Diabetes Mellitus: Oral Hypoglycemic Drugs ( a practical step-up approach )

Start with Metformin 500 mg once a day to maximum 1000 mg twice a day; take with meals; hold if CrCl< 30 ml/min/1.73 m2.

If HbA1C target not reached after 3 months, add one of-

- Sulfonylureas: Glimepiride 1 mg to max 4 mg/day, with breakfast or first main meal of the day. Beware in elderly patient as risk of hypoglycemia

- SGLT2 inhibitor: Empagliflozin 10 mg once daily in the morning, with or without food. Prefer in patients with ASCVD, heart failure or diabetic kidney disease.

- DPP-4 Inhibitor: Linagliptin 5 mg once daily, may be administered with or without food. Linagliptin can be used without dose adjustment in renal impairment, including ESRD.

- Thiazolidinediones: Pioglitazone 15 to 30 mg once daily; may be administered without regards to meal; beneficial in NAFLD. Serious side effects include worsening heart failure, increase bone fracture risk. 

If HbA1C target not reached after 3 months, add another drug of different group from the above list as per patient comorbidity and safety profile.

If goal not reached after 3 oral hypoglycemic drugs, add insulin. 

Note: Start with dual therapy if HbA1C > 9% on initial presentation. Begin insulin therapy for HbA1C > 10 % or blood glucose > 300 mg/dl at initial presentation.

HbA1C targets:

 < 7%- Most of non-pregnant adults

< 8%- history of severe hypoglycemia, limited life expectancy, advanced micro or macrovascular complications.

References:

1. ADA Standards of Medical Care in Diabetes- 2020

2. Pocket Primary Care 2nd Edition. 2018

3. Uptodate 2021

 

Diabetes Mellitus: Inpatient Insulin Therapy

 Non-critically ill patient

Hyperglycemia if blood glucose > 140 mg/dl

Treatment recommended if glucose levels persistently >=180 mg/dl

HbA1c needed for all admitted patients with diabetes or hyperglycemia ( blood glucose >= 140 mg/dl ) if not performed in the prior 3 months. 

Oral anti-diabetic agents typically discontinued during acute illness

Sliding Scale insulin alone is not appropriate to treat sustained hyperglycemia

Basal Bolus regimen- a. Basal insulin ( long acting )   

                                    b. Mealtime prandial bolus insulin ( short acting) 

                                    c. Correction insulin

Initial Dosing:

- 1st step is to estimate patient's total daily dose ( TDD)  

- For patients on insulin before admission, best indicator of insulin requirement is TDD before admission. If A1C value is elevated then increase TDD. If glycemia too tightly controlled or admitted for hypoglycemia, then reduce.

- For insulin naive patients, initial TDD is 0.3-0.6 units/kg body weight. ( Lean patients and renal sufficiency - lower dose and higher dose for obese patients and those under corticosteroid use )

- 50% of TDD- Basal insulin

- 50% of TDD - meal time bolus insulin

Withheld mealtime bolus insulin if patients are not eating or if their pre-meal glucose level is < 70 mg/dl

Correction insulin is used when glucose levels exceeds 140-150 mg/dl

    - Low scale: 1 units insulin for every 40-50 mg/dl increase above 140-150 mg/dl ( If TDD 20-42 units)

    - Moderate scale: 2 units every 40-50 mg/dl increase above 140-150 mg/dl ( If TDD 43-84 units)

    - High scale: 3 units for increase ( If TDD 85-126 units ) 

Example: Basal/Bolus insulin dose calculation for a patient weighing 80 kg with BMI 28 kg/m2 and normal renal function:

Step 1: TDD= 0.5 units/kg body weight X 80= 40 units

Step 2: Basal insulin= 50% of TDD= 50% of 40 units= 20 units of glargine

Step 3: Bolus insulin dose calculation= (50% of TDD)/3= 20/3= 6 units of rapid acting insulin before each meal

Step 4: Correction scale estimation: low scale correctional scale should be ordered

Monitor Blood Glucose at Fasting, Pre-Lunch, Pre-dinner and Bed time. Measure glucose every 4-6 hrs in NPO patients.

