Diabetes Mellitus ADA American Diabetes Association n www
Diabetes Mellitus
ADA American Diabetes Association n www. Diabetes. org n
n DM is a group of metabolic disorders of fat, carbohydrate & protein metabolism that results from defect in insulin secretion, action or both
Signs & symptoms Polyuria n Polydipsia n Fatigue n Weight loss (in type 1) n
Diagnosis Symptoms+ random glc ≥ 200 mg/d. L n An FPG≥ 126 mg/d. L(7 mmole/L) (at least 8 hr) n 2 hr postprandial ≥ 200 mg/d. L during OGTT n Hb. A 1 C ≥ 6. 5% n
Glycated Hemoglobin A 1 C (%) Mean Blood Glucose NGSP IFCC mg/dl 7 5. 3 170 8 6. 3 205 9 7. 3 240 10 8. 4 275 11 9. 5 310 12 10. 6 345 National Glycohemoglobin Standardization Program the International Federation for Clinical Chemistry Hoelzel W. et al. Clin Chem 2004; 50(1): 161 -174
Conversions n Whole blood glucose (mg/d. L) = plasma glucose (mg/d. L) ÷ 1. 12 n Plasma glucose (mmol/L) = plasma glucose (mg/d. L) ÷ 18
Biochemical Index ADA recommendations Hg. A 1 C <7% FPG 80 -130 PPG <180
Methods of Monitoring Glycemic Control
n n SMBG and Hb. A 1 c levels continue to be the two primary methods used to access glycemic control Recently, continuous glucose monitoring (CGM) of interstitial fluid has become available
Urine Ketone Testing n For when glucose concentrations consistently > 300 mg/d. L or during acute illness, symptoms of ketoacidosis and pregnancy
Principles of type 1 DM treatment
Treatment of type 1 DM n Insulin Regimen n Physical activity n
Investigational Agents for type 1 Metformin n Incretin-Based Therapies n Sodium-Glucose cotransporter 2 inhibitors n
Inulin
Type Example Rapid Glulisin, Aspart, Lispro, Short Regular Intermediate NPH Long Glargine, Detemir
Insulin Onset Peak (hr) Duration (hr) Lispro 15 -30 min 1 -2 3 -5 Aspart 15 -30 min 1 -2 3 -4 Glulisin 15 -30 min 1 -2 3 -4 Regular 0. 5 -1 hr 2 -3 4 -6 NPH 2 -4 hr 4 -8 8 -12 Detemir 2 hr -- 14 -24 Glargine 1. 5 hr --- 22 -24
Empiric insulin doses Type 1: n Initial: 0. 5 -0. 8 u/kg/d Type 2: n With insulin resistance: 0. 7 -1. 5 u/kg/d
Adverse Effects n Insulin Allergy n Localized (itching at site) n Systemic (angioedema, hypotension, anaphylaxis and death) n Hypoglycemia n Lipoatrophy n Wasting of subcutaneous fat n Benign, but cosmetically disfiguring
Hypoglycemia
n n Blood glucose <40 mg/d. L: Patient is generally symptomatic Blood glucose <20 mg/d. L can be associated with seizures and coma
n n Mild hypoglycemia: tremor, palpitations, sweating, and intense hunger. Diminished cerebral function is not present and patients are capable of self-treating mild reactions. Moderate hypoglycemia: neuroglycopenic as well as autonomic symptoms: headache, mood changes, irritability, decreased attention, and drowsiness. Patients may require assistance in treating themselves because of the presence of impaired judgment or weakness. Symptoms are more severe, usually last longer, and often require a second dose of a simple carbohydrate. Severe hypoglycemia: unresponsiveness, unconsciousness, or convulsions. These reactions require assistance from another individual for appropriate treatment. Approximately 10% of patients treated with insulin develop at least one severe episode of hypoglycemia per year that requires emergency treatment with parenteral glucagon or IV glucose
Treatment of mild hypoglycemia n n Most hypoglycemic reactions are managed readily with the equivalent of 10 to 20 g ( 15 g) of glucose “ 15 -15 -15”: 15 g of glucose followed by a second 15 g if the patient is still symptomatic after 15 minutes
