postural dizziness, syncope, dehydration)
Higher incidence of UTIs (Jardiance)
Lower efficacy (Invokana)
Invokana: Patients at risk for hyperkalemia (on ACEi or ARB)
Farxiga: Patients with h/o bladder cancer, risk factors for bladder cancer, hematuria
Patients in whom DKA may develop

68. SGLT2 inhibitors: DKA & UTI
FDA Warnings (5/15/15 & 12/4/15)
DKA
From Mar 2013 to May 2015, FDA identified 73 cases of ketoacidosis in pts with T1 or T2 DM treated w/ SGLT2i
All patients required hospitalization or treatment in an ED
Ketoacidosis not immediately recognized – BG levels were below those typically seen in DKA
some as low as 150 to 180 mg/dL
“euglycemic DKA”

69. SGLT2 inhibitors: DKA & UTI
FDA Warnings (5/15/15 & 12/4/15) (cont’d)
UTI
FDA also identified 19 cases of life-threatening blood infections (urosepsis) and kidney infections (pyelonephritis) that started as UTIs between Mar 2013 and Oct 2014
All pts were hospitalized; few required dialysis
An FDA safety review has resulted in adding warnings to the labels of SGLT2 inhibitors about the risks of too much acid in the blood and of serious UTIs  

70. Use with caution in pts predisposed to DKA
SGLT2 Inhibitors: DKA
Use with caution in pts predisposed to DKA
Factors that predispose to DKA:
insulin deficiency
T1DM
h/o pancreatitis
pancreatic surgery
insulin dose reduction
acute febrile illness
reduced calorie intake d/t illness or surgery
calorie restriction disorders
alcohol abuse
Dapagliflozin (Forxiga) – rejected by FDA (possible increased risk of cancer and liver injury) but approved in Europe
FDA panel backs Bristol diabetes drug after prior rejection
Dec 12 (Reuters) - By a lopsided vote of 13 to 1, an independent committee of medical experts on Thursday voted to recommend approval of a new type of diabetes drug from Bristol-Myers Squibb that U.S. regulators rejected two years ago due to safety concerns. The advisory panel to the U.S. Food and Drug Administration on Thursday said the benefits of the medicine, called dapaglifozin, appear to outweigh its risks. Bristol-Myers is developing the drug, which is already approved in Europe, in partnership with AstraZeneca Plc.
In another vote, of 10 to 4, the panel found the drug appeared to have a favorable cardiovascular safety profile.

71. SGLT2 Inhibitors Patient Education
Drink plenty of fluids to prevent dehydration!
Symptoms of ketoacidosis
Nausea, vomiting, abdominal pain, tiredness, and trouble breathing.
Symptoms of UTI
a feeling of burning when urinating or the need to urinate often or right away; pain in the lower part of the stomach area or pelvis; fever; or blood in the urine.
Dapagliflozin (Forxiga) – rejected by FDA (possible increased risk of cancer and liver injury) but approved in Europe
FDA panel backs Bristol diabetes drug after prior rejection
Dec 12 (Reuters) - By a lopsided vote of 13 to 1, an independent committee of medical experts on Thursday voted to recommend approval of a new type of diabetes drug from Bristol-Myers Squibb that U.S. regulators rejected two years ago due to safety concerns. The advisory panel to the U.S. Food and Drug Administration on Thursday said the benefits of the medicine, called dapaglifozin, appear to outweigh its risks. Bristol-Myers is developing the drug, which is already approved in Europe, in partnership with AstraZeneca Plc.
In another vote, of 10 to 4, the panel found the drug appeared to have a favorable cardiovascular safety profile.

