Pharmacotherapy/Treatment Of Diabetes

Diabetes is a chronic disease that causes an increase in blood sugar. It happens when the body's pancreas is unable to produce insulin or when the body cannot effectively utilise insulin it produces and releases. Insulin is a hormone that regulates blood sugar. It is synthesized by the pancreas.

Diabetes

Glucose is the primary source of energy for the human body. Absorbed from the intestine it is metabolised by energy production (by conversion to water and carbon dioxide), conversion to amino acids and proteins or keto-acids stored as glycogen.

Metabolism of glucose is regulated by complex orchestration of hormones activities. Dietary sugars are broken down into various carbohydrates. The most important is glucose, metabolised in nearly all body cells. Glucose enters the cell by facilitated diffusion (glucose transport proteins). This facilitated transport is stimulated very rapidly and effectively by an insulin signal (glucose transport into muscle and adipose cells is increased up to twenty fold). After glucose is transported into the cytoplasm, insulin then directs the disposition of it - conversion of glucose to glycogen, to pyruvate and lactate, and to fatty acids.

Diabetes is one of the most important diseases in the world. It affects people of all races. It is significantly more prevalent in adults above 18 years. The number of people with diabetes rose from 108 million in 1980 to 422 million in 2014. In 2014, 8.5% of adults aged 18 years and older had diabetes. In 2019 diabetics were the direct cause of 1.5 million deaths worldwide. Between the year 2000 and 2016 there was a 5% increase in premature mortality from diabetes. In high-income countries the premature mortality rate due to diabetes decreased from 2,000 to 2010 but then increased in 2010 to 2016. In lower-middle-income countries, the premature mortality rate due to diabetes increases across both periods. Common among African American, Hispanic, native American, Asian American and Pacific island.

Risk Factors Of Diabetes

1. Hereditary

2. Overweight above 30kgm²

3. Age above 45 years

4. Physical inactivity

5. Gestational diabetes

6. Prediabetes

7. HBP

8. Low amount of High density lipoprotein, high amount of low density lipoprotein, high cholesterol and or triglycerides

9. Have Polycystic ovary syndrome (PCOS)

Types Of Diabetes

There are three types of diabetes. However, a fourth one has been recognised. They are;

1. Type 1 diabetes is characterized by deficient insulin production and requires daily administration of insulin. It is also known as insulin dependent juvenile or childhood onset diabetes. The cause is not known. Type 1 diabetes results from an autoimmune destruction of the ß-cells of the pancreas. The terms insulin-dependent diabetes or juvenile-onset diabetes previously encompassed this type of diabetes. There are several markers of this autoimmune destruction, detectable in body fluids and tissues:

1. islet cell autoantibodies (ICAs)

2. autoantibodies to insulin (IAAs)

3. autoantibodies to glutamic acid

(GAD65)

4. autoantibodies to the tyrosine phosphatases IA-2 and IA-2ß.

Despite increased knowledge, we are still far from understanding the aetiology of Type 1 DM. There is no doubt that genetic factors are strongly implicated as several genetic factors have been identified.

2. Type 2 diabetes results from the body's inability to utilise insulin produced and released. It is also called non-insulin-dependent or adult-onset diabetes. It is common among fat people and results from excess body weight and physical inactivity.

3. Gestational diabetes is diabetes that occurs during pregnancy due to hormone changes. It does not fall into diabetes but the sugar level in the body is above normal range. Women that suffer from gestational diabetes are at an increased risk of complications during pregnancy and delivery. mother and child care at an increased risk of developing diabetes type 2 later in lifes. It is more common in fat women. The pathophysiology of gestational diabetes mellitus is not well known and includes family history of diabetes mellitus, obesity, complications in previous pregnancy(ies) and advanced maternal age. It is essential to detect pre-existing diabetes mellitus which has a much worse prognosis for the fetus.

4. Type 3 diabetes is a form of diabetes associated with Alzheimer's disease. It occurs when neurons in the brain become unable to respond to insulin which is essential for basic tasks including memory and learning. The culprit is a variant of the Alzheimer's gene known as APOE4 which is present in 20% of the population. It has been observed that more than half of Alzheimer's cases are responsible for interrupting how the brain processes insulin known as insulin impairment.

Diabetes insipidus is more like a condition whereby a person experiences excess loss of urine from the kidney.

