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I. DIABETES MELLITUS Latin words: DIABETES : excess urine (polyuria) MELLITUS : sweet, honey (glycosuria) Which is different from diabetes insipidus (latin : no taste) where the cause of polyuria is a defeciency of antidiuretic hormone (ADH)


insulin Insulin is a hormone, produced by the pancreas, which is central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen inside these tissues. Gluconeogenesis Glycogenesis Peripheral uptake of glucose in skeletal muscles and adipose tissue Glucagon


Classification 1-Type 1 DM Attributable to cellular-mediated β- cell destruction leading to insulin deficiency ( insulin required for survival ) b. Formerly known as insulin-dependent diabetes IDDM, juvenile-onset diabetes c. Most commonly presents in childhood or early adulthood but can present in any stage of life d. Usually symptomatic with a rapid onset in childhood but can be slower in older adults

2. Type 2 DM :

2. Type 2 DM a. Result of insulin resistance with subsequent defect in insulin secretion insulin resistance : insulin less effective in lowering blood glucose may be due to (obesity, genetic, pregnancy or stress) b . Accounts for 90%–95% of DM c. Formerly known as non–insulin-dependent diabetes NIDDM , adult-onset diabetes d. Often relatively asymptomatic with a slow onset e. Disturbing trends in type 2 DM in children and adolescents attributed to increase in obesity

3. Gestational diabetes :

3. Gestational diabetes a. Glucose intolerance occurring during pregnancy b. Most common in third trimester c. If a diagnosis of gestational DM is made, screen for diabetes 6-12 weeks after delivery

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4. Prediabetes a. Impaired glucose tolerance b. impaired fasting glucose Other DM types Genetic defects in β- cell function or insulin action b . Diseases of the pancreas e.g. pancreatitis (inflammation of the pancreas) Neoplasia (abnormal proliferation of cells) cystic fibrosis (scarring and cyst formation within the pancreas) c. Drug or chemical induced e.g., glucocorticoids nicotinic acid (vitamin B3) protease inhibitors (antiviral) atypical antipsychotics

DM Diagnosis:

DM Diagnosis 1. Type 1 and 2 DM diagnosis a. Glycemic parameters in nonpregnant patients i. Fasting plasma glucose (FPG) 12 hour ( N: 70-100 mg/dL ) (a) Easy and preferred method (b) 126 mg/dL or greater ii. Random plasma glucose (a) 200 mg/dL or greater with symptoms of hyperglycemia (b) Common hyperglycemia symptoms include polyuria, polydipsia, and unexplained weight loss

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iii. Oral glucose tolerance test (a) Plasma glucose concentration obtained 2 hours after a 75-g oral glucose ingestion (b) 200 mg/dL or greater (c) More sensitive and specific than FPG but more cumbersome to perform .With an abnormal test result, the patient should be tested again (preferably with the same test, but it can be any of the above on a subsequent day or by obtaining a hemoglobin A1c unless unequivocal hyperglycemia is noted ) v. A1c (glycated hemoglobin) Normal bl. Glucose produces glycated Hb As bl. Glucose elevated : glycated Hb increases A marker of previous 2-3 months (a) 6.5% or greater (b) Confirmed by repeating (unless unequivocal hyperglycemia is noted), though interval for repeating test is not provided (c) May be less sensitive than FPG but does not require fasting and has less variability from day to day (d) A1c values may be inaccurate in patients with hemolytic anemia, chronic malaria, or significant blood loss and/or recent blood transfusion

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c. Other useful diagnostic tests if type of DM present is in question C-peptide ( measure of insulin secretion, usually negligible in type 1 DM and normal or elevated in type 2 DM )

2. Prediabetes diagnosis :

2. Prediabetes diagnosis Impaired fasting glucose: FPG between 100 and 125 mg/ dL b. Impaired glucose tolerance: 2-hour plasma glucose post-OGTT (75 g) between 140 and 199 mg/ dL c. A1c between 5.7% and 6.4%

3. Gestational diabetes diagnosis :

3. Gestational diabetes diagnosis Glycemic parameters in pregnancy a. 2012 American Diabetes Association updated and simplified diagnosis criteria b. 75-g OGTT at weeks 24–28 of gestation i . Fasting: 92 mg/ dL or greater ii. 1 hour post-OGTT: 180 mg/ dL or greater iii. 2 hours post-OGTT: 153 mg/ dL or greater

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Normal Prediabetes DM FPG mg/dL < 100 100-125 ≥ 126 A1c < 5.7 % 5.7-6.4 % ≥ 6.5 % OGTT mg/dL < 140 140-199 ≥ 200

Goals of Diabetes Management in Nonpregnant Adults:

Goals of Diabetes Management in Nonpregnant Adults -Primary goal is to prevent the onset of acute or chronic complications. 1. Acute complications : - Hypoglycemia - Diabetic ketoacidosis ( DKA) : When insulin decreases, body metabolizes fatty acids for energy resulting in acidic ketone bodies hyperglycemic hyperosmolar nonketotic syndrome (NKHS ) Hyperglycemia, dehydration >>> hyperosmolar plasma 2. Chronic complications : a. Microvascular: Retinopathy, nephropathy, and neuropathy b. Macrovascular : Cardiovascular, cerebrovascular, and peripheral vascular diseases

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3. Glycemic therapy goals a. A1c less than 7.0%. (Note: The ACE/AACE guidelines recommend 6.5% or less.) i. Obtain every 6 months in patients at goal and quarterly in uncontrolled patients. ii. Less-stringent A1c targets may be appropriate in those with shorter life expectancy, advanced diabetes complications, long-standing diabetes that is difficult to control, or extensive other comorbidities. b. FPG 70–130 mg/dL. Frequency of monitoring very dependent on regimen, type of DM , and current glycemic control c. Peak postprandial glucose (1–2 hours after a meal) less than 180 mg/dL 4. Non-glycemic therapy goals a-Blood pressure less than 130/80 mm Hg b. Lipids i . Low-density lipoprotein cholesterol ( LDL-C ) less than 100 mg/ dL ; less than 70 mg/dL an option in those with existing cardiovascular disease ii. TG less than 150 mg/dL

Goals for Gestational Diabetes:

Goals for Gestational Diabetes 1. Primary goal is to prevent complications to mother and child. 2. Glycemic therapy goals (more stringent) a. FPG 95 mg/dL or less b. 1-hour postprandial glucose 140 mg/dL or less c. 2-hour postprandial glucose 120 mg/dL or less 3. Potential complications of hyperglycemia during pregnancy a. Mother: Hypertension, preeclampsia, type 2 DM after pregnancy b. Fetus/child: Macrosomia, hypoglycemia, jaundice, respiratory distress syndrome

Benefits of Optimizing Diabetes:

Benefits of Optimizing Diabetes 1. Glycemic control a. Reduce the risk of developing retinopathy, nephropathy, and neuropathy in type 1 and 2 DM. b. Prospective studies specifically designed to assess optimizing glycemic control, as well as its effect on cardiovascular events, have not shown reduced cardiovascular outcomes. c. However, the “legacy” effect seen in the Diabetes Control and Complications Trial in type 1 DM and the United Kingdom Prospective Diabetes study in type 2 DM suggests early control has future cardiovascular benefit . d. No profound benefit of very aggressive glycemic control in type 2 DM (A1c less than 6.5%) 2. Blood pressure control: Reduction in both macrovascular and microvascular complications 3. Lipid control: Reduction in LDL-C with statin therapy reduces cardiovascular complications.

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Anti Diabetes Agents in Type 2 DM:

Anti Diabetes Agents in Type 2 DM 1. Sulfonylureas 1%–2% 2. Meglitinides 0.5 %–1.5 % 3.Glucagon-lik peptide-1 agonist “ incretin ” 0.5-1% 4. Dipeptidyl peptidase-4 inhibitors 0.5%–0.8% 5. Metformin ( biguanide ) 1%–2% 6 . Thiazolidinediones (TZDs or glitazones ) 0.5%–1.4% 7 . α- Glucosidase inhibitors 0.5%–0.8 % 8-Amylin analog 0.5-1% 9-Combination products

1. Sulfonylureas:

1. Sulfonylureas a. Mechanism of action: Bind to receptors on pancreatic β- cells, leading to membrane depolarization with subsequent stimulation of insulin secretion (insulin secretagogue ) Block K channels >> membrane depolarization >> Ca influx >> secretion b. First-generation agents seldom used today e.g ., chlorpropamide, tolbutamide c. Second-generation agents e.g ., glyburide (glibinclamide DAONIL ), glipizide ( MINIDIAB ), glimepiride ( AMARYL ) Dose titration: Can increase at weekly intervals as necessary

1. Sulfonylureas:

1. Sulfonylureas d. Adverse effects i . Common: Hypoglycemia (insulin secretion) , weight gain ii. Less common: Rash, headache, nausea, vomiting, photosensitivity e. Contraindications/precautions i. Hypersensitivity to sulfonamides ii. Patients with hypoglycemic unawareness iii. Poor renal function ( glipizide may be a better option than glyburide or glimepiride in elderly patients or in those with renal impairment because drug or active metabolites are not renally eliminated) f. Efficacy i. 1%–2% A1c reduction ii. Note: For this and all medications used to treat hyperglycemia, the absolute decrease in A1c is larger for higher baseline A1c values and smaller for lower A1c values.