Treatment of moderate to severe hypoglycemia n n n Glucagon: SC or IM route into the deltoid or anterior thigh region. The dose for < 5 years: 0. 25 to 0. 5 mg 5 -10 years: 0. 5 to 1 mg; and for >10 years: 1 mg Kits with prefilled syringes containing 1 mg glucagon are available Patients who are given glucagon should be positioned so that their face is turned toward the floor As soon as the patient awakens (10– 25 minutes), he or she should be fed
n IV glucose (~10– 25 g administered as 20– 50 m. L of 50% dextrose over 1– 3 minutes) n Following the bolus injection of glucose, IV glucose (5– 10 g/hour) should be continued until the patient has gained consciousness and is able to eat
Pramlintide amylin analog n Delay gastric empting, blunts glucagon secretion, enhances satiety n FDA approval for type 1 in adults n Induction of weight loss, lower ins dose n Concurrent reduction in prandial ins dose for decrease in hypoglycemia n
Treatment of type 2 DM Regimen n Physical activity n Oral agents n Insulin n
agents for type 2 DM
Biguanides n Sulfonylurea n Non Sulfonylurea secretagogues n Alpha glucosidase inhibitors n Thiazolidinediones n DPP-4 Inhibitors n GLP-1 Analogs n SGLT-2 inhibitors n
Metformin n n n First line for type 2 Mechanism: Decrease hepatic G, Increase G uptake ↓ Hb. A 1 c: 1. 5 – 1. 7 % ↓ FPG: 50 -70 mg/d. L If not achieve to goal after 3 -6 months addition second agent Good for dyslipidemia ( ↓ 5 -10% chol, 10 -20% TG) Good for obesity or another factor favoring insulin resistance
ADRs n Gastrointestinal( diarrhea) n Lactic Acidosis (↓ lactate to Glu) Pregnancy n Hypoglycemia? Suggested by ADA for reducing risk for developing DM in patients at high risk n Contentious use causes a vit B 12 deficiency as many as 30% of patients which can present without anemia or as a peripheral neuropathy n
Sulfonylurea (SFUs) Glibenclamide, Gliclazide, Chlorpropamide Mechanism: n Stimulate insulin secretion n May decrease hepatic glucose output n Enhance peripheral glucose utilization
Sulfonylurea (SFUs) FDA approved for monotherapy and combination with insulin & metformin n Rapid onset: 1 week n Decrease in A 1 C %1. 5 -1. 7 n Decrease in FPG 50 -70 mg/dl n Decrease in PPG 92 mg/dl n
Sulfonylurea (SFUs) Common Adverse effects: Hypoglycemia n Weight gain n n Possible interaction with fluoroquinolones which also potentiate hypoglycemic action of glyburide
Non Sulfonylurea secretagogues Glinides: Repaglinide, Nataglinide n Mechanism: like SU n Rapid act & short duration compared with SU so they are given with meals to ↑ postprandial G utilization n n FDA approved monotherapy or combination with insulin/metformin
Non Sulfonylurea secretagogues Caution in patients with liver disease n ADRs: Mild Hypoglycemia Weight gain n
Dosing Repaglinide If Hg. A 1 C < 8 or first line 0. 5 mg with each meals In others: 1 -2 mg with each meals n Nateglinide 60 -120 mg TDS §
n Drug interaction n Gemfibrozil /Ketokonazole/Itraconazole & Repaglinide
Thiazolidinediones n n Rosiglitazone Pioglitazone Mechanism: Insulin sensitizers Once daily or twice , With or without food n Reduction of Hb. A 1 c - 0. 5 – 1%
Thiazolidinediones ADRs n n Mild anemia n Mild to moderate edema n Weight gain n Elevation of serum transaminases n Osteoprosis LFT every 1 -2 month at baseline , then periodically
Drug interactions Gemfibrozil: ↑ AUC of both (dose reduction of TZD) n Pioglitazone: Induction of CYP 3 A 4 n
n FDA has restricted use of rosiglitazone owing to data suggesting an elevated risk of cardiovascular events in type 2 treated with R. Rosiglitazone ---- Lipid profile +++ Pioglitazone