Symptoms Of Diabetes

1. Excess urination (polyurea)

2. Excess thirst (polydipsia)

3. Constant hunger

4. Weight loss

5. Fatigue

6. Vision changes

7. Erectile dysfunction or reduce sex drive

8. Itchy skin

9. Urine infection and yeast

The symptoms of type 1 diabetes occur suddenly. The symptoms of type 2 diabetes are less marked as they are only diagnosed after onset of complications or routine check.

Complication Of Diabetes

1. Premature birth

2. Extra baby weight

3. Jaundice

4. Stillbirth

5. Low blood sugar

6. Heart attack

7. Stroke

8. Nerve damage

9. Neuropathy

10. Nephropathy

11. Reduced blood flow

12. Foot ulcer and limb amputation

13. Diabetic retinopathy which can lead to blindness (2.6 percent globally)

14. Kidney failure

15. Hearing loss

16. Depression

17. Dementia

18. Skin condition (bacteria and fungi)

19. High blood pressure (HBP, preeclampsia) especially in gestational diabetes or type 2 diabetes that can cause caesarian section from 24-28 weeks of pregnancy.

Prevention Of Diabetes

With type 1 diabetes, there is no prevention. However, a healthy lifestyle can prolong onset of the disease and reduce complications. Type 2 can be prevented with a healthy lifestyle. Gestational and type 3 diabetes also benefits from a healthy lifestyle. The following lifestyle can help in prevention of diabetes disease and complications.

1. A healthy body weight

2. Balance exercise

3. Healthy diet (avoid or reduce sugar and saturated fat)

4. Avoid tobacco smoking and alcohol consumption

Diagnosis Of Diabetes

Random blood sugar test: A blood sample will be taken at a random time and may be confirmed by repeat testing. Blood sugar values are expressed in milligrams per deciliter (mg/dL) or millimoles per liter (mmol/L). Regardless of when you last ate, a random blood sugar level of 200 mg/dL (11.1 mmol/L) or higher suggests diabetes, especially when coupled with any of the signs and symptoms of diabetes, such as frequent urination and extreme thirst.

Fasting blood sugar test: A blood sample will be taken after an overnight fast. A fasting blood sugar level less than 100 mg/dL (5.6 mmol/L) is normal. A fasting blood sugar level from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) is considered prediabetes. If it's 126 mg/dL (7 mmol/L) or higher on two separate tests, you have diabetes.

Glycated hemoglobin (A1C) test: This blood test indicates your average blood sugar level for the past two to three months. It measures the percentage of blood sugar attached to the oxygen-carrying protein in red blood cells (hemoglobin). The higher your blood sugar levels, the more hemoglobin you'll have with sugar attached. An A1C level of 6.5 percent or higher on two separate tests indicates diabetes.

When your laboratory results show that your blood sugar level is high, an attempt will be made to determine the type. The presence of ketones — byproducts from the breakdown of fat — in your urine and autoantibodies in your blood suggests type 1 diabetes, rather than type 2.

For type 2 diabetes, Oral glucose tolerance test is added. This test is less commonly used than the others, except during pregnancy. You'll need to fast overnight and then drink a sugary liquid at the doctor's office. Blood sugar levels are tested periodically for the next two hours. Results are interpreted as follows:

1. Less than 140 mg/dL (7.8 mmol/L) is normal.

2. 140 to 199 mg/dL (7.8 mmol/L and 11.0 mmol/L) is diagnosed as prediabetes.

3. 200 mg/dL (11.1 mmol/L) or higher after two hours suggests diabetes.

Pathophysiology Of Type 1 Diabetes

In this condition the immune system attacks and destroys the insulin producing beta cells of the pancreas. There is beta cell deficiency leading to complete insulin deficiency. Thus it is termed an autoimmune disease where there are anti insulin or anti-islet cell antibodies present in blood. These cause lymphocytic infiltration and destruction of the pancreas islets. The destruction may take time but the onset of the disease is rapid and may occur over a few days to weeks.There may be other autoimmune conditions associated with type 1 diabetes including vitiligo and hypothyroidism. Type 1 diabetes always requires insulin therapy, and will not respond to insulin-stimulating oral drugs.

Pathophysiology Of Type 2 Diabetes

This condition is caused by a relative deficiency of insulin and not an absolute deficiency. This means that the body is unable to produce adequate insulin to meet the needs. There is Beta cell deficiency coupled with peripheral insulin resistance.

