TYPE 2 DIABETES MELLITUS: TREATMENT AND MANAGEMENT - BY ABDUL RAUF

Type 2 diabetes mellitus management goal is to keep the sugar level normal and the HbA1c level of 6.5 to 7%. There are a number of medications and injections available for the treatment of DM Type 2 along with lifestyle changes. These medications are as follows:

•          Biguanide (Metformin)
•          Sulfonylureas.
•      DPP-IV inhibitors.
•          GLP-1 Receptor Agonists
•          Thiazolidinediones (TZD)
•          SGLT-2 Inhibitors.
•          Alpha-Glucosidase Inhibitors.
•         Insulins.

Metformin:  A biguanide that inhibits the production of glucose by the liver and decreases the resistance of cells to insulin and in this way cells take glucose from the bloodstream. 

There are certain pros and cons of metformin:

The benefits of metformin include a decrease in the HbA1c by 1% to 2%, metformin's initial response rate is good and metformin is a low-cost medication.  One of the benefits is it can help in weight loss and do not increase weight.  There is also certain evidence that it is beneficial for cardiovascular patients who are overweight.

There are certain cons or disadvantages that it causes gastrointestinal side effects like nausea, vomiting, or gastric irritation. There are also chances of lactic acidosis with the use of Metformin.  It is also contraindicated in patients with an impaired renal function where EGFR is less then 30 ml/min and also in patients with congestive heart failure requiring medicinal treatment.

Metformin should be started at the start of diagnosis and must be taken with meals. 

Sulfonylureas:  Sulfonylurea used in DM type 2 usually is glimepiride. Sulfonylurea act by increases the production of insulin from the pancreas. It decreases HBA1c by 1% to 2%. Like metformin its initial response rate is good and its dosing is once daily only.

Sulfonylurea also having cons as its side effect is hypoglycemia, may cause weight gain and need caution in patients with hepatic and renal dysfunction, and also its cardiac safety is not known.

DPP-IV inhibitors: Dipeptidyl peptidase-4 enzyme inhibitor prevents the breakdown of incretin hormones and increases their diabetic effects. DPP-IV inhibitors work by increases insulin secretion and have fewer side effects of hypoglycemia. DPP-IV inhibitors include sitagliptin, vildagliptin, linagliptin, and saxagliptin. In Pakistan Sitagliptin and Vildagliptin is prescribed and used.  The pros are the weight remains the same and it has no side effect on weight. DPP-IV inhibitors not contraindicated in heart failure and renal insufficiency patients.  DPP-IV inhibitors inhibit the activity of DPP-IV enzyme and thus increases the incretin hormone, which in turn results in more insulin production.

DPP-IV inhibitors are used as second-line therapy after metformin does not give results in sugar control. DPP-IV can also be used with other diabetic drugs like sulfonylurea, thiazolidinediones, and metformin and can also be used with insulin. 

The disadvantages of DPP-IV inhibitors are these medicines can cause nasopharyngitis and upper respiratory infections. These medicines are also costly.  DPP-IV inhibitors are not used in diabetic ketoacidosis and not use as therapy for type 1 diabetes mellitus.

GLP- 1 RECEPTOR AGONISTS:  These stimulate the release of GLP 1 hormone the human body naturally produces and found in the gut, intestine, which gives signals to the pancreas to get ready to process carbohydrates or sugar thus help the pancreas to release more insulin. GLP-1 receptor agonists also reduce the amount of glucagon in the body.  GLP 1 medications normalize the sugar levels after meals and sugar level in the morning and also help in weight reduction. GLP-1 medications available in once daily or once weekly injectable form like Liraglutide ( Victoza ) once daily, and Deglutide (Trulicity) once weekly subcutaneous injections.

GLP-1 receptor agonists have side effects like nausea, vomiting, GI upset, or diarrhea. These side effects risks can be reduced by eating smaller meals or eating meals slowly.  

Thiazolidinediones: The antidiabetic drugs class used to reduce insulin resistance in type 2 DM.  These medicines decrease HbA1c by 1% to 2 %. Not causing hypoglycemia. Thiazolidinediones includes pioglitazone and rosiglitazone. The dosing is once daily.

The cons of thiazolidinediones are the side effect of weight gain, may cause edema, and can cause heart failure and osteopenia especially in the women population. It has a slow onset of action as these drugs show effectiveness in 10-12 weeks. 

SGLT-2 INHIBITORS:  Sodium-glucose cotransporters 2 inhibitors include empagliflozin and dapagliflozin. SGLT-2 inhibitors are used in people having type 2 DM with established heart and renal disease. The American Diabetic Association (ADA) recommends the use of SGLT-2 inhibitors for DM type 2 and diabetic kidney disease patients with eGFR of at least 30 ml/min/1.73 m² and urinary albumin to creatinine ratio (UACR) greater than 30 mg/g.  