Alpha glucosidase inhibitors Acarbose miglitol n Mechanism: Slow absorption of complexcarbohydrate n FDA approved monotherapy and combination with SU
Alpha glucosidase inhibitors Decrease in A 1 C %0. 5 -1 n Decrease in FPG 20 -30 mg/dl n Decrease in PPG 25 -50 mg/dl n n Common Adverse effects: flatulence, diarrhea n LFTs for acarbose
Incretin-Based Therapies Incretins are insulinotropic hormones secreted from specialized neuroendocrine cells in the small intestinal mucosa in response to carbohydrate ingestion and absorption. n 2 hormones accounting for most incretin effects: Glucose dependent insulinotropic polypeptide(GIP) Glucagon-like peptide-1 (GLP-1) n Both stimulate pancreatic Β cells in a glucose-dependent manner, contributing to the early-phase insulin response. GLP-1 also inhibits pancreatic a cells, thus reducing glucagon secretion. n
Dipeptidyl Peptidase-4 Inhibitors Sitagliptin n Saxagliptin n Linagliptin n Mechanism: inhibit the degradation of GIP & GLP-1 on entering the GI vasculature n
Sitagliptin It does not interfere with CYP nor does it act as an inhibitor or inducer of CYP system n It dose not increase risk of pancreatitis n Adjustment in RF usual: 100 mg/d GFR 30 -50: 50 mg/d GFR < 30: 25 mg/d n
GLP 1 like peptide agonists
Exenatide n n n n SC 5 mcg BD titrated to 10 mcg BD 0 -60 min before morning and evening meals Degradation by proteolytic enzymes in kidney, adjust in RF Efficacy: ↓Hb. A 1 c is approximately 0. 9% significantly ↓ PPG, a modest effect on FPG allow some patients to lose weight ADRs: GI( nausea, Diarrhea), caution in pancreatitis, hypoglycemia in combination with insulin/SU Interactions: If rapid absorption is necessary, it is best to take the medication 1 hour before, or 3
Liraglutide n n Efficacy: ↓Hb. A 1 c is approximately 0. 9% Dosing: 0. 6 mg/d for 1 week then 1. 2 mg/d max 1. 8 mg/d ADRs & interactions like Exenatide ↓ PPG and FPG (long half life , suppression of glucagon overnight)
SGLT 2 Inhibitors n n Sodium-Glucose Cotransporter 2 (SGLT 2) Inhibitor Dapagliflozin : (Farxiga)5 mg, 10 mg Initial: 5 mg/d; may increase to 10 mg/d Administer with or without food
Principle of DM 2 treatment
Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacological agent for type 2 diabetes. n In patients with newly diagnosed DM 2 and markedly symptomatic and/or elevated BG/ A 1 C, consider initiating insulin(with/without additional agents). n If non insulin monotherapy at maximum tolerated dose does not Achieve /maintain A 1 C target over 3 months, add a second n
A patient-centered approach should be used to guide choice of pharmacological agents. Considerations include efficacy, cost, side effects, weight, comorbidities, hypoglycemia risk, and patient preferences. Due to the progressive nature of type 2, insulin therapy is eventually indicated for many patients with type 2 diabetes.
For all patients consider initiating therapy with a dual combination when A 1 C is > %9 n Consider Insulin therapy when BG is > 300 -350 and or A 1 C > %10 -12 n Meglitinides may be used instead of SU in patients with irregular meal schedules /who develop late postprandial hypoglycemia on a SU n
Cardiovascular diseases & risk management Hypertension control n Dyslipidemia management n Antiplatelet therapy n Coronary heart disease n
Hypertension People with diabetes and hypertension should be treated to a SBP goal of 140 mm. Hg. n People with diabetes and hypertension should be treated to a DBP goal of 90 mm. Hg. n n Pharmacological therapy for patients with DM and HTN should comprise a regimen that includes either an ACE Inh or an ARBs. If one class is not tolerated, the other should be substituted.
