14th September 2024

Type 2 diabetes

Type 2 diabetes mellitus is a chronic progressive metabolic disorder, characterised by hyperglycaemia. The predominant problem is increased insulin resistance coupled with a relative deficiency of insulin. There is a slower beta cell loss compared to type 1. Although the aetiology of both differs, they both lead to hyperglycaemic states and share common macrovascular (heart disease, cerebrovascular and peripheral vascular disease) and microvascular (retinopathy, nephropathy, and neuropathy) complications.

Diagnosis

The diagnostic criteria for type 2 diabetes includes the following:

• A fasting plasma glucose of 7 mmol/l or greater
• A random blood sugar 11.1mmol/l or greater
• A HbA1c of 48 mmol/mol (6.5%) or greater
• A plasma glucose of 11.1mmol/l or greater after two hours of oral 75g glucose in the form of the tolerance test

If the patient is symptomatic, NICE advise that a single abnormal HbA1c or fasting plasma glucose result can be used for diagnosis, but it is sensible to repeat the test. In asymptomatic patients, do not diagnose based on a single abnormal result. Repeat testing is required. If the repeat test is normal, arrange for interval testing.

HbA1c is a minor haemoglobin component formed from the chemical condensation of glucose and haemoglobin. It forms slowly and is directly proportional to serum glucose concentration. The normal life of a red blood cell is 120 days. If a larger number of red cells survive for longer periods of time, then they will have more time to form HbA1c. Therefore, factors that reduce the destruction of red cells (such as splenectomy) will falsely increase the concentration of HbA1c. Factors that reduce red cell production (such as B12, folate, and iron deficiency anaemias, as well as aplastic anaemia) will reduce the number of new red cells without HbA1c, thus falsely increasing the concentration of HbA1c. Conversely, reticulocytosis (as seen in hemolytic anaemia or blood loss) and reduced red cell lifespan (as in splenomegaly or pregnancy) will falsely decrease HbA1c concentration. For unknown reasons, chronic alcohol consumption can also falsely increase HbA1c concentrations. Haemoglobinopathies cause unpredictable changes in HbA1c levels. In these circumstances, it might be better to use fructosamine levels or average glucose levels.

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.

Overview of the medications used to treat type 2 diabetes

Hyperosmolar hyperglycaemic state

In contrast to DKA, hyperosmolar hyperglycaemic state (HHS) develops over several days. It is characterised by profound fluid deficit, excessively high osmolality (2x Na + urea + glucose), and high glucose levels (>30 mmol/l) in the absence of ketosis or acidosis. Despite normal serum potassium concentrations, patients are often potassium-depleted. The treatment aims to rehydrate the patient using crystalloids and to reduce osmolality. Insulin therapy should not be routinely used as it can cause dangerously rapid reductions in osmolality, potentially leading to cerebral complications. However, in cases of mixed DKA/HHS syndromes, where acidosis and ketosis are present, insulin may be used. HHS has an extremely high mortality rate, up to ten times higher than that of DKA.

Non diabetic hyperglycaemia

Non-diabetic hyperglycaemia includes two conditions:

References

• Recommendations: Type 2 diabetes in adults: Management: Guidance (2022) NICE CKS. Available at: https://www.nice.org.uk/guidance/ng28/chapter/Recommendations
• WHO (2011). Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus (Abbreviated Report of a WHO Consultation). WHO/NMH/CHP/CPM/11.1
• DeSantis, A. and Dungan, K. (2024) Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus, UpToDate. Edited by D.M. Nathan and K. Rubinow
• Inzucchi, S.E. and Lupsa, B. (2022) Thiazolidinediones in the treatment of type 2 diabetes mellitus, UpToDate. Edited by D.M. Nathan and K. Rubinow
• Wexler, D.J. (2022) Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus, UpToDate. Edited by D.M. Nathan and K. Rubinow
• DeSantis, A. (2024) Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus, UpToDate. Edited by D.M. Nathan and K.R. Rubinow
• Dungan, K. and DeSantis, A. (2023) Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus, UpToDate. Edited by D.M. Nathan and K. Rubinow. Available at: https://www.uptodate.com/contents/dipeptidyl-peptidase-4-dpp-4-inhibitors-for-the-treatment-of-type-2-diabetes-mellitus (Accessed: 19 February 2024)
• Management of diabetes Quick Reference Guide. (2010). Available at: https://www.sign.ac.uk/assets/qrg116.pdf
• Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus: Abbreviated Report of a WHO Consultation. Geneva: World Health Organization; 2011. Annex 1, Some of the factors that influence HbA1c and its measurement. Available from: https://www.ncbi.nlm.nih.gov/books/NBK304266/
• Radin MS. Pitfalls in hemoglobin A1c measurement: when results may be misleading. J Gen Intern Med. 2014 Feb;29(2):388-94. doi: 10.1007/s11606-013-2595-x. Epub 2013 Sep 4. PMID: 24002631; PMCID: PMC3912281
• NICE Recommendations: Type 2 diabetes in adults: management; June 2022; available at Recommendations | Type 2 diabetes in adults: management | Guidance | NICE
• The Management of Diabetic Ketoacidosis in Adults; March 2023; Joint British Diabetes Societies; Prof Ketan Dhatariya, Norfolk and Norwich University Hospitals NHS Foundation Trust; available from: Joint British Diabetes Societies for Inpatient care | Diabetes UK
• Adeyinka A, Kondamudi NP. Hyperosmolar Hyperglycemic Syndrome. [Updated 2023 Aug 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482142/