SGLT-2 Inhibitors are not considered as initial therapy for the patients as the initial therapy includes diet and exercise plan and use of metformin. 

One of the benefits of SGLT-2 inhibitors are weight loss and reduction in high blood pressure. SGLT-2 inhibitors reduce blood glucose by increasing urinary glucose excretion. These medications reduce HbA1c, fasting glucose levels, and postprandial glucose levels. These have an insulin-independent mechanism of action. 

Disadvantages of SGLT-2 inhibitors are the side effects as the use of these agents can result in diabetic ketoacidosis, bone fracture, urinary tract infections, female genital yeast infection, increased urination, joint pain, nausea, vomiting, and thirst.  Patients with a past history of dehydration, amputation of any organ or peripheral vascular disease may have increased adverse effects from SGLT-2 inhibitors use and physician must consider these factors before continuing SGLT-2 inhibitors.

ALPHA-GLUCOSIDASE INHIBITORS:  These medicines also used in type 2 DM management. These medicines delay the absorption of glucose from the small intestine by inhibiting glucosidase enzymes and thus have a lowering effect on glucose level after taking food. It can lower HbA1c from 0.5% to 0.8%.  

Both alpha-glucosidase inhibitor Acarbose and biguanide Metformin can be used in combination to delay the type 2 diabetes mellitus complications.  Alpha-glucosidase inhibitors can be given as a monotherapy, as well as, can be given with any other class of antidiabetic medicines and with insulin.

Alpha-glucosidase inhibitors are contraindicated in patients with inflammatory bowel disease, diabetic ketoacidosis, or patients having partial intestinal obstruction.  One of the disadvantages is it is not used in patients having renal impairment or renal disease. One more disadvantage is dosing is not once daily, and is given in 3 doses a day. 

ADA GUIDELINES REGARDING ANTIDIABETIC MEDICATIONS MANAGEMENT

 Along with diet control and exercise the monotherapy starts with the use of metformin to achieve the HbA1c goal. If HbA1c is not achieved then dual therapy is considered. Before starting dual therapy the cardiovascular heart disease, stroke, heart attack, and any other heart-related complication must be seen by the physician, and if the patient is having heart disease then dual therapy starts with the use of SGLT2-inhibitor or GLP-1 receptor agonist.   

If the patient is not having any heart disease then start metformin with sulfonylurea, or with thiazolidinediones, or DPP IV-inhibitor, GLP-1 receptor agonists, or with insulin.  

Check for cardiovascular disease.  If atherosclerotic cardiovascular disease, then go for GLP-1 receptor agonist or SGLT2 inhibitor. If the HbA1c goal is not achieved, and the patient is unable to tolerate SGLT2 inhibitor or GLP 1 receptor agonist then consider adding other antidiabetic medicine with proven cardiovascular benefits, e.g; add DPP IV-inhibitor if the patient is not on GLP-1 receptor agonist. Another example is adding basal insulin or similarly thiazolidinediones or sulfonylurea.

If heart failure disease, then go for SGLT2- inhibitor, or GLP-1 receptor agonist.  If the HbA1c goal is not achieved then choose antidiabetic medicine depending on cardiovascular safety. Consider DPP IV inhibitor if the patient is not on GLP-1 receptor agonist or consider basal insulin or sulfonylurea. Do not use thiazolidinediones in heart failure patients.

MONOTHERAPY FOR DIABETES MANAGEMENT

If the HbA1c is less than 7.5, start monotherapy with metformin, or GLP-1 receptor agonists, or SGLT-2 inhibitor, DPP IV-inhibitor, thiazolidinediones, alpha-glucosidase inhibitor, or sulfonylurea along with diet modification and exercise.  If the desired HbA1c not achieved in 3 months then switch the patient to dual therapy. 

DUAL THERAPY FOR DIABETES MANAGEMENT

If the HbA1c is over 7.5% then dual therapy includes any one of the agents along with metformin that includes GLP-1 receptor agonist, SGLT2-inhibitor, DPP IV-inhibitor, thiazolidinediones, basal insulin, alpha-glucosidase inhibitor, or sulfonylurea along with diet modification and exercise.  

TRIPLE THERAPY FOR DIABETES MANAGEMENT

If the HbA1c again not achieved to the desired level in 3 months then triple medication therapy starts that includes metformin as 1^st line agent, 2^nd line agent used in dual therapy, and 3^rd line drug from other antidiabetic medications along with diet modification and exercise.  

