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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 ).
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.

Choosing antihyperglycaemic medication in type 2 diabetes.

Effects on cardiovascular events

See table T1.

Beneficial effects of antidiabetic drugs on cardiovascular events and chronic kidney disease

Drug group	Product	Cardiovascular benefit / patient group	Benefit in chronic kidney disease	Study
Drug group	Product	Cardiovascular benefit / patient group	Benefit in chronic kidney disease	Heart	Kidneys
Biguanides	Metformin	Beneficial / newly diagnosed patient	Yes	UKPDS 1	UKPDS1
SGLT2 inhibitors	Empagliflozin	Beneficial / secondary prevention	Yes	EMPA-REG 2	EMPA-REG OUTCOME3
	Canagliflozin	Beneficial / secondary prevention	Yes	CANVAS4	CREDENCE5
	Dapagliflozin	No benefit / primary and secondary prevention	Yes	DECLARE-TIMI 586	DAPA-CKD7
	Ertugliflozin	No benefit / secondary prevention		VERTIS8
GLP-1 analogues	Liraglutide	Beneficial / secondary prevention	Yes	LEADER 9	LEADER9
	Semaglutide s.c.	Beneficial / secondary prevention	Yes	SUSTAIN-6 10	SUSTAIN-610
	Semaglutide tbl	Possibly beneficial / secondary prevention		PIONEER-6 11
	Dulaglutide	Beneficial / secondary prevention	Yes	REWIND12	REWIND12
	Albiglutide	Beneficial / secondary prevention		HARMONY13
	Lixisenatide	No effect / secondary prevention	Yes (albuminuria)	ELIXA 14	ELIXA14
Glitazones	Pioglitazone	Beneficial in patients with stroke or TIA		IRIS 15
Glitazones	Pioglitazone	No benefit / secondary prevention		PROACTIVE 16
Insulin	Insulin	Beneficial / newly diagnosed patient	Yes	UKPDS 17	UKPDS
Sulphonylureas	Glibenclamide or glipizide	Beneficial / newly diagnosed patient	Yes	UKPDS 2	UKPDS17
Gliptins	Saxagliptin	No effect / secondary prevention	Possibly harmful	SAVOR-TIMI 18
	Sitagliptin	No effect / secondary prevention	No effect	TECOS 19	TECOS19
	Alogliptin	No effect / secondary prevention	No effect	EXAMINE 20	EXAMINE20
	Linagliptin	No effect / secondary prevention	No effect	CARMELINA 22	CARMELINA21

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

Oral antidiabetic drugs and GLP-1 analogues

Product	Regular maintenance dose	Number of doses	Reduction in HbA_1c¹⁾ , mmol/mol (percentage units)	Weight change²⁾	Hypoglycaemias
Biguanides
Metformin	2 000 mg	Twice daily	15 (1.5)	No change	None
SGLT2 inhibitors (glucose reabsorption inhibitors)
Empagliflozin	10-25 mg	Once daily	6 (0.6)	Slight decrease (-0.8 kg)	None
Dapagliflozin	10 mg	Once daily	6 (0.6)	Slight decrease (-2.0 kg)	None
Canagliflozin	100-300 mg	Once daily	6 (0.6)	Slight decrease (-1.6 kg)	None
Ertugliflozin	5-15 mg	Once daily	5 (0.5)	Slight decrease (-2.0 - -2.4 kg)	None
GLP-1 analogues
Liraglutide s.c.	1.8 mg	Once daily	4 (0.4)	Slight decrease (-2.3 kg)	None
Semaglutide s.c.	0.5-1.0 mg	Once a week	7-10 (0.7-1.0)	Slight decrease (-2.9 - -4.3 kg)	None
Semaglutide tbl	14 mg	Once daily	7 (0.7)	Slight decrease (-3.4 kg)	None
Dulaglutide s.c.	1.5 mg	Once a week	6 (0.6)	Slight decrease (-1.5 kg)	None
Lixisenatide s.c.	20 µg	Once daily	4 (0.4)	Slight decrease (-0.4 kg)	None
Insulin sensitizers (glitazones)
Pioglitazone	15-45 mg	Once daily	10-15 (1.0-1.5)	Slight increase (3.6-4.0 kg)	None
Enhancers of insulin secretion
Sulphonylureas
Glimepiride	4-6 mg	Once daily	10-15 (1.0-1.5)	Slight increase	+
Glibenclamide	10.5-14 mg	Twice daily	10-15 (1.0-1.5)	Slight increase	++
Glipizide	10-15 mg	Twice daily	10 (1.0)	Slight increase	+
Glinides (phenylalanine derivatives)
Repaglinide	12 mg	3 times daily	10 (1.0 )	Slight increase	+
DPP-4 inhibitors
Alogliptin	25 mg	Once daily	6 (0.6)	None	None
Linagliptin	5 mg	Once daily	6 (0.6)	None	None
Saxagliptin	5 mg	Once daily	6 (0.6)	None	None
Sitagliptin	100 mg	Once daily	6 (0.6)	None	None
Vildagliptin	50 mg	Twice daily	6 (0.6)	None	None

¹⁾ Average reduction in different trials, baseline HbA_1c approximately 64 mmol/mol (8.0%)
²⁾ Weight change not taking into account the weight gain occurring as a result of correcting the hyperglycaemia, characteristic of all drugs, except SGLT2 inhibitors.

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

Sulphonylureas

Sulphonylureas reduce blood glucose levels by enhancing insulin secretion.
The starting dose may be small, but the dose should be increased rapidly, aiming at the maximum doses (daily dose of glimepiride 6 mg, glibenclamide 10-14 mg, glipizide 15 mg - with these doses HbA_1c can be expected to decrease by about 15 mmol/mol (1.5 percentage units)). If the HbA_1c concentration is above 86 mmol/mol (10%), diabetic control will not be achieved by prescribing only one oral antidiabetic drug.
Adverse effects are quite rare, but hypoglycaemias may occur Sulphonylurea for Type 2 Diabetes. Prolonged hypoglycaemia is seen particularly in the elderly. Glimepiride is administered once daily, glibenclamide twice daily and glipizide three times daily. Glipizide is shorter acting than glibenclamide.
During sulphonylurea use weight increases in direct proportion to the correction of blood glucose control due to the decrease in glucosuria (approximately 1.5 kg/1% decrease in HbA_1c).
Severe renal insufficiency is a contraindication to sulphonylurea therapy.
Drug interactions should be considered.

Other enhancers of insulin secretion Meglitinide Analogues (Glinides) for Type 2 Diabetes Mellitus

Repaglinide is a short-acting phenylalanine derivative that increases insulin secretion and should be taken before meals. The effects on diabetic organ changes have not been studied.
Convincing evidence of benefits as compared with older sulphonylureas is lacking.
An effect comparable to that of glibenclamide (10 mg) is obtained with repaglinide 4 mg three times daily.

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.

References

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