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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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c is limited (5-25 mmol/mol) and varies depending on the product; see Table T1.
  • If HbA1c 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 groupProductCardiovascular benefit / patient groupBenefit in chronic kidney diseaseStudy
HeartKidneys
BiguanidesMetforminBeneficial / newly diagnosed patientYesUKPDS 1UKPDS1
SGLT2 inhibitorsEmpagliflozinBeneficial / secondary preventionYesEMPA-REG 2EMPA-REG OUTCOME3
CanagliflozinBeneficial / secondary preventionYesCANVAS4CREDENCE5
DapagliflozinNo benefit / primary and secondary preventionYesDECLARE-TIMI 586DAPA-CKD7
ErtugliflozinNo benefit / secondary preventionVERTIS8
GLP-1 analoguesLiraglutideBeneficial / secondary preventionYesLEADER 9LEADER9
Semaglutide s.c.Beneficial / secondary preventionYesSUSTAIN-6 10SUSTAIN-610
Semaglutide tblPossibly beneficial / secondary preventionPIONEER-6 11
DulaglutideBeneficial / secondary preventionYesREWIND12REWIND12
AlbiglutideBeneficial / secondary preventionHARMONY13
LixisenatideNo effect / secondary preventionYes (albuminuria)ELIXA 14ELIXA14
GlitazonesPioglitazoneBeneficial in patients with stroke or TIAIRIS 15
No benefit / secondary preventionPROACTIVE 16
InsulinInsulinBeneficial / newly diagnosed patientYesUKPDS 17UKPDS
SulphonylureasGlibenclamide or glipizideBeneficial / newly diagnosed patientYesUKPDS 2UKPDS17
GliptinsSaxagliptinNo effect / secondary preventionPossibly harmfulSAVOR-TIMI 18
SitagliptinNo effect / secondary preventionNo effectTECOS 19TECOS19
AlogliptinNo effect / secondary preventionNo effectEXAMINE 20EXAMINE20
LinagliptinNo effect / secondary preventionNo effectCARMELINA 22CARMELINA21

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

Summary of oral antidiabetic drugs

  • See Table T2

Oral antidiabetic drugs and GLP-1 analogues

ProductRegular maintenance doseNumber of dosesReduction in HbA1c1) , mmol/mol (percentage units)Weight change2) Hypoglycaemias
Biguanides
Metformin2 000 mgTwice daily15 (1.5)No changeNone
SGLT2 inhibitors (glucose reabsorption inhibitors)
Empagliflozin10-25 mgOnce daily6 (0.6)Slight decrease (-0.8 kg)None
Dapagliflozin10 mgOnce daily6 (0.6)Slight decrease (-2.0 kg)None
Canagliflozin100-300 mgOnce daily6 (0.6)Slight decrease (-1.6 kg)None
Ertugliflozin5-15 mgOnce daily5 (0.5)Slight decrease (-2.0 - -2.4 kg)None
GLP-1 analogues
Liraglutide s.c.1.8 mgOnce daily4 (0.4)Slight decrease (-2.3 kg)None
Semaglutide s.c.0.5-1.0 mgOnce a week7-10 (0.7-1.0)Slight decrease (-2.9 - -4.3 kg)None
Semaglutide tbl14 mgOnce daily7 (0.7)Slight decrease (-3.4 kg)None
Dulaglutide s.c.1.5 mgOnce a week6 (0.6)Slight decrease (-1.5 kg)None
Lixisenatide s.c.20 µgOnce daily4 (0.4)Slight decrease (-0.4 kg)None
Insulin sensitizers (glitazones)
Pioglitazone15-45 mgOnce daily10-15 (1.0-1.5)Slight increase (3.6-4.0 kg)None
Enhancers of insulin secretion
Sulphonylureas
Glimepiride4-6 mgOnce daily10-15 (1.0-1.5)Slight increase+
Glibenclamide10.5-14 mgTwice daily10-15 (1.0-1.5)Slight increase++
Glipizide10-15 mgTwice daily10 (1.0)Slight increase+
Glinides (phenylalanine derivatives)
Repaglinide12 mg3 times daily10 (1.0 )Slight increase+
DPP-4 inhibitors
Alogliptin25 mgOnce daily6 (0.6)NoneNone
Linagliptin 5 mgOnce daily6 (0.6)NoneNone
Saxagliptin5 mgOnce daily6 (0.6)NoneNone
Sitagliptin100 mgOnce daily6 (0.6)NoneNone
Vildagliptin 50 mgTwice daily6 (0.6)NoneNone
1) Average reduction in different trials, baseline HbA1c 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 HbA1c 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 HbA1c can be expected to decrease by about 15 mmol/mol (1.5 percentage units)). If the HbA1c 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 HbA1c).
  • 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 HbA1c 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

    • Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):854-65. [PubMed]
    • Zinman B, Wanner C, Lachin JM et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015;373(22):2117-28. [PubMed]
    • Wanner C, Inzucchi SE, Lachin JM et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016;375(4):323-34. [PubMed]
    • Neal B, Perkovic V, Matthews DR. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377(21):2099. [PubMed]
    • Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019;380(24):2295-2306. [PubMed]
    • Wiviott SD, Raz I, Bonaca MP et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019;380(4):347-357. [PubMed]
    • Heerspink HJL, Stefánsson BV, Correa-Rotter R et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med 2020;383(15):1436-1446. [PubMed]
    • Cannon CP, Pratley R, Dagogo-Jack S et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N Engl J Med 2020;383(15):1425-1435. [PubMed]
    • Marso SP, Daniels GH, Brown-Frandsen K et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375(4):311-22. [PubMed]
    • Marso SP, Bain SC, Consoli A et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375(19):1834-1844. [PubMed]
    • Husain M, Birkenfeld AL, Donsmark M et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2019;381(9):841-851. [PubMed]
    • Gerstein HC, Colhoun HM, Dagenais GR et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394(10193):121-130. [PubMed]
    • Hernandez AF, Green JB, Janmohamed S et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392(10157):1519-1529. [PubMed]
    • Pfeffer MA, Claggett B, Diaz R ym. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med 2015;373(23):2247-57. [PubMed]
    • Kernan WN, Viscoli CM, Furie KL ym. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med 2016;374(14):1321-31. [PubMed]
    • Dormandy JA, Charbonnel B, Eckland DJ et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366(9493):1279-89. [PubMed]
    • Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):837-53. [PubMed]
    • Scirica BM, Bhatt DL, Braunwald E ym. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369(14):1317-26. [PubMed]
    • Green JB, Bethel MA, Armstrong PW ym. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2015;373(3):232-42. [PubMed]
    • Zannad F, Cannon CP, Cushman WC ym. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 2015;385(9982):2067-76. [PubMed]
    • Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA) http://clinicaltrials.gov/ct2/show/NCT01897532
    • Davies MJ, D'Alessio DA, Fradkin J et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018;61(12):2461-2498. [PubMed]
    • Buse JB, Wexler DJ, Tsapas A et al. 2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2020;63(2):221-228. [PubMed]
    • Nauck MA, Meier JJ. MANAGEMENT OF ENDOCRINE DISEASE: Are all GLP-1 agonists equal in the treatment of type 2 diabetes? Eur J Endocrinol 2019;181(6):R211-R234. [PubMed]
    • Tuttle KR, Brosius FC 3rd, Cavender MA et al. SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation. Am J Kidney Dis 2021;77(1):94-109. [PubMed]
    • Cosentino F, Cannon CP, Cherney DZI et al. Efficacy of Ertugliflozin on Heart Failure-Related Events in Patients With Type 2 Diabetes Mellitus and Established Atherosclerotic Cardiovascular Disease: Results of the VERTIS CV Trial. Circulation 2020;142(23):2205-2215. [PubMed]
    • McMurray JJV, Solomon SD, Inzucchi SE et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 2019;381(21):1995-2008. [PubMed]
    • Packer M, Anker SD, Butler J et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med 2020;383(15):1413-1424. [PubMed]
    • Fitchett D, Zinman B, Wanner C et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J 2016;37(19):1526-34. [PubMed]