Peripheral insulin resistance means that although blood levels of insulin are high there is no hypoglycaemia or low blood sugar. This may be due to changes in the insulin receptors that bring about the actions of the insulin.

Obesity is the main cause of insulin resistance. In most cases over time the patients need to take insulin when oral drugs fail to stimulate adequate insulin release.

Pathophysiology Of Gestational Diabetes

Gestational diabetes is caused when there are excessive counter-insulin hormones of pregnancy. This leads to a state of insulin resistance and high blood sugar in the mother. There may be defective insulin receptors.

Pharmacotherapy/Treatment Of Type 1 Diabetes

Treatment for type 1 is the use of insulin and healthy lifestyle. There are different types of insulin. Choice depends on the severity of the disease. Generally, the goal is to keep your daytime blood sugar levels before meals between 80 and 130 mg/dL (4.44 to 7.2 mmol/L) and your after-meal numbers no higher than 180 mg/dL (10 mmol/L) two hours after eating. A1C is below 7 percent, which translates to an estimated average glucose of 154 mg/dL (8.5 mmol/L).

Types Of Insulin

1. Short-acting (regular) insulin: Short-acting insulin starts to work within 30 minutes and lasts 6 to 8 hours.

2. Rapid-acting insulin: Rapid-acting insulin starts to work within 15 minutes and its effects last for 3 to 4 hours.

3. Intermediate-acting (NPH) insulin: Intermediate-acting insulin starts to work within 1 to 2 hours and lasts 12 to 18 hours.

4. Long-acting insulin: Long-acting insulin starts to work a few hours after injection and lasts 24 hours or longer.

Insulin can't be taken orally to lower blood sugar because stomach enzymes will break down the insulin, preventing its action. You'll need to receive it either through injections or an insulin pump. The latest development uses Artificial pancreas. Medication can be prescribed for treating high blood pressure, high cholesterol, etc. Low dose aspirin is sometimes given when there is suspicion of heart related complications.

Blood sugar must be regularly monitored in type 1 diabetes. This is important before driving and exercise.

Pharmacotherapy/Treatment Of Type 2 Diabetes

Medications for type 2 diabetes are designed to increase insulin output by the pancreas, decrease the amount of glucose released from the liver, increase the sensitivity (response) of cells to insulin, decrease the absorption of carbohydrates from the intestine, and slow emptying of the stomach, thereby delaying nutrient digestion and absorption in the small intestine.

Class Of Drugs For Type 2 Diabetes

Alpha Glucosidase inhibitors

delay the absorption of carbohydrates from the small intestine and thus have a lowering effect on postprandial blood glucose and insulin levels. They inhibit one of the enzymes responsible for the breakdown of carbohydrates e.g. acarbose. They come with side effects such as diarrhoea, abdominal pain and gas.

Dose Of Acarbose

Initially 25 mg orally every 8 hours, at meals (with first bite). Can increase to 50 or 100 mg orally every 8 hours at 4-8 week intervals based on 1 hour postprandial glucose or glycosylated hemoglobin levels, and on tolerance.

Maximum Dose for <60 kg: 50 mg every 8 hours and >60 kg: 100 mg every 8 hours. Can be used for Type 2 DM mono treatment or with sulfonylurea.

Biguanide

preventing the production of glucose in the liver, improving the body's sensitivity towards insulin and reducing the amount of sugar absorbed by the intestines e.g. metformin.

Metformin is a drug that increases sensitivity of the body to insulin and decreases the amount of glucose produced by the liver. This is the first drug of choice in diabetes type 2 . It also suppresses appetite which is beneficial for weight reduction. This is not a very strong drug for reducing body sugar. It can be used with other classes of antidiabetic drugs. Its main side effects are nausea and diarrhoea. It may also cause low blood sugar in very rare cases.

Dose Of Metformin

Dose is dependent on the response. Immediate-release tablet or solution:

Initial: 500 mg orally every 12 hours or 850 mg every 12 hours with meals; increase dose in increments of 500 mg/week or 850 mg every 2 Weeks on the basis of glycemic control and tolerability

Maintenance dose: 1500-2550 mg/day orally divided every 8-12 hours with meals. Do not exceed 2550 mg/day.