1. Sulfonylureas:

1. Sulfonylureas

2. Meglitinides ”glinid”:

2. Meglitinides ” glinid ” a. Mechanism of action: Very similar to that of sulfonylureas in increasing insulin secretion from the pancreas but with a more rapid onset and shorter duration of activity b. Glucose-dependent activity c. Two currently available: Repaglinide (NovoNorm) and nateglinide (starlix) d. Dosing i. Repaglinide (a) Initial: 0.5–1 mg 15 minutes before meals (b) Maximal daily dose: 16 mg ii. Nateglinide (a) 120 mg before meals (b) 60 mg if A1c near goal iii. Repaglinide can be increased in weekly intervals if needed.

2. Meglitinides:

2. Meglitinides e. Adverse effects: Hypoglycemia (though less than with sulfonylureas), weight gain, upper respiratory infection f. Contraindications/precautions i. Hypersensitivity ii. Caution in concomitant use of repaglinide and gemfibrozil , can lead to greatly increased repaglinide levels g. Efficacy: i. 0.5%–1.5 % A1c reduction (repaglinide shown to reduce A1c more than nateglinide) ii. Most effective on postprandial glucose excursions (change in glucose from before and after meal)

2. Meglitinides:

2. Meglitinides

3. GLP-1 analog :

3. GLP-1 analog a. Mechanism of action: Synthetic analog of human GLP-1 that binds to GLP-1 receptors, resulting in glucose-dependent insulin secretion, reduction in glucagon secretion, and reduced gastric emptying; promotes satiety c. Dosing i. Exenatide (BYETTA) (a) Initial: 5 mcg subcutaneously twice daily administered no more than 60 minutes before morning and evening meals (b) Maximal daily dose: 20 mcg/day (c) Dose titration from 5 to 10 mcg twice daily after 1 month if tolerated ii. Liraglutide (VICTOZA) (a) 0.6 mg subcutaneously once daily for 1 week ( regardless of mealtime ) (b) Dose titration from 0.6 to 1.2 mg/day if tolerated (c) Maximal daily dose: 1.8 mg/day iii. Both agents available in prefilled, multidose syringes

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d. Adverse effects i. Nausea, vomiting, diarrhea very common ii. Hypoglycemia (INSULIN SECRETION) common with concurrent sulfonylurea (consider reduction in sulfonylurea dose if adding exenatide) iii. Postmarketing reports of pancreatitis, acute renal failure or impairment e. Contraindications/precautions i. Impaired renal function, CrCl less than 30 mL/minute ii. History of severe GI tract disorder iii. History of pancreatitis iv. For liraglutide: Contraindicated in patients with a personal or family history of medullary thyroid carcinoma (adverse effect found in rodent studies but not in humans) f. Efficacy i. A 0.5%–1.1% reduction in A1c ii. Effects on postprandial hyperglycemia better than fasting glucose concentrations iii. Modest weight loss

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3. GLP-1 analog

4. Dipeptidyl peptidase-4 inhibitors”Glptins”:

4. Dipeptidyl peptidase-4 inhibitors”Glptins ” Mechanism of action: -Inhibits the break down of glucagon-likepeptide-1 (GLP-1) secreted during meals, which in turn increases pancreatic insulin secretion, limits glucagon secretion, slows gastric emptying, and promotes satiety b. Two agents available : sitagliptin (Januvia) and saxagliptin ”Onglyza ” , vildagliptin ”Galvus ” c. Dosing i. Sitagliptin: 100 mg once daily (a) Reduce with CrCl between 30 and 50 mL/minute to 50 mg once daily. (b) Reduce with CrCl less than 30 mL/minute to 25 mg once daily. ii. Saxagliptin: 5 mg once daily (Reduce with CrCl equal to 50 mL/minute or less to 2.5 mg once daily.)

4. Dipeptidyl peptidase-4 inhibitors:

4. Dipeptidyl peptidase-4 inhibitors

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d. Adverse effects i. Upper respiratory and urinary tract infections, headache ii. Hypoglycemia with monotherapy is minimal, but increased frequency with concurrent sulfonylurea therapy (can lower dose of sulfonylurea when initiating) iii. Sitagliptin has had some postmarketing reports of : acute pancreatitis, angioedema (swelling in skin and subcutanous tissue) , Stevens-Johnson syndrome (fever - sore throat - ulcers in mouth and tongue – conjunctivitis – rash in face), and anaphylaxis . e. Contraindications/precautions i. Previous hypersensitivity to the agents ii. History of pancreatitis f. Efficacy: 0.5 %–0.8% reduction in A1c