72. SGLT-2 Inhibitor Comparison Chart (hand-out pg 5)
Canagliflozin (Invokana)
Dapagliflozin (Farxiga)
Empagliflozin(Jardiance)
Efficacy
↓ A1C by ~ 0.7 to 1 percentage point
↓ A1C by ~ 0.5 to 0.7 percentage points
↓ A1C by ~ 0.4 to 0.9 percentage points
eGFR must be
> 45 mL/min
> 60 mL/min
Dose
100 mg/day, before 1st meal of day; ↑ to 300 mg if needed and if eGFR > 60
5 mg/day, taken in morning, with or w/out food; ↑ to 10 mg if needed
10 mg/day, taken in morning, with or w/out food;
↑ to 25 mg if needed
Advantages
Low risk of hypoglycemia
↓ wgt by % (~ 5 lb)
↓ systolic BP by ~3 to 5 mm Hg
↑ HDL by ~8%
↓ wgt by ~ 5 lb
↓ wgt by ~ 3 lb
Disadvantages
↑ LDL by ~4 to 8%
↑ LDL by 2.9%
↑ LDL by ~5-7%
Common side effects
Genital yeast infections (women: 10-11%; men: 4%)
UTI: 4 to 6%
Increased urination
Dehydration
Hyperkalemia
Genital yeast infections (women: 7-8%; men: 3%)
Nasopharyngitis
Genital yeast infections (women: 5-6%; men: 2-3%)
UTI: 8 to 9%
Use with Caution in Patients
> 65 years old (more prone to volume depletion; lower efficacy)
At risk for hyperkalemia (ACEi or ARB)
Prone to DKA
> 65 years old (more prone to volume depletion)
With h/o bladder cancer, bladder cancer risk factors, hematuria
> 75 years old (more prone to volume depletion & UTIs)
Patient Education
(1) Drink plenty of fluids; (2) Talk to HCP if ↓ in kcal intake; (3) Sx of DKA; (4) Sx of UTI
Dapagliflozin (Forxiga) – rejected by FDA (possible increased risk of cancer and liver injury) but approved in Europe
FDA panel backs Bristol diabetes drug after prior rejection
Dec 12 (Reuters) - By a lopsided vote of 13 to 1, an independent committee of medical experts on Thursday voted to recommend approval of a new type of diabetes drug from Bristol-Myers Squibb that U.S. regulators rejected two years ago due to safety concerns. The advisory panel to the U.S. Food and Drug Administration on Thursday said the benefits of the medicine, called dapaglifozin, appear to outweigh its risks. Bristol-Myers is developing the drug, which is already approved in Europe, in partnership with AstraZeneca Plc.
In another vote, of 10 to 4, the panel found the drug appeared to have a favorable cardiovascular safety profile.

73. 2-drug combination therapy
Monotherapy
– vs –
2-drug combination therapy

74. Monotherapy – vs – 2-drug combination therapy
In general, monotherapy with an oral diabetes medication reduces A1C by ~1 percentage point
Metformin ↓ A1C to a greater degree than do the DPP-4i (~1.2% - vs - ~0.8%)
Combination therapies reduce A1C by an additional ~1%
Metformin + any other drug (SU, TZD, DPP-4i, GLP-1): similar efficacy
AHRQ. Comparing Medicines for Adults with Type 2 Diabetes.

75. Combination Oral Medications
Secretagogues + Metformin
Metaglip: Glipizide / Metformin
Glucovance: Glyburide / Metformin
PrandiMet: Repaglinide / Metformin
Secretagogue + TZD
Duetact: Glimepiride / Pioglitazone
Avandaryl: Glimepiride / Rosiglitazone
TZD + Metformin
Actoplus Met: Pioglitazone / Metformin
Avandamet: Rosiglitazone / Metformin

76. Combination Oral Meds (cont’d)
DPP-4 Inhibitor + Metformin
Janumet: Sitagliptin / Metformin
Janumet XR: Sitagliptin / Metformin XR
Kombiglyze XR: Saxagliptin / Metformin
Jentadueto: Linagliptin / Metformin
Kazano: Alogliptin / Metformin
DPP-4 Inhibitor + TZD
Oseni: Alogliptin / Pioglitazone

77. Combination Oral Meds (cont’d)
SGLT2 Inhibitor + Metformin
Invokamet: Canagliflozin / Metformin (Aug 2014)
Xigduo XR: Dapagliflozin + Metformin XR (Oct 2014)
Synjardy: Empagliflozin + Metformin (Aug 2015)
SGLT2 Inhibitor + DPP-4 Inhibitor
Glyxambi: Tradjenta / Jardiance (Feb 2015)