Extended-release tablet or suspension:

500 mg orally every day with dinner; titrate by 500 mg/day every week; not to exceed 2000 mg/day. It can be used in off label type 2 diabetes prevention with 850 mg orally every day. Target dosing: 850 mg orally every 12 hours.

The Dipeptidyl Peptidase (DPP)–4 Inhibitors

Decrease the breakdown of the incretin hormones such as glucagon-like peptide 1 (GLP-1). Incretin is the hormone that tells the body to release insulin after eating. DPP4 removes incretin from the body. Inhibiting DPP4 leads to an increase in insulin in the body e.g. vildagliptin.

Vildagliptin Dose

When used as monotherapy, in combination with metformin, in combination with thiazolidinedione, in combination with metformin and a sulphonylurea, or in combination with insulin (with or without metformin), the recommended daily dose of vildagliptin is 100 mg, administered as one dose of 50 mg in the morning and one dose of 50 mg in the evening.

When used in dual combination with a sulphonylurea, the recommended dose of vildagliptin is 50 mg once daily administered in the morning. In this patient population, vildagliptin 100 mg daily was no more effective than vildagliptin 50 mg once daily. When used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be considered to reduce the risk of hypoglycaemia. Doses higher than 100 mg are not recommended.

Sulphonylurea

stimulating the production of insulin in the pancreas and increasing the effectiveness of insulin in the body e.g. glimepiride

Glimepiride Dose

Glimepiride rapidly lowers blood sugar (hypoglycemia). A Possible side effect is weight gain and an allergy to sulfa. Initial: 1-2 mg orally every morning after breakfast or with first meal; may increase dose by 1-2 mg every 1-2 weeks; not to exceed 8 mg/day. Use in monotherapy or, if glycemic response to glimepiride is inadequate at maximum dose, with insulin or metformin.

Thiazolidinediones (TZD)

bind avidly to peroxisome proliferator-activated receptor gamma in adipocytes to promote adipogenesis and fatty acid uptake (in peripheral but not visceral fat). They help insulin work better in the body e.g. pioglitazone

Pioglitazone increases sensitivity to insulin with side effects like heart failure, bone fractures and weight gain. These are the reasons that they are not used except in very rare cases. Can be used alone or with insulin or insulin secretagogues.

Pioglitazone Dose

15-30 mg orally with meal everyday initial; may increase dose by 15 mg with careful monitoring to 45 mg everyday maximum.

Monitor ALT at the start of treatment, every month for 12 months, every 3 months thereafter. In coadministration with insulin secretagogue (eg, sulfonylurea), decrease insulin secretagogue dose. In coadministration with insulin, decrease insulin dose by 10-25%. In co-administration with strong CYP2C8 inhibitors (eg, gemfibrozil), limit maximum pioglitazone dose to 15 mg everyday.

Sodium-glucose Co-transporter-2 Inhibitors

work by inhibiting SGLT2 in the proximal convoluted tubule (PCT) in the kidney, to prevent reabsorption of glucose and facilitate its excretion in urine. As glucose is excreted, its plasma levels fall leading to an improvement in all glycemic parameters. It is used with diet and exercise to lower blood sugar in adults. Medicines in the SGLT2 inhibitor class include canagliflozin, dapagliflozin, and empagliflozin. They can be used along with metformin, sulphonylurea, pioglitazone and insulin.

The most common side effects of SGLT2 inhibitors include: Genital yeast infections in men and women, Urinary tract infections (UTIs), Increased urination, Kidney problems, Flu like symptoms, Constipation, Nasal congestion and Urinary discomfort.

Glucagon-like peptide-1 receptor agonists (GLP-1)

exerts its main effect by stimulating glucose-dependent insulin release from the pancreatic islets. It has also been shown to slow gastric emptying, inhibit inappropriate post-meal glucagon release, and reduce food intake. GLP-1 is an incretin, a hormone that signals the body to release insulin after eating. They are stronger in effect than DPP4 and are called incretin mimetic. The GLP-1 receptor agonists currently approved in the United States for the treatment of type 2 diabetes include exenatide (obtain from Gila monster lizard and administered twice daily), liraglutide and lixisenatide (administered once daily), and the once-weekly agents exenatide extended-release, albiglutide, and dulaglutide. Side effects include weight loss, nausea and pancreatitis.