 

Critically Ill Patients 

 Recommended glucose range in acute critical illness= 140-180 mg/dl

Continuous IV insulin is preferred and it is initiated when blood sugar > 180 mg/dl

Transition from IV insulin to SC basal bolus preferred as patient starts feeding reliably

IV insulin should be continued for atleast 4 hours after the glargine insulin dose is administered during transition.

 

Diabetes Mellitus: Outpatient Insulin Therapy

Insulin Indication: Patients with DM-2 with HbA1c >10% or on 3 medicines with HbA1c > goal on 2 occasions, 3 months apart 

HbA1C goal- Generally < 7%, but consider < 8% if old age, decreased life expectancy, risk of hypoglycemia  

Initiation

- Start basal insulin ( 0.1-0.2 mg/kg/day ), safe to start Glargine 10 units HS, increase by 2 units every 3rd night until Fasting Blood sugar < 130 mg/dl

The patient can be started with basal insulin 20 units if BMI > 30 and all blood sugars > 200 mg/dl

( Continue Metformin or other agents based on cost, complexity )

If basal insulin required is > 0.5 units/kg/day,  or HbA1C > goal and postprandial hyperglycemia despite fasting sugar at goal,  

1. Add 1 rapid acting insulin injection before largest meal: 4 units insulin/meal, increase by 2 units   every 3rd day until postprandial blood glucose < 180 mg/dl. ( Discontinue sulfonylurea before starting prandial insulin ). Add prandial glucose before all meals if not controlled.

OR 

2. Change to premixed insulin twice daily. 70/30 (Premixed 70% NPH/30% regular insulin before breakfast ( 2/3rd total current basal dose) plus 70/30 before dinner ( 1/3rd current basal dose). Increase by 2 units every 3rd day until blood glucose target is reached.

Insulin Troubleshooting

a. If fasting BG is increased, increase Glargine or evening NPH, consider checking 2 am blood glucose to rule out overnight hypoglycemia

b. If Prelunch  glucose increased, add or increase breakfast insulin

c. If Predinner glucose increased, add or increase AM NPH or lunchtime insulin

 

Note: Self Monitoring of blood glucose is advised. All patients should be educated about the symptoms and self-treatment of hypoglycemia. The ADA recommends the following: (1) check the blood glucose level if signs or symptoms of hypoglycemia are present; (2) if the blood glucose level is less than 70 mg per dL, treat with 15 g of fast-acting carbohydrate, such as 120 ml of fruit juice or three or four glucose tablets; and (3) recheck the blood glucose level after 15 minutes to ensure that it has normalized

 

References:

1. Thompson Amanda et al. Am Fam Physician. 2018 Jan 1;97(1):29-37

2. The Massachusetts General Hospital Handbook of Primary Care. Pocket book. 2nd Edition

 

Dyslipidemia: Pharmacological Treatment

 

Primary prevention 

- Make treatment decisions based on 10 year ASCVD clinical risk calculation (http://tools.acc.org/ASCVD-Risk-Estimator-Plus)

-  In all patients of Diabetes aged 40 to 75 years, start a moderate dose statin regardless of estimated 10 year risk.

- In age 40-75 years without diabetes, if LDL-C ≥ 70 mg/dl at ASCVD risk >7.5%, start moderate intensity statin therapy.