78. 12 Classes of Diabetes Meds
Oral
DPP-4 Inhibitors
Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Linagliptin (Tradjenta)
Alogliptin (Nesina)
Bromocriptine (Cycloset)
Colesevalam (Welchol)
SGLT2 inhibitors
Canagliflozin (Invokana)
Dapagliflozin (Farxiga)
Empagliflozin (Jardiance)
Biguanides (Metformin)
Sulfonylureas (SFU)
Glipizide (Glucotrol)
Glyburide (Micronase)
Glimepiride (Amaryl)
Meglitinides (glinides)
Repaglinide (Prandin)
Nateglinide (Starlix)
Thiazolidinediones (TZD)
Rosiglitazone (Avandia)
Pioglitazone (Actos)
-glucosidase inhibitors
Acarbose (Precose)
Miglitol (Glyset)
Insulin
secret-
agogues
+ 17 combination oral meds!

79. 12 Classes of Diabetes Meds (cont’d)
Injectable
Injectable / Inhalable
GLP-1 Receptor Agonists
Liraglutide (Victoza)
Exenatide (Byetta)
Exenatide ER (Bydureon)
Albiglutide (Tanzeum)
Dulaglutide (Trulicity)
Amylin analog
Pramlintide (Symlin)
Insulin
Injectable
Inhalable

80. Insulin Types (before Feb 2015)
Traditional (human) insulin
Short-acting insulin (Regular)
Humulin R, Novolin R
Intermediate-acting (NPH)
Humulin N, Novolin N
Insulin analogs
Rapid-acting (bolus)
Faster onset, higher peak, shorter duration than Regular
Humalog, Novolog, Apidra
Long-acting (basal)
Lantus, Levemir
Premixed insulins
All these are “U-100” (100 units insulin/mL)
Until Feb 2015 the only insulin that was NOT U-100 was “U-500 Regular insulin”
Insulin Therapy1-3
All insulin products are produced by recombinant DNA (rDNA) technology1
Examples of conventional insulins are regular (short-acting insulin) and NPH (intermediate-acting)2
An insulin analogue is a derivative of human insulin that has undergone one or more chemical modifications to alter the time-action profile of the insulin
Onset and duration of action more closely mimic physiologic insulin secretion2
Insulin analogues are available as rapid (bolus), long-acting (basal), and premixed formulations2
Overall, analogues have the following benefits over conventional insulin therapies, which may lead to improved adherence and glycemic control3:
More closely match physiologic human insulin profiles
More convenient
Less risk of hypoglycemia
Also, analogues may cause less weight gain, perhaps due to less perceived need to include snacks to reduce the risk of hypoglycemia3
Brange J, Vølund A. Insulin analogs with improved pharmacokinetic profiles. Adv Drug Deliv Rev. 1999;35:
DeWitt DE, Hirsch, IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus. JAMA. 2003;289:
Freeman JS. Insulin analog therapy: improving the match with physiologic insulin secretion. J Am Osteopath Assoc. 2009;109:26-36.
NPH=neutral protamine Hagedorn.
1. Brange J, Vølund A. Adv Drug Deliv Rev. 1999;35: DeWitt DE, Hirsch IB. JAMA. 2003;289: 80

81. 12 Classes of Diabetes Meds (cont’d)
Injectable / Inhalable
Insulin (only new insulins listed)
Injectable
Rapid acting:
Humalog U-200 (May 2015)
Long acting:
Toujeo (Glargine) U-300 (Feb 2015)
Ultra-long acting:
Tresiba (Degludec) U-100 & U-200 (Sept 2015)
U-500
Humulin R U-500 KwikPen (Jan 2016)
Inhalable
Afrezza – insulin inhalation powder (June 2014)

82. New Insulins Humalog KwikPen U-200 (May 2015)
Recommended if taking > 15 u Humalog/meal
Holds double the amount of Humalog as U100 pen
U-200 pen contains 600 units (U-100 pen – 300 units)
More for convenience (less likely to run out of insulin)
No dose conversions required
Dialing 1 unit delivers 1 unit of insulin