5. Metformin (biguanide):

5. Metformin (biguanide) -Mechanism of action: Reduces hepatic gluconeogenesis . has favorable effects on insulin sensitivity and intestinal absorption of glucose - Dosing i. Initial: 500 mg once or twice daily (once daily with extended-release formulations) ii. Maximal daily dose: 2550 mg (more commonly 2000 mg/day) iii. Can increase at weekly intervals as necessary iv. Small initial dosage and slow titration secondary to gastrointestinal (GI) disturbances

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c. Adverse effects Common : Nausea , vomiting, diarrhea, epigastric pain Less common: Decrease in vitamin B12 levels, lactic acidosis (rare) Anaerobic metabolism of glucose >> lactate >> acidosis Lactic acid is byproduct of (glucose and amino acids) increases due to : Overproduction ( hypoperfusion ) and/or decreased metabolism (liver) iii. Signs or symptoms of lactic acidosis include acidosis, nausea, vomiting, increased respiratory rate, abdominal pain, shock, and tachycardia

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d. Contraindications/precautions i. Renal impairment: Serum creatinine 1.5 mg/dL or greater in men and 1.4 mg/dL or greater in women or reduced creatinine clearance (CrCl; CrCl cutoff is not well established, but it may be as low as 30 mL/minute). Renal insufficiency increases risk of lactic acidosis. ( as kidney is responsible of acid-base balance) ii. Age 80 years or older iii. High risk of cardiovascular event or hypoxic state (decreased O2 >> anaerobic metabolism of glucose >> lactic acid ) iv. Hepatic impairment (metabolism of lactate) v. Congestive heart failure (especially if prone to exacerbations) vi. Interrupt therapy if undergoing procedures using iodinated contrast dye because of its nephrotoxicity. Reinitiate after 48 hours, and normal serum creatinine oncentrations are ach ieved. e. Efficacy: i. 1%–2% A1c reduction ii. Some benefit in TG reduction and weight loss iii. Considered first-line therapy unless contraindicated on the basis of adverse effect profile, reduction in A1c, cost, and limited data on reduction of cardiovascular events in overweight patients

5. Metformin (biguanide):

5. Metformin (biguanide)

6. Thiazolidinediones (TZDs or glitazones):

6. Thiazolidinediones (TZDs or glitazones) a. Mechanism of action i. Peroxisome proliferator-activated receptor γ (PPAR γ ) agonist When activated : ii. Increases expression of genes responsible for glucose metabolism, resulting in improved insulin sensitivity b. Two agents available: Pioglitazone ( Actos,Glustin ) and rosiglitazone (avandia) i. In September 2010, the U.S. Food and Drug Administration (FDA) initiated restricted access to rosiglitazone secondary to continued concerns about its cardiovascular safety. ii. When fully implemented, it will be restricted to patients unable to obtain glycemic control with other agents and when pioglitazone is not used for medical reasons . c. Dosing i. Pioglitazone (a) Initial: 15 mg once daily (b) Maximal daily dose: 45 mg ii. Rosiglitazone (a) Initial: 1–2 mg once daily (b) Maximal daily dose: 8 mg iii. Dose titration is slower with these agents, and the maximal effect of a dose change may not be observed for 8–12 weeks.

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d. Adverse effects i. Weight gain ii. Fluid retention (particularly peripheral edema), worse with insulin use ( manufacturer of rosiglitazone states to no longer use with insulin). Edema less responsive to diuretic therapy iii. Risk of bone fractures iv. Increased risk of heart failure (a) Both have a black box warning . (b) More than 2-fold higher relative risk, though absolute risk is quite small v. Controversial increase in myocardial infarction and cardiovascular death with rosiglitazone e. Contraindications/precautions i. Hepatic impairment ii. Class III/IV heart failure iii. Existing fluid retention f. Efficacy i. 0.5%–1.4% A1c reduction ii. Both increase HDL-C , but pioglitazone has more favorable effects on reducing LDLC and TG than rosiglitazone.