Pregnancy & DM Target BP goals of SBP 110– 129 mm. Hg and DBP 65– 79 mm. Hg are reasonable, as they contribute to improved long-term maternal health. n During pregnancy, treatment with ACE Inh and ARBs is contraindicated n Chronic diuretic use during pregnancy has been associated with restricted maternal plasma volume, which may reduce uteroplacental perfusion n Effective and safe in pregnancy: methyldopa, n
↓HDL cholesterol, often associated with↑ TG are the most prevalent pattern of dyslipidemia in type 2 DM n In adults, a screening lipid profile is reasonable at the time of first diagnosis, at the initial medical evaluation, and/or at age 40 and periodically (e. g. , every 1– 2 years) n Intensify lifestyle therapy and optimize glycemic control for patients with elevated TG (150 mg/d. L and/or low HDL cholesterol (40 mg/d. L men, 50 mg/d. L women). n
Dyslipidemia management n Combination therapy (statin/fibrate and statin/niacin) has not been shown to provide additional cv benefit above statin alone and is not generally recommended.
Antiplatelet therapy Consider ASA (75– 162 mg/d) as a primary prevention strategy in those with type 1/2 at increased cv risk ; This includes most men >50 y or women > 60 y who have at least 1 additional major risk factor (family history of CVD, HTN, smoking, dyslipidemia, or albuminuria). n ASA should not be recommended for CVD prevention with DM at low CVD risk such as in men < 50 y and women < 60 y with no major additional CVD risk factors n In patients between above, clinical judgment is required. n
Antiplatelet therapy Use ASA (75– 162 mg/d) as a secondary prevention strategy in those with DM and a history of CVD n For patients with CVD and documented ASA allergy, clopidogrel (75 mg/day) should be used n Dual antiplatelet therapy is reasonable for up to a year after an acute coronary syndrome (ticagrelor, or prasugrel) if PCI was n
CORONARY HEART DISEASE In patients with known CVD, use ASA and statin therapy (if not contraindicated) and consider ACE inh to reduce the risk of cv events. n In patients with a prior MI, b-blockers should be continued for at least 2 years after the event. n In patients with symptomatic HF, thiazolidinedione should not be used. n In patients with stable CHF, metformin may be used if renal function is normal but should be avoided in unstable or hospitalized patients with CHF. n
Microvascular complications Nephropathy n Retinopathy n Neuropathy n
NEPHROPATHY n Optimize glucose control to reduce the risk or slow the progression of diabetic kidney disease. n Optimize BP control to reduce the risk or slow the progression of diabetic kidney disease. n At least once a year, quantitatively assess urinary albumin (e. g. , urine albumin to-creatinine ratio [UACR]) and GFR) in patients with type 1 duration of >5 years and in all patients with type 2
Continued monitoring of UACR in patients with albuminuria is reasonable to assess progression of diabetic kidney disease. n Either an ACE inh or ARB is suggested for the treatment of the non pregnant patient with modestly elevated urinary albumin excretion (30– 299 mg/day) and is recommended for those with urinary albumin excretion > 300 mg/day. n An ACE inh or ARB is not recommended for the primary prevention of diabetic kidney disease in patients with diabetes who have normal blood pressure and normal UACR (<30 mg/g). n When ACE inh, ARBs, or diuretics are used, monitor Sr cr and potassium levels for the development of increased creatinine or changes in potassium n
Diabetic neuropathy All patients should be screened for diabetic peripheral neuropathy (DPN) starting at diagnosis of type 2 and 5 years after the diagnosis of type 1 and at least annually thereafter n Screening for signs and symptoms (e. g. , orthostasis, resting tachycardia) of cardiovascular autonomic neuropathy (CAN) should be considered with more advanced disease n Tight glycemic control is the only strategy convincingly shown to prevent or delay the development of DPN and CAN in patients with type 1 and to slow the progression of neuropathy in n
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