There are different types of medications available for diabetes mellitus with each having their own mechanism of action and side effects. The best drug should be chosen by a doctor assessing the condition of the patient – please note all these are prescription medicines and need to be taken properly, under medical-supervision and with correct dosage and at the right timings. You must, at all times, follow instructions from your doctor. Never self-medicate.
Basically, anti-diabetic drugs can be categorized into two classes:
A. Oral anti-diabetic drugs:
This includes the following classes:
- Insulin secretagogues: sulphonylureas and non-sulphonylureas(Glinides/Meglitinide)
- Biguanides
- Thiazolidinediones
- a-glucosidase inhibitors
- Di-peptydyl Peptidase-4 (DPP-4) inhibitors/gliptins
- Sodium-glucose co-transporter 2 (SGLT2) inhibitors
B. Injectable anti-diabetic drugs:
- Insulin preparations
- Glucagon-like peptide 1 (GLP1) agonists
According to A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes, a tier system is used to prescribe medicines depending on how validated (tested) the medication is. The tier is divided into steps depending on the stage of diabetes and how the patient responds to the lifestyle changes and medicines.
Tier 1: This includes the best established, most-effective and most cost effective therapeutic strategies to control blood sugar. This is also the most preferred strategy for patients with type 2 diabetes. The tier is divided into 3 steps.
- Step 1: These are prescribed at when someone is diagnosed with type 2 diabetes. Apart from a lifestyle change, a mild medication that is well tested, has low and less severe side-effects and is cheap is prescribed.
- Step 2: A second medication is added when step 1 fails to control blood sugar well enough within 2-3 months of having started step 1.
- Step 3: When step 2 does not work well enough to achieve the required blood glucose control, injectable insulin is started as step 3 – some medicines may be reduced slowly and then discontinued. A third medication may be added, but is not preferred.
Tier 2: These are less-well tested therapies and are only used under special circumstances. These medicines may have more severe side-effects and hence are not usually prescribed.
Other: These are not much preferred as their effectiveness in lowering glucose is lower. They also may have limited clinical data and can be more expensive. However, under certain circumstances, these may be the appropriate choice for some patients.
Let’s have an overview of these drugs:
Tier 1, Step 1:
Biguanide:
Metformin is the only biguanide available in most of the world, but very unlikely to cause hypoglycemia because it does not change the level of insulin in the body. It is also termed as a euglycemic agent which means that it may restore the blood sugar to normal or non-diabetic levels. It aids in weight loss and is the drug of choice for obese patients. It can be taken alone or in combination with other drugs and insulin.
| How it works | Decreases glucose production by liver. Delays intestinal absorption of glucose. Increases uptake of glucose. |
| Effectiveness | Moderately effective – 1 to 2% point reduction in level of glucose bound to hemoglobin (A1C levels). |
| Convenience | Very convenient. |
| Side effects | Loss of appetite, weight loss, diarrhea, nausea, vomiting, stomach- upset, weakness, metallic taste in mouth. Please contact your doctor if any of these last for a longer time or become worse. WARNING: Lactic acidosis may occur in patients with kidney or liver dysfunction or in people who take alcohol excessively. Lactic acidosis is a severe and potentially fatal condition where there is a buildup of lactic acid in the body leading to excessive acidity in the body. If you have the following symptoms contact your doctor immediately: nausea, vomiting, generalized muscle weakness/cramping, rapid breathing, unusual sleepiness, tiredness. |
| Doses and timing | 500-850 mg tablet 2-3 times daily. |
| Precaution( use cautiously or avoid) | Kidney impairment, general anesthesia, X-ray or scanning using iodinated contrast materials. The elderly above age 80 are at a higher risk of getting side effects – they should have a kidney function test before taking this medication. |
| Pregnancy category(FDA classification) | B |
| Cost | 100 tablets $10 – $16. |
Tier 1, Step 2:
A) Sulphonylureas:
They are mostly used as add-on therapy with metformin. They induce weight gain and are not ideal for obese patients. Effectiveness and side-effects for this class of drugs vary from person to person. The most commonly used sulphonylureas are glibenclamide (also known as glyburide), gliclazide, glimepiride and glipizide.