6. Thiazolidinediones (TZDs or glitazones):

6. Thiazolidinediones (TZDs or glitazones)

7. α-Glucosidase inhibitors:

7 . α- Glucosidase inhibitors Mechanism of action: Slows the absorption of glucose from the intestine into the bloodstream by slowing the breakdown of large carbohydrates into smaller absorbable sugars b. agents available: Acarbose ( Glucobay ) c. Dosing i . Initial: 25 m g 3 times/day at each meal ii. Maximal daily dose: 300 mg iii. Slow titration, increasing as tolerated every 4–8 weeks to minimize GI adverse effects

7. α-Glucosidase inhibitors:

7 . α- Glucosidase inhibitors d. Adverse effects i. Flatulence, diarrhea, abdominal pain ii. Increased liver enzymes observed with high doses of acarbose e. Contraindications/precautions: Inflammatory bowel disease, colonic ulcerations, intestinal obstruction f. Efficacy i. 0.5%–0.8% reduction in A1c ii. Targets postprandial glucose excursions iii. May not be as effective in patients using low-carbohydrate diets

7. α-Glucosidase inhibitors:

7 . α- Glucosidase inhibitors

Amylin analog :

Amylin analog a. Mechanism of action: Synthetic analog of human amylin. Amylin is cosecreted with insulin and has effects similar to GLP-1 described above. b. Pramlintide is currently the only agent in this class available in the United States. Can be used in either type 1 or type 2 DM as adjunctive therapy in patients receiving insulin b. Adverse effects i . Black box warning for severe hypoglycemia (INSULIN SECRETION) , especially in patients with type 1 DM ii. Nausea, vomiting, anorexia, headache c. Contraindications/precautions i . Substantial gastroparesis (delayed gastric emptying rate) ii. History of poor adherence or monitoring of blood glucose iii. Hemoglobin A1c greater than 9% iv. Hypoglycemia unawareness or frequent bouts of hypoglycemia d. Efficacy i . A 0.5%–1% reduction in A1c ii. Very effective at controlling postprandial glucose excursions

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c . Dosing i . Type 1 DM (a) Initial: 15 mcg subcutaneously immediately before main meals (b) Must reduce dose of preprandial rapid-acting, short-acting, or combination insulin products by 50% (c) Maximal daily dose: 60 mcg with each meal (d) Dose should be titrated in 15-mcg increments, as tolerated, no more rapidly than every 3 days. ii. Type 2 DM (a) Initial: 60 mcg subcutaneously immediately before main meals (b) As above, must reduce preprandial insulins by 50% (c) Maximal daily dose: 120 mcg with each meal (d) Dose should be titrated in 60-mcg increments, as tolerated, no more rapidly than every 3–7 days iii. Use of prefilled pens is strongly recommended when possible versus using a syringe and vial to reduce risk of dosing errors (dosing instructions with U-100 syringes and vial in package insert). iv. Cannot be mixed with insulin products, requires increased frequency of daily injections

Amylin analog :

Amylin analog

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9 . Combination products

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Insulin 1. Categorized on the basis of therapy duration after injection a. Short acting: Regular human insulin ( Humalin R) ( actrapid ).

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b. Rapid acting: Insulin aspart ( novorapid ) , lispro ( humalog ) , glulisine ( apidra )

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c. Intermediate acting: Neutral protamine Hagedorn (NPH) ( insulatard )

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d. Long acting Insulin glargine ( lantus ) and detemir ( levemir ), cannot be mixed with other insulins

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2. Combination products ( NPH /either regular or r apid-acting insulin): 70/30, 75/25 ( mixtard 70/30) ( novomix )


Insulin hypoglycemia

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Insulin Duration Chart Basal/Bolus Regimen

Therapeutic Insulin Management of Type 1 DM:

Therapeutic Insulin Management of Type 1 DM 1. First step is to estimate TDI requirements. 2. Weight-based estimate if insulin naïve (new, 1 st time ) a. 0.3–0.6 unit/kg/day b. Requirements higher if treating DKA near initial diagnosis of DM c. Honeymoon phase shortly after initiation of treatment often requires lower daily insulin needs. Honeymoon phase : pancreas is not completely destroyed >> secretes unpredictable amounts of insulin 3. One common approach is to use older insulin formulations ( NPH and regular insulins). a. Two-thirds of TDI given before morning meal . Two-thirds of this given as NPH and onethird as regular insulin b. One-third of TDI given before evening meal (or regular given before meal and NPH at bedtime). Again, two-thirds of this given as NPH and one-third as regular insulin c. Advantages: Daily insulin injection frequency 2–3 times/day and inexpensive d. Disadvantages: Does not mimic natural insulin secretion pattern, prone to hypoglycemic events

Therapeutic Insulin Management of Type 1 DM:

Therapeutic Insulin Management of Type 1 DM 4. Another approach is basal/bolus insulin therapy (a.k.a. physiologic insulin therapy). a. Use of newer insulin analogs to better mimic natural insulin secretion patterns b. Provides day-long basal insulin to prevent ketosis and to control FPG c. Provides bolus insulin to control postprandial hyperglycemia d. Basal insulins: Insulin glargine once daily or insulin detemir once or twice daily e. Bolus insulins: Rapid-acting insulin f. Basal requirements are 50% of estimated TDI. g. Bolus requirements are 50% of estimated TDI split three ways before meals . i. Provides initial estimate about prandial insulin needs ii. Typically, patients will begin to estimate bolus requirements based on the amount of carbohydrates to be ingested. (according to meals) h. Advantages over (NPH plus regular) approach: More physiologic , less hypoglycemia , more flexible to patient mealtimes i. Disadvantages: Cost and increased frequency of daily injections Note: The same process of basal/bolus insulin therapy can apply to a patient with type 2 DM who is receiving intensive insulin therapy with or without oral DM medications.

