Oral Antidiabetic Drugs and GLP-1 Analogues

Essentials

• Antidiabetic drugs are only one aspect of pharmacological treatment in type 2 diabetes (control of glucose, lipids, hypertension and coagulation: see Comprehensive Treatment and Follow-Up of Type 2 Diabetes).
• Oral medication should be introduced at an early stage. In the absence of contraindications, medication should be started when the HbA_1c concentration exceeds 48-53 mmol/mol (6.5-7.0%) despite non-pharmacological intervention. If blood glucose is only mildly elevated and if it is likely that the patient is able to normalize it through lifestyle changes Intensive Weight Management for Remission of Type 2 Diabetes, it is worth starting treatment with non-pharmacological therapy, even if it would not be required for the reimbursement for medicine expenses.
• Metformin is recommended as the first blood sugar lowering drug Metformin Monotherapy for Type 2 Diabetes Mellitus for most patients. SGLT2 inhibitors are the primary choice in patients with heart or kidney failure.
• If lifestyle changes and metformin do not lower HbA_1c to below 53 mmol/mol (7.0%), the choice of the next drug should be individually defined (Flowchart 1).
• If one antidiabetic drug does not lower the HbA_1c concentration to below 53 mmol/mol (7.0%), add another and possibly a third antidiabetic drug unless there are contraindications. The mean effect of oral drugs on HbA_1c is limited (5-25 mmol/mol) and varies depending on the product; see Table T1.
• If HbA_1c remains higher than 53 mmol/mol (7.0%) despite oral medication, start using an injectable GLP-1 analogue or insulin Insulin Added on Metformin in Type 2 Diabetes (see also Insulin Therapy in Type 2 Diabetes) or a combination of these.

Effects on cardiovascular events

• See table T1.

Effects on heart failure

• All SGLT2 inhibitors have been shown to reduce hospital treatment for heart failure significantly, by about 32% Sglt-2 Inhibitors in Type 2 Diabetes.
• Of SGLT2 inhibitors empagliflozin, at least, reduces cardiovascular mortality of patients with heart failure, as well as the progression of kidney disease in both people with and people without diabetes Sglt-2 Inhibitors in Type 2 Diabetes.
• GLP-1 analogues or other blood glucose lowering drugs have not been shown to reduce hospital treatment for heart failure.

Effects on kidney failure

• GLP-1 analogues (semaglutide, liraglutide, dulaglutide) Glucagon-Like Peptide Analogues (GLP-1 Analogues) for Type 2 Diabetes and SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) Sglt-2 Inhibitors and GLP-1 Agonists for Diabetes and Chronic Kidney Disease have been shown to reduce the development of diabetic nephropathy (eGFR reduction, dialysis, kidney transplantation, mortality from nephropathy).
• A good glucose balance (insulin, metformin, sulphonylurea) has been shown to slow down the development of diabetic nephropathy, neuropathy and retinopathy in people with newly diagnosed type 2 diabetes (see Table T1).

Summary of oral antidiabetic drugs

• See Table T2

Biguanides

MetforminRisk of Lactic Acidosis with Metformin in Type 2 Diabetes, Metformin Monotherapy for Type 2 Diabetes Mellitus

• Metformin is often recommended as the drug of choice if there are no contraindications. It can also be combined with any other antidiabetic drugs (combined products).
• Metformin reduces blood glucose levels by inhibition of hepatic glucose production. It does not induce hypoglycaemia or affect the liver fat content.
• To produce an effect the dose must be adequately high (2-2.5 g/day). The treatment is begun with, for example, 500 mg/day followed by increases of 500 mg/week to up to the 2-2.5 g/day.
• Abdominal complaints are the most troublesome adverse effect of metformin, leading to discontinuation of the treatment in approximately 10% of the patients.
• In order to eliminate the risk of lactic acidosis metformin must not be given to patients with
  • liver disease
  • renal failure (Check dosage from locally available pharmaceutical resources/databases; Persistent proteinuria warrants further investigations)
  • alcohol abuse
  • obvious cardiac insufficiency or other conditions leading to hypoxia.
• Advanced age does not prevent the use of the drug; however, the creatinine concentration should be normal before and during the therapy in the elderly.
• Metformin treatment must be interrupted during severe infections, elective surgery and trauma. If the patient is to undergo a procedure involving the administration of intravenous contrast medium, ensure that renal function is normal prior to the procedure.

