1. New Non Insulin Drugs for Management of Type2DM
Muhammad Mudassar Amin, MD.
Cameron Regional Medical Center.

2. Disclosure
I have no conflict of interest in regards to this presentation.

3. Contents
1) What is DM2 2) consensus statement by AACE and ACE about DM2 management 3) Glucose homeostasis 4) GLP 1 Agonists 5) DPP4 inhibitors 6) SGLT2 Inhibitors 7) Bromocriptine QR 8) Amylin mimetics (Pramlinitide) 9) AACE and ACE guidelines 10) References 11) Q & A

4. What is DM2
According to ADA and WHO; An asymptomatic individual with any of the following fasting plasma glucose values ≥126 mg/dL OR two-hours plasma glucose value of ≥200 mg/dL during an oral glucose tolerance test (OGTT); OR A1C values ≥6.5 percent; OR A patient with classic symptoms of hyperglycemia, a random plasma glucose ≥200 mg/dl. Underlying mechanisms Insulin resistance (Environmental/Obesity) and Impaired insulin secretion (genetics)

5. CONSENSUS STATEMENT BY THE AACE AND ACE ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT
ALGORITHM – 2016 EXECUTIVE SUMMARY
1) Lifestyle optimization is essential for all patients with diabetes
2) The HbA1C target should be individualized based on numerous factors, such as age, life
expectancy, comorbid conditions, duration of diabetes, risk of hypoglycemia , patient motivation, and
adherence. An A1C level of ≤6.5% is considered optimal if it can be achieved in a safe and affordable
manner.

6. 3)The choice of diabetes therapies must be individualized based on attributes specific to both patients and the medications. Medication attributes that affect this choice include antihyperglycemic efficacy, mechanism of action, risk of inducing hypoglycemia, risk of weight gain, ease of use, likely adherence, cost, and safety in heart, kidney, or liver disease.
4) Minimizing risk of hypoglycemia is a priority.
5) Minimizing risk of weight gain is a priority.
6) Combination therapy is usually required and should involve agents with complementary mechanisms of action.
7) Comprehensive management includes lipid and BP therapies and treatment of related comorbidities.

7. Drug treatment of DM2
ACP 11/2012

8. Glucose Homeostasis GLP-1 is one of a family of
naturally occurring gut
hormones that is released
in the setting of a meal,
but not with intravenous
carbohydrate, and stimulates
insulin synthesis and secretion..

9. Glucose Homeostasis
Orally consumed carbohydrates, proteins and lipids induce secretion of GLP 1 from intestinal L cells. However, GLP1 mediated insulin secretion from Beta cells is only observed in the presence of elevated glucose levels.
The activity of GLP1 and its receptor agonists is self limiting, ceasing when blood glucose levels fall in response to secreted insulin.
Exogenous insulin and Sulfonylurea based therapies, continue to act even after an ideal glucose concentration is achieved and hence can cause over-correction and hypoglycemia.

10. Glucagon-like peptide-1 receptor agonists (GLP 1 Receptor Agonists)
GLP-1 receptor agonists reproduce or enhance the actions of the naturally occurring peptide GLP-1. Synthetic GLP-1 receptor agonists are resistant to degradation by the enzyme dipeptidyl peptidase-4 (DPP-4) and therefore have a longer half-life, facilitating clinical use. They bind to the GLP-1 receptor and stimulate glucose-dependent insulin release from the pancreatic islets.

11. GLP 1 Receptors Agonists; Clinical Use
1) They can be used in combination with metformin (and/or another oral agent), when weight loss or avoidance of hypoglycemia is a primary consideration. 2) They are not considered as initial therapy for the majority of patients with type 2 diabetes. 3) Among GLP-1 receptor agonists, long- rather than short-acting agents should be preferred primarily due to patient convenience. 4) GLP-1 receptor agonists generally should not be combined with DPP-4 inhibitors, as there does not appear to be additive effect on glucose lowering

12. Available GLP 1 Receptor Agonists
Generic Name
Brand Name
Frequency of administration
Dosing
Liraglutide
Victoza
SQ Daily
0.6mg-1.8mg
Exenatide
Byetta
SQ BID
5mcg-10mcg
Exenatide XR
Bydureon
SQ weekly
2mg
Albiglutide
Tanzeum
30-50mg
Dulaglutide
Trulicity mg
Glycemic Efficacy:
In comparison with placebo, GLP-1 receptor agonists reduced glycated hemoglobin (A1C) by approximately 1 percentage point.