Therapeutic Insulin Management of Type 1 DM:

Therapeutic Insulin Management of Type 1 DM 5. Correctional insulin needs a. Always a need to occasionally correct for hyperglycemic excursions (postprandial ) despite optimal basal/bolus therapy b. “ 1800 Rule ”: 1800/TDI = # mg/dL of glucose 1 unit of rapid-acting insulin will lower i. For example: If TDI is 60 units, 1800/60 = 30, suggesting 1 unit of rapid-acting insulin will reduce blood glucose concentrations by 30 mg/dL. When blood glucose goes unexpectedly high, a correction bolus can be used After lunch it was 260 mg/dL , target 140 mg/dL Difference = 120 correction = 30 120/ 30 = 4 units of rapid-acting insulin is needed ii. Some advocate the “ 1500 Rule ” when using regular human insulin. c. More patient-specific than traditional sliding-scale insulin

Therapeutic Insulin Management of Type 1 DM:

Therapeutic Insulin Management of Type 1 DM 6. Continuous subcutaneous insulin infusion (insulin pump) a. Device allows very patient-specific hourly basal dosing and bolus insulin dosing. b. Uses rapid-acting insulins c. Requires considerable patient education and carbohydrate counting

Therapeutic Insulin Management of Type 1 DM:

Therapeutic Insulin Management of Type 1 DM 7. Assessing therapy and dosage adjustment a. Know the goals for fasting and postprandial glucose concentrations. b. Identify when patient is at goal and not at goal (hypo- or hyperglycemia). Look for consistent trends rather than isolated events. c. Identify which insulin affects problematic glucose concentrations. d. Adjust insulin dose or patient behavior accordingly. e. Same process for treating type 2 DM applies (see below)

Therapeutic Insulin Management of Type 2 DM:

Therapeutic Insulin Management of Type 2 DM 1. Given the progressive nature of type 2 DM, a stepwise approach is usually required. 2. American Diabetes Association tier 1 ( well-validated core therapies: best established, most clinically effective , and most cost-effective ) a. Step 1 : Unless contraindicated, metformin and lifestyle modifications to improve diet and exercise b. Step 2: With inadequate glycemic control with metformin therapy i. Add sulfonylurea or ii. Use basal insulin ( intermediate- or long-acting insulin: 10 units/day or 0.2 unit/kg ). Titrate basal insulin to obtain FPG between 70 and 130 mg/dL. c. Step 3 : With inadequate glycemic control with combination therapy: Lifestyle, metformin, and intensive insulin therapy i. Add rapid-acting insulin preprandially to basal insulin therapy. ii. Which meals to target depends on patient-specific glucose concentrations.

Therapeutic Insulin Management of Type 2 DM:

Therapeutic Insulin Management of Type 2 DM 3. American Diabetes Association tier 2 ( less well-validated therapies: less well established , may be used when risk of hypoglycemia is more undesirable than usual [i.e., those with hazardous jobs, etc.]) a. Step 1: As above (metformin- diet- exercise) b. Step 2: Either a or b below i. Add pioglitazone . (a) If inadequate control, add sulfonylurea (b) If inadequate control with metformin-pioglitazone-sulfonylurea , change to metformin-basal insulin combination ii. Add exenatide . If inadequate control, change to metformin-pioglitazone-sulfonylurea combination or change to metformin-basal insulin combination c. Step 3: As above 4. Initial insulin therapy: Use insulin early with any of the following baseline characteristics: a. Hemoglobin A1c greater than 10% b. Random glucose greater than 300 mg/dL or fasting glucose greater than 250 mg/dL c. Hyperglycemic symptoms d. Presence of urine ketones (KETONURIA)

Therapeutic Insulin Management of Type 2 DM:

Therapeutic Insulin Management of Type 2 DM 5. Changing from oral DM medications to insulin-only management (e.g., because of adverse effects, contraindications , lack of efficacy of oral medications) a. Can follow NPH/regular insulin or basal/bolus approach similar to that in type 1 DM described above b. The TDI requirements in type 2 DM are usually higher than in type 1 DM. 6. Changing from NPH to long-acting insulin (either insulin glargine or detemir ) a. If adequate glycemic control already obtained, initiate insulin glargine at 80% of total daily NPH dose b. Detemir may be initiated on a unit-to-unit basis (as NPH) and may require higher daily insulin dosages after conversion, but this is determined by glycemic response.