Glucose transport protein 2 (SGLT2) inhibitors Sglt-2 Inhibitors in Type 2 Diabetes, Sglt-2 Inhibitors and GLP-1 Agonists for Diabetes and Chronic Kidney Disease

• SGLT2 inhibitors are selective inhibitors of SGLT2, a mediator of glucose and sodium reabsorption in the kidneys. They reduce the blood glucose concentration by increasing glucosuria. The drugs also cause natriuresis and increase diuresis, consequently lowering the blood pressure.
• The SGLT2 inhibitors empagliflozin and canagliflozin reduce cardiovascular events in persons with type 2 diabetes and with increased cardiovascular risk Sglt-2 Inhibitors in Type 2 Diabetes.
• All SGLT2 inhibitors reduce the need for hospitalization for heart failure by an average of about 30% Sglt-2 Inhibitors in Type 2 Diabetes.
• All SGLT2 inhibitors reduce the progression of diabetic nephropathy by about 40% (eGFR reduction more than 40%, need for dialysis or kidney transplantation, death) Sglt-2 Inhibitors and GLP-1 Agonists for Diabetes and Chronic Kidney Disease. SGLT2 inhibitors prevent the progression of kidney disease equally effectively regardless of the baseline eGFR level. The blood glucose lowering effect of SGLT2 inhibitors decreases with decreasing eGFR levels, and SGLT2 inhibitors should not be started for the treatment of hyperglycaemia unless eGFR is > 60 ml/min/1.73 m² .
• The drugs can be combined with other antidiabetic drugs, also with insulin, in people with type 2 diabetes.
• A baseline HbA_1c of 64 mmol/mol (8.0%) is reduced by an average of approximately 0.7 percentage units.
• Not recommended for lowering blood glucose levels in moderate renal failure (eGFR < 60 ml/min/1.73 m² ) or in severe liver failure.
• The drugs increase the occurrence of infections of the genital organs, e.g. vulvovaginitis and balanitis (3- to 8-fold compared to placebo). The risk of ketoacidosis is also increased about 3-fold.

GLP-1 analogues Glucagon-Like Peptide Analogues (GLP-1 Analogues) for Type 2 Diabetes

• Exenatide, liraglutide, lixisenatide, dulaglutide and semaglutide are GLP-1 analogues that are administered subcutaneously usually once or twice daily or once weekly. Of GLP-1 analogues, liraglutide and semaglutide have been shown to reduce the occurrence of cardiovascular events Sglt-2 Inhibitors in Type 2 Diabetes. Semaglutide is also available in tablet form.
• GLP-1 analogues have a similar mode of action to that of GLP-1, and they lower HbA1c clearly more than gliptins. They also slow the rate of stomach emptying. This effect at least partly explains the weight reduction but also causes nausea (in about 40% of the patients, at least in the initial phase). The drugs also suppress appetite through the central nervous system.
• GLP-1 analogue therapy significantly reduces weight.
• GLP-1 analogues can be used instead of insulin when HbA1c concentration exceeds 53 mmol/mol (7.0%) despite oral drug therapy. The drugs can be combined with other oral antidiabetic drugs or their combinations, or with basal insulin treatment or with combination therapy of basal insulin and drug(s).

Glitazones

PioglitazonePioglitazone for Type 2 Diabetes Mellitus

• Pioglitazone improves insulin sensitivity of the liver, decreases the liver fat content and reduces the need of insulin.
• Pioglitazone reduces the risk of myocardial infarction and stroke in patients who have previously had a stroke or TIA.
• Indicated for the treatment of hyperglycaemia as monotherapy or in combination with other antidiabetic drugs.
• Particularly effective in patients with high insulin need and fatty liver or NASH Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH).
• When starting the treatment, the patient must not have signs or symptoms of cardiac failure because pioglitazone may cause fluid retention (in 5%) and cardiac insufficiency.
• A clinically insignificant decrease in hemoglobin (5-10 g/l) occurs in most patients.
• Glitazones increase the risk of bone fractures.

Enhancers of insulin secretion

DPP-4 inhibitors (gliptins) Incretin-Based Therapy with Dipeptidyl Peptidase 4 Inhibitors in Type 2 Diabetes

• Gliptins include sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin. These drugs suppress the degradation of GLP-1 (glucagon-like-peptide), a hormone that stimulates insulin secretion and inhibits glucagon secretion. GLP-1 is secreted in the L cells of the small intestine when blood glucose concentration increases. Unlike sulphonylureas, gliptins do not cause hypoglycaemia when used as monotherapy, and their effect on body weight is neutral. Drawbacks include their limited effect on hyperglycaemia (about 0.6 percentage unit decrease in HbA_1c when the baseline level is 64 mmol/mol [8.0%]) and that they do not have an effect on cardiovascular events.
• Can be combined with any other antidiabetic drug.
• With linagliptin it is not necessary to change the dosage in a patient with renal failure.
• No significant adverse effects have been described in association with these drugs.