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Drug Selection in Type 2 Diabetes Mellitus

By Dr. Nwamaka Osakwe

Optimal blood sugar control is essential to limiting the complications of type 2 diabetes mellitus (T2DM). But with several classes of drugs to choose from, creating the proper regimen may be difficult. Keep reading to learn more about selecting glucose-lowering medications for patients with T2DM.

Goal of therapy

Before creating a drug regimen, it is important to take a careful history, examination, and vital investigations. “The history should be complete and include the family and social history,” said Dr. Rilwan Adan, Head of the Diabetes Center at Lions Eye Hospital Kenya.

The history, examination, and investigation may reveal certain conditions that preclude the use of some medications. Conversely, certain conditions create a compelling need to choose one class of glucose-lowering agent over another.

“Diabetes management is individualized because every case is different. Therefore, it is important to consider not only the clinical aspect but also the social determinants of health,” Dr. Adan said. Her suggestion aligns with the American Diabetes Association’s recommendation for a patient-centered treatment plan. Furthermore, drugs should be used in addition to lifestyle changes, as exercise and diet play a vital role in diabetes management.

The goals of treatment are to: 

  • Control blood sugar
  • Prevent delay complications of T2DM
  • Avoid hypoglycemia
  • Limit adverse effects of medication.

Considerations when selecting drugs

It is essential to consider comorbid conditions like obesity, hypertension, heart failure, atherosclerotic cardiovascular disease, and chronic kidney disease. For example, patients with obesity may benefit from drugs that cause weight loss. 

Another issue to consider is the affordability of these medications, says Dr. Adan. “I may have a patient who is at high cardiovascular risk, and I want to put them on the newer agents with cardiovascular benefits, but most of them are expensive for many patients.” There is no need to prescribe a medication a patient cannot afford since it would impact adherence. In some instances, it may be appropriate to select a cheaper drug or a drug in the patient’s insurance plan (for those on insurance).

Other patient-related factors such as social history, lifestyle, occupation, and health insurance are also important. For example, a patient with retinopathy who lives alone may have difficulty using insulin with a syringe.

Sometimes, management needs require that a patient is on a specific medication. To illustrate, patients who are insulinopenic need insulin. Based on this need, a regimen that includes insulin may be necessary. But, “many physicians have inertia to initiate insulin,” according to Dr. Adan, and this should not be. Instead, Dr. Adan suggests using simple language the patient understands to explain why you’re recommending insulin, as this approach will help to promote acceptance with patients.

Knowing the different classes of drugs and their benefits, side effects, and contraindications is essential when selecting the appropriate medication for each patient.

Classes of drugs

Oral Medications

  1. Biguanides: Metformin is currently the only approved drug in this class of drugs. Metformin increases insulin sensitivity. As such, it increases the peripheral uptake and the use of glucose. Other mechanisms of action are the reduction of hepatic gluconeogenesis and intestinal reabsorption of glucose.

    Metformin is the recommended first-line agent for T2DM. It is also associated with weight loss making it a helpful medication for obese patients.

    Side effects include diarrhoea, nausea, and vomiting. Vitamin B12 deficiency has also been reported with long-term use. Furthermore, metformin is associated with lactic acidosis and is not recommended for patients with eGFR less than 30ml/min.
  1. Sulphonylureas: These stimulate the pancreas to release insulin. Examples are gliclazide, glipizide, glibenclamide (also known as glyburide), and glimepiride. 

    Sulphonylureas are effective and cheap, making them a popular drug with many patients. However, using sulphonylureas carries a risk of hypoglycemia. Other side effects include weight gain, nausea, and skin reactions.
  1. Dipeptidyl peptidase-4 (DPP-4) inhibitors: These are also called gliptins.

    Dipeptidyl peptidase-4 are enzymes that break down incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). These incretin hormones are released following an oral meal. Therefore, they cause an increase in insulin secretion and a fall in glucagon secretion.

    By inhibiting DPP-4 enzymes, DPP-4 inhibitors increase the half-life of incretins resulting in increased insulin secretion and reduction in blood sugar levels. Examples include sitagliptin, saxagliptin, linagliptin, alogliptin, and vildagliptin.

    They are usually administered daily and are regarded as weight-neutral medications.

    Side effects include a higher risk of upper respiratory tract infections.
  1. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors: These are also called gliflozins. The SGLT-2 receptors found in the proximal tubules of the kidneys are responsible for reabsorbing filtered glucose back into the bloodstream. By blocking SGLT-2 receptors, these medications prevent the reabsorption of filtered glucose. This inhibition leads to glucosuria and a fall in blood glucose levels.

    The use of SGLT-2 inhibitors has been associated with weight loss, a fall in blood pressure, and improved cardiovascular and renal outcomes.

    SGLT-2 inhibitors are contraindicated in dialysis-dependent patients. Furthermore, there is a risk of urinary tract infections, genital infections, diabetic ketoacidosis, amputation, and hypotension.