83. New Insulins Toujeo® (Insulin Glargine) SoloSTAR pen U-300 (Feb 2015)
a once-daily long-acting basal insulin (~36 hr duration)
3x as concentrated as Lantus
approved for adults with type 1 and type 2 diabetes
to be administered at same time every day
dose counter shows number of units to be injected – no dose conversion is required

84. New Insulins Toujeo® SoloSTAR pen U-300
released more gradually than Lantus
onset of action ~6 hr (vs ~1-2 hr)
maximum glucose lowering effect may take 5 days
when titrating dose, wait 3 to 4 days between dose increases
“for patients controlled on Lantus, expect that a higher daily dose of Toujeo will be needed…” (
in clinical trials, 11% to 17.5% more Toujeo was needed to achieve same glycemic target
Compared to Lantus:
significantly lower risk of nocturnal hypoglycemia
less weight gain
(Riddle 2014; White 2016)

85. New Insulins Tresiba (Degludec) – Ultra long-acting (Sept 2015)
1st basal insulin molecule approved by FDA in 10 yr
Others: Glargine (Lantus) & Detemir (Levemir)
Duration of action: > 42 hr (d/t delayed absorption)
Indicated for adults 18 years and older
Available in U-100 & U-200 formulations

86. New Insulins Tresiba (Degludec)
Injection is given once a day, virtually any time of day (within 8 to 40 hr after last injection)
Sunday: 8:00 p.m.
Monday: 7:00 a.m. (11 hr after last injection)
Tuesday: 10:00 p.m. (39 hr after last injection)…
and achieve same glycemic control as Glargine (Lantus) administered at same time every day

87. New Insulins Tresiba (Degludec)
When titrating the dose, wait 3 to 4 days between dose increases
The dose window for both pens shows the number of insulin units to be delivered
NO conversion is needed

88. New Insulins Humulin R U-500 KwikPen (Jan 2016) not a new insulin
what is new:
pen vs vial
no dose conversion needed

89. New Insulins Inhaled insulin Exubera (Pfizer)
FDA approved in 2006
Pfizer withdrew it from the market in 2007
Afrezza – insulin inhalation powder (2014)

90. New Insulins Afrezza – insulin inhalation powder (2014)
Rapid-acting inhaled insulin
Administered at beginning of a meal
Available as single-use cartridges of 4, 8 and 12 units

91. New Insulins Afrezza – insulin inhalation powder Inhaler: Cartridges:
Fully assembled:

92. New Insulins
Afrezza – insulin inhalation powder

93. New Insulins Afrezza – insulin inhalation powder
Afrezza causes ↓ in lung function over time
Pulmonary function should be assessed
before initiating
after 6 months
annually
even in the absence of pulmonary symptoms
27% pts treated w/ Afrezza reported cough

94. New Insulins Afrezza – insulin inhalation powder
suffering from a low level of prescriptions!

95. Summary of the 11 Classes of Non-Insulin Therapies for Diabetes (hand-out pg 6)
Oral Medications
Injectable Medications
Metformin
Insulin secret-agogues
Thiazolidine-diones (TZDs)
α-glucosidase inhibitors
DPP-4 inhibitors
Bromo-criptine (Cycolset)
Cole-sevalam (Welchol)
SGLT2 inhibitors
GLP-1 receptor
agonists
Amylin analog (Symlin)
Sulfonyl-
ureas
Megli-
tindes
Mechanism of Action
↓ hepatic glucose production; ↑ insulin sensitivity
↑ insulin secretion from -cells in pancreas
↑ insulin sensitivity in peripheral tissue (muscle, fat, liver)
↓ rate of carbohydrate digestion
Prolong survival of GLP-1, thereby ↑ insulin &
↓ glucagon secretion in a glucose dependent manner
Unknown; may ↓ the hypo-thalamic drive that stimulates early morning hepatic glucose output
Unknown; may ↓ glucose absorption
Glucuretics: ↑ urinary glucose excretion
Mimics GLP-1:
↑ insulin &
↓ glucagon secretion in a glucose dependent manner; ↓ rate of gastric emptying; stimulates satiety center in brain
Amylin-like effect (inhibits glucagon secretion; slows gastric emptying)
A1C reduction
1.0 – 1.2
1.25
Nat 0.75;
Rep ~1
rosi
pio
(at dose of > 150 mg/d)
~0.75
0.1 – 0.6
0.5
0.5 – 1.0
~1.0
0.5 – 0.7
Adverse Events /
Risks / Cautions
GI disturb-ances, lactic acidosis (rare but serious), HOLD before & after contrast dye studies
Hypo-glycemia,
weight gain, low durability
Heart failure, edema, wgt gain, bone fractures
GI disturb-ances; only glucose tabs or gel will be effective in treating hypo-glycemia
Acute pancreatitis,
URI, cold sx, hyper-sensitivity / allergic rxns, joint pain, heart failure [?]
Hypo-tension
if taking ergot meds (eg, Cafergot); syncope
May ↑ TG - not recom-mended if TG > 500;
Constipa-tion, nausea, dyspepsia
Genital yeast infections, UTI, polyuria, dehydration  hypo-tension, DKA
Pancreatitis, N/V, injection site rxns, gastro-paresis; monitor renal function
Nausea,
hypo-glycemia

