Pratap sagar Tiwari, MD, Internal Medcine,

Lecturer, NMCTH

UNDERSTANDING DIABETES..PART 4 THE DRUGS

CASE SUMMARY

• A 30 yrs old M was brought in ERD in the state of unconsciousness.

(Note: Coma is a symptom, not a diagnosis.)

Pic taken from http://censorbugbear-reports.blogspot.com/2010/03/shocking-neglect-of-comatose-patient-at.html

RECAP OF PREVIOUS PARTS

• Causes of patient in state of coma• Definition of terms related to consciousness• Causes of Coma in a Diabetic Patient• Insulin Synthesis/ Secretion• Regulation of Glucose hemostasis• Response of hypoglycemia in normal & DM• Hypoglycemia & symptoms• DKA /HHS• Abnormal respiration patterns• DM- introduction, diagnosis, classification, prediabetes, GDM

PHARMACOLOGICAL MANAGEMENT

ASPIRIN

• Consider aspirin therapy (75–162 mg/ day) as a primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk . C

• This includes most men aged >50 years or women aged >60 years who have at least one additional major risk factor (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria).

STATIN

• Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients:

1. with overt CVD

2. without CVD who are over the age of 40 years and have one or more other CVD risk factors (family history of CVD, hypertension, smoking, dyslipidemia,or albuminuria).

ACE INHIBITOR

• An ACE inhibitor or ARB for the primary prevention of diabetic kidney disease is not recommended in diabetic patients with normal blood pressure and albumin excretion <30 mg/24 h. B

• Either ACE inhibitors or ARBs (but not both in combination) are recommended for the treatment of the nonpregnant patient with modestly elevated (30–299 mg/24 h) C or higher levels (.300 mg/24 h) of urinary albumin excretion. A

OHA• Biguanides eg Metformin

• Thiazolidinediones eg Pioglitazone

• Sulfonylureas eg Glimepiride

• Meglitinide eg Mitiglinide, Repaglinide, Nateglinide

• Glucosidase inhibitors eg Acarbose, voglibose, miglitol

• Dipeptidyl peptidase IV inhibitors eg Sitagliptin

• SGLT2 inhibitor: eg Dapagliflogin, canagliflozin

PARENTERAL

• Insulin

• GLP-1 receptor agonists eg Exenatide, Liraglutide

• Amylin agonists eg pramlintide

OHA

• Increase insulin release (sulfonylureas & meglitinides)& IBT

• Increase insulin action (metformin & thiazolidinediones)

• Modify intestinal absorption of sugar (alpha-glucosidase inhibitor)

Insulin secretagogues

Insulin Sensitizers

BIGUANIDES: METFORMIN• MOA:

1. ↑ glycolysis and glucose removal from blood

2. ↓ hepatic and renal gluconeogenesis

3. ↓ glucose absorption in GI tract

4. ↓ reduce plasma glucagon levels

5. Can be used as monotherapy or dual therapy

6. Dosage: should be taken with meals and should be started at a low dose to avoid intestinal side effects. The dose can be increased slowly as necessary to a maximum of 2550 mg/day (850 mg TID).

7. Advantage: doesnot cause hypoglycemia , weight gain and also act as lipid loweirng agent

8. Disadvantage: GI side effects, lactic acidosis, B12 deficiency

Joint guidelines from the AACE and ACE recommend that metformin be initiated as first line monotherapy unless a contraindication such as renal disease, hepatic disease, gastrointestinal intolerance or risk of lactic acidosis coexists. [1]

1.Rodbard HW, Jellinger PS, Davidson JA et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on Type 2 diabetes mellitus: an algorithm for glycemic control. Endocr. Pract. 15(6), 540–559 (2009).

SULFONYLUREAS• MOA: stimulate insulin secretion. bind co-receptor of B cell K+channel, result in

depolarization of cell, ↑[Ca+2] stimulates insulin secretion. ↓ glucagon secretion.

• Tolbutamide, chlorpropamide: 1st gen

• Glyburide, glipizide and glimiperide: 2nd gen

• Can be used as monotherapy or dual therapy

• Advantage: Hypoglycemia effects

• Disadvantage: Hypoglycemia, weight gain, nausea, skin reactions, photosensitivity, abnl LFTS , leucopenia

• Glimiperide: Initial: 1-2 mg PO qAM before meal; may increase dose by 1-2 mg every 1-2 weeks; not to exceed 8 mg/day

• Glipizide: 2.5-20 mg PO qDay or q12hr; not to exceed 40 mg/day

MEGLITINIDES: REPAGLINIDE AND NATEGLINIDE • Non sulphonylurea Insulin secretagogues

• Short-acting drugs similar to SU’s in mechanism

• OOA is faster and the half-life is shorter. Fast acting, taken just prior to meals

• Start at 0.5 mg before each meal ,3-4 times a day

• Minimal renal clearance; may be useful in renal pts (especially repaglinide)

• A/E: Hypoglycemia a risk if meals delayed, avoid in liver failure and caution in RF

• Monotherapy or combined BUT NOT WITH SULPHONYLUREAS

• Repaglinide: Initial dose 0.5 mg PO with no prior treatment, or 1-2 mg with prior treatment

THIAZOLIDINEDIONES• MOA: They act by binding to the Peroxisome Proliferative insulin activated

receptors enhancing Sensitizing effects of insulin at liver, muscle as well as fat tissues also by inhibiting glucose formation by liver.