13. GLP 1 RA; Systemic effects
Hypoglycemia
Neutral
Weight
loss
NAFLD benefit
Mild
CHF
Hepatic Impairment
No dosage adjustment necessary
Renal Impairment
No dosage adjustment necessary except Exenatide is contraindicated with CrCl<30mg/ml.
GI Symptoms
Moderate

14. GLP RA; Adverse effects
1) Primarily GI, Nausea, Vomiting. Nausea more common with exenatide once weekly. 2) Hypoglycemia rare (usually when taken with other hypoglycemic) 3) Pancreatitis (If patient develops pancreatitis, don’t restart and don’t initiate if there is h/o pancreatitis) 4) Injection site reactions more common with exenatide once weekly Avoid use if there is personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B

15. DPP4 Inhibitors
DPP-4 inhibitors are a class of oral diabetes drugs that inhibit the enzyme DPP-4. DPP-4 is a ubiquitous enzyme expressed on the surface of most cell types that deactivates GIP and GLP-1; therefore, its inhibition could potentially affect glucose regulation through multiple effects. However, DPP-4 inhibitors have a modest effect on GLP-1 levels, compared with giving GLP-1 agonists.

16. DPP4 Inhibitors; Indication/Clinical Use
1) Used as add-on drug for patients who are inadequately controlled on metformin, a TZD, or a SU. 2) Used as monotherapy in patients who are intolerant of or have contraindications to metformin, SU, or TZDs, such as patients with CKD or who are at high risk for hypoglycemia. 3) They are not considered as initial therapy for the majority of patients with type 2 diabetes.

17. Available DPP4 inhibitors
Generic Name
Brand Name
Frequency of administration
dosing
Sitagliptin
Januvia
Oral Daily
25mg, 50mg, 100mg
Saxagliptin
Onglyza
2.5mg, 5mg
Linagliptin
Tradjenta
5mg
Alogliptin
Nesina
6.25mg, 12.5mg, 25mg
Sitagliptin/Metformin
Janumet
50/500, 50/1000
Saxagliptin/Metformin
Komboglyze XR
2.5/1000, 5/500, 5/1000
Linagliptin/Metformin
Jentadueto
2.5/500, 2.5/850, 2.5/1000
Glycemic efficacy:
In comparison with placebo, DPP4 Inhibitors reduced glycated hemoglobin (A1C) by approximately %.

18. DPP4 Inhibitors, Systemic Effects
Hypoglycemia
Neutral
Weight
NAFLD benefit
CHF
Hepatic Impairment
Usually no dose adjustment necessary
Renal Impairment
Dose adjustment necessary based on Cr Clearance
GI Symptoms

19. DPP4 Inhibitors; Adverse Effects
Generally are tolerated very well. . Commonly reported side effects include headache, nasopharyngitis, and upper respiratory symptoms. Acute pancreatitis has been reported in association with DPP-4 inhibitors. At present, there is insufficient data to know if there is a causal relationship. DPP-4 inhibitors should be discontinued in patients who develop pancreatitis. DPP-4 inhibitors should not be initiated in a patient with a history of pancreatitis.

20. Glucose Homeostasis in Kidneys
In people without diabetes, about 180 g of glucose is filtered daily by the renal glomeruli,
and is then reabsorbed in the proximal convoluted tubule (PCT). SGLT2 (Sodium Glucose
Co-Transporter 2) expressed in proximal tubule mediates reabsorption of about 90% of
filtered glucose load.

21. SGLT2 Inhibitors
The SGLT2 is expressed in the proximal tubule and mediates reabsorption of approximately 90 percent of the filtered glucose load. SGLT2 inhibitors promote the renal excretion of glucose and thereby modestly lower elevated blood glucose levels in patients with type 2 diabetes.

22. SGLT2 Inhibitors; Clinical Use
Used as adjunct in patients with inadequate control on metformin and in patients who are unwilling to consider injection therapy and in whom weight gain is a significant issue.
Used as an adjunct in patients with inadequate glycemic control on two oral agents (eg, metformin and SU)
Used as an adjunct in patients not adequately controlled on metformin and insulin therapy, in whom GLP-1 receptor agonists are contraindicated and increasing insulin dosing would lead to weight gain
SGLT2 inhibitors are not considered as initial therapy for the majority of patients with type 2 diabetes.