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II. TREATMENT OF DM COMPLICATIONS A. Hypoglycemia B. Diabetic Ketoacidosis C. Nephropathy D. Retinopathy E. DM Neuropathies F. Cardiovascular Disease G. Preventive Immunizations

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A. Hypoglycemia 1. Degree of intervention depends on glucose concentrations and presence of symptoms . 2. Symptoms are very patient-specific. 3. Definition: Plasma glucose less than 70 mg /dL with or without symptoms 4. Mild to moderate hypoglycemia Nausea, hunger, sweating, tachycardia, numbness, headache, blurred vision, weakness, confusion a. Oral ingestion of 15–20 g of glucose or equivalent b. Repeat glucose concentration in 15 minutes and, if still less than 70 mg/dL, repeat . 5. Severe hypoglycemia (altered consciousness , requires assistance from others) Hypothermia, seizures, coma a. Glucagon 1 mg intramuscularly b. Intravenous dextrose if patient does not respond to glucagon

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B. Diabetic Ketoacidosis When insulin decreases, body metabolizes fatty acids for energy resulting in acidic ketone bodies Serum ketones : 1) Neutral : acetone 2) Ketoacids : hydroxybutyric acid – acetoacetic acid 1. More common in type 1 DM but can occur in type 2 DM 2. Usually occurs because of a precipitating factor that considerably stresses the body, resulting in increased counterregulatory hormones a. Inappropriate (including nonadherence) or inadequate insulin therapy and infection are the two most common causes. b. Other causes: Myocardial infarction , pancreatitis , stroke , drugs (e.g., corticosteroids ) 3. Results in significant hyperglycemia , dehydration , and ketoacidosis 4. Common signs/symptoms : Polyuria, polydipsia, vomiting, dehydration, weakness, altered mental status, coma, abdominal pain, Kussmaul respirations (deep labored respiration , gasping) , tachycardia, hyponatremia, hyperkalemia (normally, insulin shifts K intracellularly)

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B. Diabetic Ketoacidosis 5. Treatment a. Treat underlying cause if known. b. Fluid replacement i. 0.45%–0.9% sodium chloride depending on baseline serum sodium concentrations ii. Change to 5% dextrose with 0.45% sodium chloride when serum glucose is less than 200 mg/dL. c. Insulin i. Goal is to stop ketosis , not to get glucose concentrations to normal. ii. Intravenous bolus : 0.1 unit/kg (7 units for 70 kg patient) iii. Intravenous infusion : (a) 0.1 unit/kg/hour (increase if not a 50- to 75-mg/dL drop in serum glucose in the first hour) (b) Alternatively, 0.14 unit/kg/hour if no insulin bolus is given (c) If not at least a 10% decrease in serum glucose obtained in first hour, give 0.14 unit/kg intravenous bolus (d) Reduce infusion rate to 0.02–0.05 unit/kg/hour when serum glucose reaches 200 mg/dL, and keep glucose between 150 and 200 mg/dL until DKA resolves. iv. Interrupt insulin treatment if baseline serum potassium is less than 3.3 mEq/L and until corrected.

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B. Diabetic Ketoacidosis d. Potassium Urinary and GIT loss >>> decreases K Insulin defeciency >>> increases K Give according to serum K level i. 20–30 mEq/L of intravenous fluid if baseline serum potassium greater than 3.3 but less than 5.3 mEq/L ii. Hold if 5.3 mEq/L or greater. iii. 20–30 mEq potassium per hour if baseline less than 3.3 mEq/L (while holding insulin) e. Intravenous bicarbonate if serum pH less than 6.9 f. DKA considered resolved and can be converted to subcutaneous insulin when serum glucose is less than 200 mg/dL and at least two of the following: i. Venous pH is greater than 7.3 . (N = 7.35- 7.45) ii. Serum bicarbonate is 15 mEq/L or greater. (N = 22-26) iii. Calculated anion gap of 12 mEq/L or less Diff. Between major cations and anions in serum = (Na + K ) - (cl + HCO3) if increased inicates : acidosis