• Decrease insulin resistance, Major site of action-adipose tissue

• A/E: weight gain, edema, anemia, pulmonary edema and congestive heart failure, liver toxicity, slow OOA

• Advantage: relatively safe in patients with impaired renal function because they are highly metabolized by the liver and excreted in the feces; doesnot cause hypoglycemia.

• Pioglitazone: 15-30 mg PO with meal qDay initial; titrate to 45 mg qDay

ALPHA-GLUCOSIDASE INHIBITORS: ACARBOSE, MIGLITOL

• Inhibits enzymes in the small intestinal brush border that are responsible for the breakdown of oligosaccharides and disaccharides into monosaccharide suitable for absorption.1

• Less effective than SU’s, metformin, used mainly as added agent when needed

• SE: flatulence, diarrhea

• Doses over 50 TID increase SE with little added benefit 1. Lebovitz HE. Alpha-glucosidase inhibitors. Endocrinol Metab Clin North Am 1997;26:539-51

NEWER DRUGS

• Dipeptidyl peptidase IV inhibitors

• GLP-1 receptor agonists

• SGLT2 inhibitor

DIPEPTIDYL PEPTIDASE IV INHIBITORS

Pic taken from : http://en.wikipedia.org/wiki/Incretin

INCRETINS• A group of GI hormones that stimulate a ↓ in BG levels.

• Do so by causing an ↑ in the amount of insulin released from the b cells of IOL after eating.

• They also slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying .

• They also inhibit glucagon release from the a cells of IOL.

• Eg: glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide .

• Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).

DIPEPTIDYL PEPTIDASE IV INHIBITORS• The first agent of the class - sitagliptin - was approved by the FDA in

2006.[1]

• MOA: to ↑ incretin levels (GLP-1 and GIP),[2] which ↓ glucagon release, which in turn ↑ insulin secretion, ↓ gastric emptying, and ↓ BG levels.

• Dont use with insulin or SU. Use with caution in Renal impairment

• Eg: sitagliptin, vildagliptin ,linagliptin

• Sitagliptin : 25,50,100 mg PO OD with or without food

• A/E: nasopharyngitis, headache, nausea, hypersensitivity and skin reactions, Heart failure, Pancreatitis and pancreas cancer risk.

1. "FDA Approves New Treatment for Diabetes" (Press release). U.S. Food and Drug Administration. October 17, 2006. Retrieved 2006-10-17.2. McIntosh, C; Demuth, H; Pospisilik, J; Pederson, R (2005). "Dipeptidyl peptidase IV inhibitors: How do they work as new antidiabetic agents?". Regulatory Peptides 128 (2): 159–65.

GLP-1 RECEPTOR AGONISTS • GLP-1 receptor agonists enhance glucose-dependent insulin

secretion by the pancreatic beta-cell, suppress inappropriately elevated glucagon secretion, and slow gastric emptying.

• Disadvantages :GI A/E ,[1] their administration by injection, from 2 times/d- 1 time/wk .

• Hypoglycaemia, especially when associated with SU.[1], pancreatitis, nausea, vomiting n diarrhea.

• Eg: exenatide (5-10 mg sc before meal),liraglutideShyangdan, DS; Royle, P; Clar, C; Sharma, P; Waugh, N; Snaith, A (Oct 2011). "Glucagon-like peptide analogues for type 2 diabetes mellitus.". The Cochrane database of systematic reviews (10): CD006423

SGLT2 INHIBITORSGLT2 is a protein that facilitates glucose reabsorption in the kidney. SGLT2 inhibitors block the reabsorption of glucose in the kidney, increase glucose excretion, and lower BG levels

EG: empagliflozin, canagliflozin, dapagliflozin, ipragliflozin

Pic taken from : http://www.diabetesincontrol.com/images/sglt2/sglt2-1hdiw.png

Canagliflozin: 100 mg Po od before meal

AMYLIN AGONISTS• Cosecreted with insulin from the pancreatic β-cells.

• Plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

• Pramlintide , was recently approved for adult use in patients with both DM T1 and T2.

• Insulin and pramlintide, injected separately but both before a meal, work together to control the post-prandial glucose excursion.[1]

1. Amylin Pharmaceuticals, Inc. 2006. Archived from the original on 13 June 2008. Retrieved 2008-05-28.

INSULIN: CLINICAL USES

1. T1 diabetes mellitus

2. Insulin-independent patients: failure to other drugs

3. Diabetic complications: DKA , HHS

4. Critical situations of diabetic patients: fever, severe infection, pregnancy, trauma, operation

INSULIN

SIDE EFFECTS OF INSULIN THERAPY

• Hypoglycaemia

• Weight gain

• Peripheral oedema (insulin treatment causes salt and water retention in the short term)

• Insulin antibodies (animal insulins)

• Local allergy (rare)

• Lipodystrophy at injection sites

Reference: L BEATRIZ, F MARK. Oral Agents in the Management of Type 2 Diabetes Mellitus. Am Fam Physician. 2001 May 1;63(9):1747-1757.

END OF SLIDESReferences:

1.Harrison's Principles of Internal Medicine, 18th Edition

2.Davidson Practice of Medicine

3.Uptodate 20.3

4.Standards of Medical Care in Diabetesd 2014. American Diabetes Association. Diabetes Care Volume 37, Supplement 1, January 2014

5.Medscape.com

6.Mercksmanual

DKA

• 30 yrs old male ,thinly built .

• H/o significant loss of weight

• Presentation : coma .H/o fever

• Kussmaul breathing , signs of dehydration , dry skin ,hypotension, tachycardia, weak rapid pulse

• Raised blood sugar and Urice