STARTING INSULIN THERAPY WHEN ORAL ANTIDIABETICS NOT RESPONDING IN TYPE 2 DIABETES MELLITUS

The guidelines of ADC suggest lifestyle changes and 1 or 2 oral antidiabetic agents and then go to basal insulin therapy.  The first step is to consider the HbA1c of the patient and if HbA1c is less than 8 and the patient is already taking 1-2 antidiabetic oral agents then the patient must be started on basal insulin with the total daily dose of 0.1 to 0.2 units/kg, and if the HbA1c is greater than 8 % then 0.2-0.3 units/kg.  The steps are to follow the oral antidiabetic agents at the same dosage, and add a single dose of basal insulin or basal insulin analog in the evening time starting at 0.2 units to 0.3 units/kg depending on the fasting glucose level must be under 130dl/ml in the morning. Basal insulin used usually is NPH (Intermediate-acting) or the basal insulin analog Glargine or Detemir (long-acting).

NPH Insulin onset of action is 2-4 hours whereas peak concentration reached in 4-10 hours and effective for 10-16 hours. Long-acting insulins Detemir and Glargine onset of action is not known, no pronounced peak, but the duration of action is up to 24 hours.  The efficacy of NPH and Glargine is very similar. If the patient is using NPH insulin must use insulin in the evening time and if the patient is using Detemir or Glargine, can be started in the evening, also can be started in the morning. Insulin titrations must be done every 2-3 days to achieve the glycemic goal. If fasting blood glucose is above 180 mg/dl and 20% additional insulin, if fasting blood glucose is 140-180 mg/dl add 10% additional insulin and if less than 140mg/dl, add 1 unit of insulin.

In patients where basal insulin is not enough to achieve glycemic control, the physicians have to consider controlling the postprandial glucose level. So, the patient can be given premix insulin or the basal-bolus insulin; or insulin in combination with other hormones.

Premixed insulin 70/30 used alone or in combination with antidiabetic oral agents with the dose of 0.2-0.3 units/kg/day-divided 2/3 dose in the morning and 1/3 dose in the evening.

Insulin dose adjustment can be done by increasing insulin by 2 units every week if blood glucose 140-180 mg/dl and by 4 units every week if blood glucose is above 180mg/dl. 

Glargine insulin causes minimum chances of hypoglycemia, weight gain as compare to premixed insulin 70/30. 

Ultra long-Acting Basal Insulins are highly concentrated Glargine insulin and Degludec long-acting basal analog insulin. Glargine concentrated insulin onset of action is 6 hours, whereas Degludec insulin onset of action is 1 hour. Glargine U-300 half-life is approximately 23 hours, Degludec insulin half-life is approximately 25 hours. Steady-state concentrations of Glargine U-300 is 4 days whereas Degludec 2-3 days.  Glargine U-300 effective for less than or equal to 36 hours, whereas Degludec effective for 42 hours. 

A basal-bolus insulin combination involves the diabetic patient taking both basal and bolus insulin throughout the day. It is a way to control blood sugar levels without needing to eat meals at particular times each day and helps in achieving normal blood sugar levels. Bolus insulin includes short-acting and rapid-acting insulins. Long-acting insulin once a day along with rapid-acting or short-acting insulins 2-3 times a day to achieve glycemic control.

The benefits of basal-bolus insulin regimen in type 2 diabetes is that it's effective in 2/3 population in achieving HbA1c goals, and has a neutral cardiovascular profile. The disadvantages of the basal-bolus insulin regimen are low adherence to therapy, weight gain, and risk of hypoglycemia. 

If the patient having postprandial hyperglycemia after basal insulin therapy then optimized postprandial glucose control required.  For that basal insulin therapy is added to the GLP-1 receptor agonist or with DPP IV-inhibitor or with SGLT2-inhibitor.  All these three ways of the regimen are effective in controlling the postprandial glucose level. The basal insulin plus basal-bolus insulin is exactly controlling the glucose level same as basal insulin + GLP-1 receptor agonist daily or every week.  GLP-1 increases insulin secretion, reducing glucagon secretion, and therefore, decreases glycogenolysis, or hepatic glucose production. This delays gastric emptying so the patient does not desire any meal that is decreased appetite. GLP-1 reduces body weight, reduces HBA1c, and reduces the insulin dose. 

Other options are the use of basal insulin with DPP IV or SGLT2 inhibitors.

 The patient did life changes modifications, then add metformin, then add basal insulin then added basal insulin to basal-bolus, then added GLP-1 agonist, or DPP IV-inhibitor or SGLT2-inhibitor to the basal insulin.  DPP IV- inhibitors and SGLT2-inhibitor not causes weight gain and cardioprotective so can be good agents use to control HbA1c. 

Hopefully, this article must help in the understanding of the antidiabetic medications used along with lifestyle changes in diabetes mellitus management.