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C. Nephropathy 1. Screen annually with random spot collection of urine albumin/creatinine ratio starting at diagnosis in type 2 DM and after 5 or more years in type 1 DM. a. Normal : Less than 30 mg/g (or micrograms per milligram) b. Microalbuminuria : 30–299 mg/g c. Macroalbuminuria : 300 mg/g or greater 2. Estimate CrCl yearly as well. Role of ACE inhibitor or ARB : decreases protein excretion (alubuminuria) 3. With type 1 DM , hypertension , and any degree of nephropathy: ACE inhibitor therapy 4. With type 2 DM , hypertension , and microalbuminuria : ACE inhibitor or ARB therapy 5. With type 2 DM , hypertension , macroalbuminuria , and serum creatinine greater than 1.5 mg/ dL: ARB therapy 6. The above differences in choice of drug class reflect what has been documented in the literature. 7. ACE inhibitors and ARBs are often used regardless of whether the patient has hypertension. 8. Dietary protein restriction as renal function declines

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D. Retinopathy 1. Screen annually with dilated and comprehensive eye examinations starting at diagnosis in type 2 DM and after 5 or more years in type 1 DM. 2. Frequency can be reduced to every 2–3 years after one or more normal examinations. 3. No specific pharmacotherapy recommended except to adequately control glucose concentrations

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E. DM Neuropathies 1. Can have nerve damage in any area of the body 2. Screen for distal polyneuropathy using monofilament once yearly (pressure of 12 locations in foot and assess if patient feels pressure) a. Screen after 5 years of type 1 DM and at diagnosis with type 2 DM . b. Diminished sensitivity is a significant risk factor for diabetes-related foot ulcer and increases the need for frequent visual inspection by patients if it exists. 3. Treatment of neuropathies is for symptomatic improvement and does not prevent progression . 4. Symptoms are patient-specific but may include numbness , burning , and tingling sensation .

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E. DM Neuropathies 5. Neuropathic pain a. Tricyclic antidepressants ( amitriptyline , desipramine ) i. Effective but limited because of anticholinergic effects (some recommend using secondary amine tricyclic antidepressants (e.g., desipramine , nortriptyline ) because they may have a lower anticholinergic effect than tertiary amines (e.g., amitriptyline , imipramine ) ii. Daily dose is less than doses used for depression. b. Anticonvulsants ( gabapentin , lamotrigine , pregabalin ) i. Comparative data of gabapentin and pregabalin against tricyclic antidepressants show similar efficacy with fewer adverse effects . Adverse effect profile is still significant ( fatigue, dizziness ) ii. Pregabalin is the only anticonvulsant approved for use in DM neuropathic pain. c. Selective serotonin reuptake inhibitor/selective serotonin and norepinephrine reuptake inhibitor ( duloxetine , paroxetine ( seroxat ) , citalopramn ( cipram ) i. Duloxetine only approved agent in this category ii. No comparative data with other agents d. Tramadol/acetaminophen e. As effective as gabapentin, different adverse effect profile

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E. DM Neuropathies 6. Gastroparesis a. Autonomic neuropathy causes considerable nausea/vomiting after meals because of delayed gastric emptying. b. N onpharmacologic strategies i. More frequent but smaller meals ii. Homogenize food. c. Pharmacologic treatment i. Metoclopramide : 10 mg before meals: Risk of tardive dyskinesia or extrapyramidal Reactions (bradykinesia, parkinson lik esymptoms, tremor , rigidity) ii. Erythromycin : 40–250 mg before meals motilin agonist , increase gastric motility

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F. Cardiovascular Disease 1. Most common cause of morbidity and mortality as well as health care expenditures in DM 2. Proper DM management should always focus on cardiovascular disease risk reduction 3. Stress and continually assess blood pressure and lipid goals described above. ( B.P. 130/80 mm Hg) ( TG < 150 mg/dL - LDL-C < 100 mg/dL) 4. Blood pressure management a. Given lower goal than for essential hypertension, often requires more antihypertensive medications b. Hypertensive regimen should include an ACE inhibitor or ARB . (protinuria) 5. Lipid management a. Assess fasting lipid profile . b. Statin therapy recommended regardless of baseline lipid levels for: i. Established cardiovascular disease ii. No history of cardiovascular event but older than 40 years with at least one cardiovascular risk factor other than DM c. A 30%–40% reduction in LDL-C can be an alternative goal in those who do not attain an LDL-C less than 100 mg/dL. d. TG goal : Less than 150 mg/dL e. HDL-C goal : Greater than 40 mg/dL for men , greater than 50 mg/dL for women

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F. Cardiovascular Disease 6. Antiplatelet therapy a. Low-dose aspirin ( 75–162 mg /day) i. With existing cardiovascular disease ii. For primary prevention if 10-year risk is greater than 10% (includes most men older than 50 and women older than 60 who have at least one cardiovascular risk factor) b. Clopidogrel for those intolerant of aspirin therapy G. Preventive Immunizations 1. Annual influenza vaccine 2. Pneumococcal polysaccharide vaccine

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B y Dr Mohammed Omar

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