    Examples are canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin.
  1. Thiazolidinediones: These are also called glitazones. Thiazolidinediones increase insulin sensitivity. As such, they require insulin to work. It takes about 3-4 months to achieve maximal effect. In addition, they carry a risk of weight gain and are associated with fluid retention. 

    Examples are pioglitazone and rosiglitazone. Rosiglitazone has been linked with myocardial infarction.
  1. Meglitinides: They are insulin secretagogues. Examples are repaglinide, nateglinide and mitiglinide.

    They carry a risk of hypoglycemia but not as much as the sulphonylureas. Weight gain, especially when taken with another insulin secretagogue, is possible.
  1. Alpha-glucosidase inhibitors: These agents inhibit intestinal enzymes responsible for carbohydrate breakdown. They prevent the breakdown of complex carbohydrates into simple sugars, resulting in a delay in carbohydrate absorption. Alpha-glucosidase inhibitors are taken with meals and help control postprandial glucose levels. Examples are acarbose and miglitol.

    Side effects from unabsorbed carbohydrates in the gut are bloating and flatulence. Therefore, they are contraindicated in patients with intestinal obstruction, inflammatory bowel disease, chronic intestinal disease, and diabetic ketoacidosis.
  1. Others: Bile acid sequestrants (such as colesevelam) and dopamine agonists (such as bromocriptine) have also been demonstrated to lower blood glucose levels. 

    Bromocriptine increases insulin sensitivity and is approved for treating T2DM. Side effects include hypotension, compulsive behaviour, and somnolence. Bromocriptine is administered orally and avoided in people with hypersensitivity to ergot and ergot-related products.

    Colesevelam has a modest effect in lowering blood glucose when combined with diet modifications, exercise, and other diabetes medications.

Injectables

  1. Insulin: It is primarily used in Type-1 DM but also T2DM. Insulin is administered subcutaneously, intramuscularly, and intravenously.

    Insulin increases the cellular uptake of glucose and promotes glycogenesis and lipogenesis. Various forms of insulin are available, such as rapid-acting, short-acting, intermediate-acting, and long-acting insulin. One common side effect of insulin is hypoglycemia.

    Devices used to administer insulin are syringes, insulin pens, insulin pumps, and jet injections.
  1. Glucagon-like peptide-1 (GLP-1) agonists: These are also known as incretin mimetics. Glucagon-like peptide-1 is a hormone that stimulates the pancreas to release insulin after oral glucose intake. In addition, this hormone also inhibits glucagon release and slows gastric emptying. The GLP-1 agonists mimic the actions of the incretin hormone GLP-1. They stimulate insulin release, inhibit glucagon release, and delay gastric emptying. 

    In addition to lowering blood glucose, the GLP-1 agonists promote weight loss, lower blood pressure and reduce total cholesterol levels.

    GLP-1 agonists are contraindicated in people with a family history of medullary thyroid cancer or multiple endocrine neoplasias.

    Side effects of GLP-1 agonists include nausea, vomiting, and diarrhoea. In addition, the risk of hypoglycemia is higher when combined with insulin secretagogues.

    Most GLP-1 agonists are injectables, including dulaglutide, albiglutide, liraglutide, exenatide, and lixisenatide. In addition, Semaglutide is available as an injectable and oral medication.
  1. Dual GLP-1 and GIP co-agonists: These agents stimulate both GLP-1 and GIP receptors leading to the reduction of blood sugar levels. As earlier stated, incretin hormones (GLP and GIP) stimulate insulin release, delay gastric emptying, and decrease glucagon secretion. The only agent currently FDA approved is tirzapetide.

    Tirzapetide reduces glycated haemoglobin levels and lowers weight by up to 11.7kg. It is administered subcutaneously once a week.

    Side effects include nausea, vomiting, diarrhoea, and constipation.
  1. Amylinomimetics: An example is pramlintide which is administered subcutaneously. Amylinomimetics slow gastric emptying. They also inhibit glucagon secretion, thereby reducing gluconeogenesis. 

    They carry a risk of hypoglycemia and are contraindicated in patients with hypoglycemia unawareness. Furthermore, their mechanism of action is contraindicated in patients with gastroparesis.

    Side effects include nausea and vomiting.

Final words

Proper blood sugar control is essential, says Dr Adan. The main pathophysiologic pathway for complications, including cardiovascular and renal complications, is related to poor sugar control. As such, using whatever drugs the patients can afford may be necessary. In addition, it may be best for patients who experience hypoglycemia to be on medications with a lower risk of inducing hypoglycemia.

At the end of her interview, Dr Rilwan Adan emphasized the need for holistic patient management through evidence-based and guideline-directed approaches. Dr Adan believes Africa should invest in research, as real-world evidence from our part of the world is crucial and can guide how we manage our patients.

To learn more about T2DM and its treatment:

Click here for the International Diabetes Federation clinical practice recommendations for managing type 2 diabetes in primary care.

Click here for the American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes.

Where available, it is advised to follow the Ministry of Health guidelines in your local setting.

Nwamaka Osakwe, FWACP, MBBS, is an award-winning physician who loves writing about health and wellness. You can reach her here

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