Exenatide Dose

Exenatide dose is immediate-release: 5 mcg SC q12hr within 60 minutes prior to meal initially; after 1 month, may increase to 10 mcg q12hr.

Pramlintide

is an injectable amylin analogue drug for diabetes, By mimicking the actions of the naturally occurring hormone amylin, pramlintide complements insulin by regulating the appearance of glucose into the circulation after meals via three primary mechanisms of action: slowing gastric emptying, suppressing inappropriate post-meal glucagon secretion, and increasing satiety. Pramlintide is sold as an acetate salt. Side effects include redness, swelling, bruising, or itching at the pramlintide injection site. Others are loss of appetite, stomach pain, excessive tiredness, dizziness, cough, sore throat, joint pain.

Pramlintide Dose For Type 1 Diabetes

Initial: 15 mcg SC immediately prior to major meals. Increase by 15 mcg q3 Days (if not significant nausea occurs). Reduce postprandial short-acting insulin dose by 50%. Maintenance: 30-60 mcg SC

Pramlintide For Type 2 Diabetes

Initial: 60 mcg SC immediately prior to major meals. After 3-7 days increase to 120 mcg prior to meals (if not significant nausea occurs). Reduce postprandial short-acting insulin dose by 50%. Maintenance dose of 60-120 mcg SC.

Pharmacotherapy/Treatment Of Gestational Diabetes

Gestational diabetes can only be managed by insulin or methyldopa as they are the only safe solutions in pregnancy.

Methyldopa

Methyldopa is a centrally-acting alpha-2 adrenergic agonist used to manage hypertension alone or in combination with hydrochlorothiazide, and to treat hypertensive crises.The more common side effects that can occur with methyldopa include: drowsiness, headache, lack of energy, weakness, dizziness, lightheadedness, fainting, nausea or vomiting.The most common side effects of methydopa include: drowsiness, weakness, and headache.

Methyldopa Dose

Hypertension

Initial: 250 mg PO q8-12hr for 2 days, increase q2Days PRN. Maintenance: 250-1000 mg/day divided q6-12hr PO, usually no more than 3 g/day. IV (methyldopa): 250-1000 mg infusion over 30-60 minutes q6-8hr PRN; no more than 4 g/day

Hypertensive Crisis

20-40 mg/kg/day divided IV q6hr. No more than 65 mg/kg/day or 3 g/day (whichever is less).

Bile Sequentrants

The bile acid sequestrants are a group of resins used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by combining with bile constituents and preventing their reabsorption from the gut. Bile acid sequestrants are medicines that help lower your LDL (bad) cholesterol. Too much cholesterol in your blood can stick to the walls of your arteries and narrow or block them. These medicines work by blocking bile acid in your stomach from being absorbed in your blood. E.g. cholestyramine The initial observation of a glucose-lowering effect of a BAS was reported from a study that evaluated cholestyramine in patients with dyslipidemia and type 2 diabetes; 8 g cholestyramine twice daily reduced plasma glucose levels by 13% after 6 weeks (12).

Dopamine Agonists

Dopamine agonists lower glucose release by the liver e.g. bromocriptine. Based on animal and human studies, timed bromocriptine administration within 2 h of awakening is believed to augment low hypothalamic dopamine levels and inhibit excessive sympathetic tone within the central nervous system (CNS), resulting in a reduction in postmeal plasma glucose levels due to enhanced suppression of hepatic glucose production. Bromocriptine has not been shown to augment insulin secretion or enhance insulin sensitivity in peripheral tissues (muscle). Addition of bromocriptine to poorly controlled type 2 diabetic patients treated with diet alone, metformin, sulfonylureas, or thiazolidinediones produces a 0.5–0.7 decrement in HbA1c. Bromocriptine also reduces fasting and postmeal plasma free fatty acid (FFA) and triglyceride levels.

Supplements For Diabetes

1. Garlic

2. cinnamon

3. apple

4. lipoic acid

5. aloe vera

6. ginseng

7. magnesium

8. ginkgo biloba

9. heartworm

10. chromium

11. vitamin B6, B12, C and E.

Diet For Diabetes

1. Whole grains

2. fruits

3. nonfat dairy products

4. beans

5. lean meat

6. vegetables

7. poultry or fish

Eat small meals each time many times a day. avoid heavy meals. Engage in exercise programme and weight reduction.