Maj Y DixitCol J Muthukrishnan, SM

New therapies in Diabetes Mellitus

• Harrison’s 19th Ed• Medicine Update 2016• Prasad-Reddy L, Isaacs D. A clinical review of GLP-1 receptor agonists: efficacy and safety in

diabetes and beyond. Drugs in Context 2015; 4: 212283. • Mundil D, Cameron-Vendrig A, Husain M. GLP-1 receptor agonists: a clinical perspective on

cardiovascular effects. Diab Vasc Dis Res. 2012;9(2):95–108.• William T. Cefalu and Matthew C. Riddle. SGLT2 Inhibitors: The Latest“New Kids on the Block”!

Diabetes Care 2015;38:352–354• Comparison of insulin degludec with insulin glargine in insulin-naive subjects with Type 2

diabetes: a 2-year randomized, treat-to-target trial. Diabetes Med 2013 Nov;30(11):1298-304.• Artificial Pancreas: Past, Present, Future Claudio Cobelli, Eric Renard, and Boris Kovatchev.

Diabetes, Vol. 60, November 2011• Comparison of dual-hormone artificial pancreas, single-hormone artificial pancreas, and

conventional insulin pump therapy for glycaemic control in patients with type 1 diabetes: an open-label randomised controlled crossover trial. The Lancet. Volume 3, No 1 p17–26, January 2015

References

• Incretin based therapy• SGLT 2 receptor inhibitors• Newer basal insulin• Artificial Pancreas

New Therapies

• Glucagon like peptide-1 agonists

Incretin based therapy

Role of Incretin

GLP-1 AgonistsDrug Initial Titrate Max Dose Adjustments

Exenatide IR (Byetta®)

5 mcg BID within 60 mins of a meal

- 10 mcg Renal impairment: CrCl 30-50 mL/min: use cautionCrCl < 30 mL/min: not recommendedHepatic impairment: not studied

Exenatide ER (Bydureon®)

2 mg once weekly N/A 2 mg once

weekly

Liraglutide (Victoza®)

0.6 mg once daily 1.2 mg once

daily1.8 mg once daily

Renal & hepatic impairment: use caution – limited experience

Albiglutide (Tanzeum®)

30 mg once weekly

↑ to 50 mg once weekly if inadequate response

50 mg once daily

Renal impairment: use cautionHepatic impairment: not studied

Dulaglutide (Trulicity®)

0.75 mg once weekly

↑ to 1.5 mg once weekly if inadequate response

1.5 mg once weekly

Renal impairment: use cautionHepatic impairment: use with caution

• Benefits– Potential preservation of Beta cell function– No hypoglycemia– Weight loss– Decreases blood pressure– Improves lipid profile

• Side effects– GI intolerance– Injection site reactions– ? Acute pancreatitis – ? Medullary Carcinoma of thyroid

GLP-1 Agonists

GLP-1 Agonist• Achieve level of GLP-1

which is beyond biological level

• Weight loss

DPP-4 inhibitors• Oral administration

GLP-1 Agonists vs DPP-4 inhibitors

• GLP-1 agonist achieved greater HbA1c reduction as compared to DPP-4 inhibitors

• Several oral GLP-1 agonists are under development

– ORMD-0901

– NN9924 & NN9928

• MKC253 is inhaled GLP-1 agonist under development

• Continuous application of Exenatide by a subcutaneous device

DUROS

– Once yearly application

– Presently in phase 3

GLP-1 Agonists

• Sodium glucose co-transporter 2 inhibitors• Improve glucose control by increasing urinary

glucose excretion

SGLT-2 inhibitors

William T. Cefalu and Matthew C. Riddle. SGLT2 Inhibitors: The Latest“New Kids on the Block”! Diabetes Care 2015;38:352–354

SGLT-2 inhibitors

CanagliflozinDapagliflozinEmpagliflozin

SGLT-2 inhibitors

• Benefits– Reduces HbA1c by 0.9%– Weight reduction– Blood pressure reduction– Reduces risk of coronary events

• Side effects-– Increased UTI– Genital mycotic infections– Hyperkalemia– Orthostatic hypotension

SGLT-2 inhibitors

• Novel dual inhibitor of SGLT1 and SGLT2 - (LX4211)

New developments

• Molecular structure similar to human insulin • Deletion of threonine at B30 and addition of 16-

carbon fatty acid to lysine at B29• Forms dihexamers in solution • Multi-hexamers after subcutaneous injection

Insulin Degludec

• Benefits– Plasma half-life of 25 h in vivo– Duration of action beyond 42 h– Administered once daily– Significantly lower risk of nocturnal hypoglycemia

as compared with glargine.