96. Summary of Diabetes Medications
Most medications for Type 2 diabetes address the underlying pathophysiologic defects
Progressive ↓ in insulin secretion
Insulin resistance
↑ hepatic glucose output
Blunted incretin response
↑ renal glucose threshold
Other medications (not discussed in this presentation)
Modify physiologic processes related to nutrient absorption (α-glucosidase inhibitors) or have mechanisms of action that are not completely understood (Cycloset, Welchol)

97. Insulin secret-agogues
Stimulate the satiety center
↓ glucose uptake
TZD
 glucose uptake
GLP-1
↓ hepatic glucose production
 hepatic glucose production
↓ rate of gastric emptying
Metformin
↑ renal glucose threshold
Insulin secret-agogues
GLP-1
↓ renal glucose threshold
SGLT2 inhibitors
DPP-4i
↓ insulin secretion
 Insulin secretion & ↓ glucagon secretion
 Insulin secretion
GLP-1
Incretin-based therapies
↓ GLP-1 &
resistance to GIP
 GLP-1

98. Summary of Guidelines
Metformin, unless contraindicated, is considered first-line therapy
If Metformin is contraindicated or poorly tolerated, or if pt needs dual or triple therapy, medications should be chosen on the basis of factors such as
Efficacy
Complementary mechanisms of action
Risks / potential side effects (hypoglycemia, wgt gain, nausea, DKA, pancreatitis, heart failure)
Cardiovascular outcomes
Cost / insurance coverage
Dosing frequency (QD, TID, QW) or complexity
Consideration of patient’s goals and values

99. Reliable resources for more information
ADA Position Statements
AACE Consensus Statement
NIH’s Daily Med website
Prescribing Information
DiabetesPro SmartBrief ( alerts)

100. Position & Consensus Statements
Inzucchi SE et al. Management of hyperglycemia in type 2 diabetes: A patient-centered approach – Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), Diabetes Care, 2012; 35(12):
Inzucchi SE et al. Management of hyperglycemia in type 2 diabetes, 2015: A patient-centered approach (update to the above position statement), Diabetes Care 2015;38:
Garber et al. Consensus statement by the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) on the comprehensive type 2 diabetes management algorithm Executive Summary 2016, Endocrine Practice 2016;22(1):

101. See hand-out packet, pg 1
Inzucchi, Diabetes Care 2015;38:

102. See hand-out packet, pg 2
Garber et al, Consensus statement by AACE and ACE Executive Summary 2016, Endocrine Practice 2016;22(1):

103. NIH’s “Daily Med” (http://dailymed.nlm.nih.gov)
“The drug labeling information on this website has been reformatted to make it easier to read…”

104. Prescribing Information
For example: Let’s say you can’t remember if Bydureon is contra-indicated in renal impairment or not.
Simply use Google to search for “Bydureon Prescribing Information.”
Once you’ve got the pdf, go to “Edit” and choose “Find.”

106. Type “renal” in the search box

108. DiabetesPro SmartBrief https://www.smartbrief.com

109. Joyce Vergili EdD, RD, CDN, CDE, FANDs
Questions?
Joyce Vergili EdD, RD, CDN, CDE, FAND