14th September 2024

Management

Prevention is the best strategy for diabetes management. High risk individuals should be screened and managed appropriately with structured educational programmes. Cardiovascular complications (myocardial infarctions and strokes) are the main cause of mortality amongst this group highlighting the importance of reducing risk and control of blood glucose. Management consists of a combination of drug treatment, education and lifestyle modifications including smoking cessation, reducing stress, exercise and change in diet. The main oral diabetic medications are shown below. Insulin can be considered instead of starting a third line medication.

Metformin

First-line drug treatment is metformin, a biguanide. The mechanism is not entirely clear, however it decreases hepatic gluconeogenesis and increases insulin sensitivity in the peripheral tissues. It can cause weight loss and rarely leads to hypoglycaemia, but it is known to cause gastrointestinal side effects. In view of this, the drug should be stepped up gradually over weeks, or clinicians can switch to a more tolerable modified release (MR) alternative. Contraindications include metabolic acidosis or a significantly reduced renal function (eGFR <30 or Creatinine >150).

Target HbA1c starts at 48 mmol/mol (6.5%) with lifestyle modifications and/or metformin. If, despite these measures, HbA1c rises to 58 mmol/mol (7.5%) or higher, drug treatment should be intensified. Dual and triple therapy agents include dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones, sulphonylureas, glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors. If three agents fail to control HbA1c, insulin-based treatment should be considered.

DPP-4 inhibitors

Examples of DPP-4 inhibitors include sitagliptin, vildagliptin and linagliptin. During digestion, the gastrointestinal tract secretes incretin hormones (GLP-1, GIP) that stimulate insulin and inhibit glucagon. DPP-4 inactivates GLP-1 therefore inhibitors would enhance the incretin effect after meals and improve blood glucose control. There is a small risk of acute pancreatitis from DPP-4 inhibitors related to extra simulation of the pancreas though the full mechanism is unclear. These medications do not cause weight gain.

Thiazolidinediones

Pioglitazone, a thiazolidinedione, is an agonist of the peroxisome proliferator-activated receptor gamma (PPAR-γ). Agonism at this receptor induces changes that reduce peripheral insulin resistance. It can worsen heart failure, cause bladder cancer, lead to weight gain, and cause skeletal fractures due to reduced bone density.

Sulphonylureas

Sulphonylureas include gliclazide, glibenclamide and glipizide. They directly stimulate pancreatic beta cells to release insulin. The increased insulin can lead to the adverse effects of frequent hypoglycaemia and weight gain.

GLP-1 agonists

GLP-1 is an incretin secreted by intestinal L cells. GLP-1 agonists are mainly injectables; however, there are oral options as well. Similar to DPP-4 inhibitors, they enhance the incretin effect, stimulating insulin, inhibiting glucagon, and delaying gastric emptying. These agents do not typically cause hypoglycaemia and are well known to induce significant weight loss. Doctors can consider prescribing these when diabetes is not adequately treated with three medications. Furthermore, BMI must be above 35 kg/m², and reductions in HbA1c (1%) and weight (3%) must be observed after six months of treatment. GLP-1 agonists have been associated with acute pancreatitis, biliary disease, and hypersensitivity reactions.

SGLT2 inhibitors

These novel agents have been shown to be useful in those with elevated cardiovascular risks. SGLT are glucose transporter proteins found throughout the body, with SGLT2 located in the proximal tubule of the nephron. Inhibitors block glucose reabsorption in the kidney, leading to increased urinary glucose excretion. Examples of these agents are dapagliflozin and empagliflozin. Due to increased glycosuria, there is an increased risk of urinary tract infections, fungal infections, and DKA. These medicines should be used in addition to metformin in anyone who has pre-existing cardiovascular disease or is at high risk of developing cardiovascular disease.