Insulin Degludec

Comparison of insulin degludec with insulin glargine in insulin-naive subjects with Type 2 diabetes: a 2-year randomized, treat-to-target trial. Diabetes Med 2013 Nov;30(11):1298-304.

t

• Hypoglycemia unawareness/Recurrent hypoglycemia• Erratic meal timings• Those with irregular exercise schedules• Those who cannot monitor blood sugar frequently• Children and elderly

When to use newer insulins

Kalra S, Gupta Y, Unnikrishnan AG. Flexibility in insulin prescription. Indian J Endocr Metab 2016: 20:408-11

• Type 1 diabetes mellitus is a chronic autoimmune disorder

resulting from destruction of β cells of pancreas

• Uncontrolled hyperglycemia causes various microvascular and

macrovascular complications

• These patients require good glycemic control and hence frequent

blood sugar monitoring

• A major drawback of intensification of insulin therapy is 3 times

higher risk of hypoglycemia

Artificial Pancreas

Artificial Pancreas: Past, Present, Future Claudio Cobelli, Eric Renard, and Boris Kovatchev. Diabetes, Vol. 60, November 2011

• Pioneering work by Kadish et al in 1964• Artificial Pancreas based on using

– intravenous glucose measurement – infusion of insulin – Infusion of glucose

• First commercial device – Biostator developed in 1977• In the late 1980s, an implantable system was introduced

using intravenous glucose sensing and intraperitoneal insulin infusion

History

• Artificial Pancreas: Past, Present, Future Claudio Cobelli, Eric Renard, and Boris Kovatchev. Diabetes, Vol. 60, November 2011

Biostator

• Large devices worn in a backpack• Intravenous route of glucose sensing and insulin

infusion unsuitable for outpatient use• Extensive surgical procedures needed for sensor and

pump implantation• Glucagon not included in delivery devices

Issues

• Continuous subcutaneous insulin infusion (CSII) came into being in 1990s

• Continuous glucose monitoring (CGM) systems were developed about 10 yrs ago

• Both these systems coupled together attempted to mimic a physiological insulin delivery pattern of the pancreas

Artificial Pancreas

• This system fell short of physiological replacement modality because glucagon was not included in therapy

• Patient still had to take the burden of decision making

Artificial Pancreas

• Components– Continuous glucose monitoring (CGM) system– Prefixed computer algorithm– Dual subcutaneous insulin infusion – delivers both rapid

acting insulin and glucagon• Monitoring is done every 5-10 mins• Automated insulin dosing

New Artificial Pancreas

New Artificial Pancreas

• RCT (2014) - Haidar et al compared dual-hormone artificial pancreas, single-hormone artificial pancreas and continuous subcutaneous insulin infusion

• Single-hormone and dual-hormone artificial pancreas systems provided better glycemic control than did conventional insulin pump therapy

Recent developments

Comparison of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy for glycaemic control in patients with type 1 diabetes: an open-label randomised controlled crossover trial. The Lancet. Volume 3, No 1 p17–26, January 2015

• No single device integrating all the components is yet available• During a hypoglycemic episode, interstitial glucose and blood

glucose values can be markedly different• Relatively slow absorption of subcutaneous insulin causing delay in

action• Altered absorption at the subcutaneous delivery site – underdosing

of insulin – risk for DKA• Glucagon forms amyloid fibrils within few hrs of reconstitution and

has to be prepared daily• Glucagon fibrils are cytotoxic and can even cause pump occlusion

Limitations

• A patient-centered approach should be used to guide the choice of pharmacologic agents.

• Considerations include efficacy, hypoglycemia risk, impact on weight, potential side effects, cost and patient preferences

• If noninsulin monotherapy does not achieve target A1C after 3 months, add a second oral agent, a glucagon-like peptide 1 receptor agonist or basal insulin

• In patients with established atherosclerotic cardiovascular disease, empagliflozin or liraglutide should be considered as they have been shown to reduce cardiovascular and all-cause mortality

Conclusion