23. Available SGLT2 Inhibitors
Generic Name
Brand Name
Frequency Of Administration
Dosing
Canagliflozin
Invokana
Oral Daily
100mg, 300mg
Dapagliflozin
Farxiga
5mg, 10 mg
Empagliflozin
Jardiance
10 mg, 25mg
Glycemic efficacy:
SGLT2 Inhibitors cause mean reductions in A1C compared with placebo ranging between 0.5 to 1.1 percent.

24. A prior history of myocardial infarction or stroke might favor choosing empagliflozin, based on the results of the empagliflozin and cardiovascular outcomes study.
7028 patients with DM2 (mean A1C 8%) and CVD were randomly assigned to empagliflozin, 10 or 25 mg, or placebo once daily. The majority of patients were taking metformin, antihypertensives, and lipid-lowering agents (equally distributed in both groups) to control blood glucose, blood pressure, and cholesterol. Approximately 48 percent of patients in each group were taking insulin.
After three years, the primary outcome (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in fewer patients assigned to empagliflozin than to placebo.
Whether the beneficial cardiovascular effects in those with overt CVD are specific to empagliflozin, or represent a class effect of the SGLT2 inhibitors, is unknown at this time. Canagliflozin and dapagliflozin cardiovascular trials in progress.

25. SGLT2 Inhibitors; Systemic Effects
Hypoglycemia
Neutral
Weight
Loss
NAFLD Benefit
CHF
Neutral; Increased LDL
Hepatic Impairment
No adjustment necessary
Renal Impairment
Dose adjustment necessary based on Cr Clearance
GI Symptoms

26. SGLT2 Inhibitors; Side effects
2 to 4 fold increased incidence of vulvovaginal candidiasis, reported in 10 to 15 percent of women.
Increase rate of urinary tract infections.
May cause symptomatic hypotension especially in older patients on diuretics and ACEI2 (osmotic diuresis).
"Euglycemic" (usually meaning plasma glucose <250 mg/dL) diabetic ketoacidosis has been reported in patients with type 2 diabetes taking SGLT2 inhibitors. Serum ketones should be obtained in any patient with nausea, vomiting, or malaise while taking SGLT2 inhibitors, and SGLT2 inhibitors should be discontinued if acidosis is confirmed.
Renal function should be assessed prior to initiation of SGLT2 inhibitors and monitored during treatment. There have been post marketing reports of acute kidney injury.

27. SGLT2 Inhibitors; Cautions
SGLT2 inhibitors should not be used in patients with 1) Type 2 diabetes eGFR <60 mL/min (dapagliflozin) or <45 mL/min (canagliflozin, empagliflozin) 2) Ketosis-prone type 2 diabetes They should be used with caution with medications that predispose to acute renal injury ( NSAIDs, ACE inhibitors/ARBs, diuretics) and comorbidities that might predispose to acute renal injury (hypovolemia, heart failure).

28. Bromocriptine QR
Quick-release bromocriptine (bromocriptine-QR) (Cycloset) was approved in 2009 for treatment of type 2 diabetes. The exact anti-diabetic mechanism of action of bromocriptine-QR is unknown. The advantages of bromocriptine-QR were minimal risk of hypoglycemia, neutral effect on weight, and reassuring cardiovascular safety over 1 year of use. Common side effects include nausea, vomiting, dizziness, and headache. Randomized placebo-controlled trials showed that the mean reduction in hemoglobin A1c (HbA1c) levels by bromocriptine-QR was % when compared with placebo after 24 weeks of therapy.

29. Amylin Mimetics (Pramlinitide/Symlin)
Amylin is hormone released from Beta cells of pancreas along with insulin after a meal. Like insulin, its completely absent in type 1 Diabetics. It 1) Slows gastric emptying 2) Promotes satiety via hypothalamic receptors. 3) Inhibits glucagon secretion Pramlinitide is analogue of Amylin. Approved by FDA for both Type 1 (30-60mcg SQ QAC) and Type 2 diabetic patients (120 mcg SQ QAC) who use prandial insulin. Cant be mixed in syringe with insulin. Common side effects include Nausea, anorexia, fatigue, abdominal pain

30. Where to start and Where to go

32. References AACE/ACE Comprehensive DM2 Management Algorithm 2017.
Uptodate.com
Pubmed.com
NEJM.org
Annals of Internal Medicine