- In age 20-75 years with LDL-C ≥ 190 mg/dl, offer maximally tolerated statin therapy

- Add Ezetimibe to maximally tolerated statin therapy in adults who have diabetes and a 10-year risk of ≥ 20% to reduce LDL-C levels by ≥ 50%

-Add PCSK9 inhibitor in 40 to 75 years of age with baseline LDL-C level  ≥ 220 mg per dL and who achieve an on-treatment LDL-C level of ≥ 130 mg per dL while receiving maximally tolerated statin and ezetimibe therapy/

 

Secondary Prevention

- For secondary prevention, use at least a moderate-dose statin as the mainstay of treatment

- Initiate or continue high-intensity statin therapy in patients who are ≤ 75 years who have clinical ASCVD ( ACS, MI, Stroke, TIA, PAD ) with the aim of achieving a ≥ 50% reduction in LDL-C levels

- Add Ezetimibe for patients with clinical ASCVD who taking maximally tolerated statin therapy, who are judged to be at very high risk, and LDL-C level of ≥ 70 mg/dL

 

Repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated every 3 to 12 months as needed 

Note:

Moderate Intensity Statin: Atorvastatin 10 to 20 mg, Rosuvastatin 5 to 10 mg, Simvastatin 20 to 40 mg

High Intensity Statin: Atorvastatin 40 to 80 mg, Rosuvastatin 20 to 40 mg

Ezetimibe dose: 10 mg once daily

Hypertriglyceridimia

- For primary prevention, pharmacologic management of fasting serum triglyceride levels less than 500 mg/dL is not indicated

- ASCVD < 5% and TG < 150 mg/dl- Lifestyle modification and routine surveillance

- ASCVD 5%-7.4% and TG 150-499 mg/dl- Intensify Lifestyle modification and discuss statin use

- ASCVD 7.5%-19.9% and TG 150-499 mg/dl- Intensify Lifestyle modification and consider statin use

-ASCVD >20% and TG 150-499 mg/dl- Intensify Lifestyle modification and add statin- Consider Icosapent if TG still within 150 and 499

- TG > 500 mg/dl- Initiate Fibrate, Omega 3 FA or Niacin to bring TG < 500 

Note: Lifestyle modifications- Reduce excessive alcohol use, tobacco cessation, implementing nutritional changes (limit refined carbohydrates and added sugar, increasing foods lower on the glycemic index and foods containing omega-3 fatty acids), and do high- or moderate-intensity aerobic and resistance exercises

 

References:

1. Arnold M et al, Am Fam Physician. 2021 Apr 15;103(8):455-458 

2. 2018 AHA guideline on Management of Blood Cholesterol 

Combined Oral Contraceptive Pills ( OCP )

Common Brands in Nepal : Sunaulo Gulab, Ovral L, Nilocon White

Standard Composition:  Levonorgestrel 0.15 mg/ Ethinyl Estradiol 0.03 mg . One cycle contains 21 hormonal tablets and 7 Iron tablets

First discuss with the female about its benefits including non contraceptive benefits like improvement in menorrhagia, dysmenorrhea, anemia, pre-menstrual syndrome, acne, hirsutism. 

Also talk about possible risks like Hypertension, Venous Thromoboembolic conditions, MI

- Confirm the female is not pregnant

- Obtain Blood Pressure

- Review Past Medical History for Contraindications- Uncontrolled HTN, History of VTE, advanced DM, Migraine with aura, Known ASCVD, Cirrhosis

- Obtain smoking history ( Not given in smokers more than 35 years of age )

Initiation Plan: 

- Quick start: Take 1st Pill as soon as prescription filled, need backup contraception for 7 days

- 1st day start: Take 1st Pill on 1st day of period, backup contraception not needed

- Sunday start: Take 1st Pill on Sunday after period begins, need backup for 7 days

 

When to Use Backup contraception:

- Missed pills more than or equals to 2 pills ( backup for 7 days )

- When there is use of medication which decrease efficacy of OCP like anticonvulsants, griseofulvin,  Rifampin

  

Note:

- Counsel Patients about side effects which typically resolve within 2-3 months. They include headache, nausea, mastalgia, (hirsutism, acne, weight gain- may need to switch to 3rd/4th generation progesterone with less androgenic effect ) , breakthrough bleeding, amenorrhea  

- Followup the female at 3 months to check BP, evaluate for tolerance and side effects. If pregnancy occurs while on OCP, discontinue upon diagnosis and reassure the patient there is no harm to the fetus due to OCP at time of conception.