| How it works | Insulin secretagogues - Promotes insulin secretion acting on beta cells of pancreas. This action is independent of glucose. |
| Effectiveness | Moderately effective – 1 to 2% point reduction in level of glucose bound to hemoglobin(A1C levels). |
| Convenience | Very convenient. |
| Side effects | Hypoglycemia (especially with longer acting sulphonylureas like chlorpropamide and glienclamide, in people who eat irregularly and in people who drink alcohol excessively), weight gain, stomach upset, increased sensitivity to light. Rare side effects: liver problems which may lead to jaundice, allergic reaction (itchy red skin or rashes), anemia, thrombocytopenia (reduction in the number of platelet cells in the blood which leads to increased bruising), andsevere reduction in the number of white blood cells.. |
| Doses and timing | Glibenclamide: 2.5-20mg daily in 1-2 divided doses Gliclazide: 40-320mg daily in 1-2 divided doses Glimepiride: 1-6mg daily in 1-2 divided doses Glipizide: 2.5-40mg daily in 1-2 divided doses. |
| Precaution (use cautiously or avoid) | Use cautiously in hepatic (liver) or renal (kidney) impairment. Should be avoided in case of allergy to sulphonylureas. Consult your doctor before taking any other medication (including anything that seems safe – like aspirin) while taking this class of medicines. This is because these can have interactions with other medicines which can be dangerous. |
| Pregnancy category (FDA classification*) | C
Glibenclamide is category B. |
| Cost | 100 tablets $11 – $32. |
B) Insulin preparations:
In tier 1, step 2, insulin can be given as an add-on therapy to bring the blood glucose levels down to normal. This is usually prescribed at this stage when sulfonylureas cannot be taken by the patient with type 2 diabetes for any reason. In tier 1, step 3, where add-on medication fails to reduce blood glocuse, intensive treatment with insulin is given along with metformin. There are various types of insulin preparations available in the market. They differ from each other in terms of efficacy and duration of action. These preparations can be categorized into 4 groups based on the speed of action: Short acting, intermediate acting, long acting, rapid acting. Biphasic insulins are the ones containing a mix of these insulins.
- Short-acting insulin:
Regular (soluble) insulin or Insulin-R is the short acting insulin which acts within 0.5-1 hour; action reaches a peak in 1-4 hours and lasts for 4-8 hours. This type of insulin may be prescribed in some cases during the initial therapy along with food. Regular insulin can be given intravenously and is the drug of choice in critically ill or hospital-bound patients. It may cause hypoglycemia and needs to be taken 30 min to 1 hour before a meal. This type is usually given together with intermediate or long acting insulin.
| How it works | Stimulates glucose uptake by cell and reduces blood glucose level. |
| Effectiveness | Very effective – 1.5 to 3.5% point reduction in level of glucose bound to hemoglobin(A1C levels) |
| Convenience | Less convenient. |
| Side effects | Hypoglycemia, lipodystrophy (abnormal mass of fat under the skin), allergic reaction. |
| Doses and timing | The dose depends on blood sugar level. Should be taken 30 minutes before each meal subcutaneously. |
| Precaution( use cautiously or avoid) | Adjust dose requirement cautiously to prevent hypoglycemia. |
| Pregnancy category(FDA classification) | B |
| Cost | 3 ml penfill $4-$5. |
- Intermediate-acting insulin:
Also known as Isophane insulin or NPH (Neutral Protamine Hagedorn) or Lente insulins, these are intermediate-acting in nature. They take 1-3 hours for the onset of action, which reaches a peak at 4-8 hours and lasts for 7-14 hours. When patients are started on insulin, this is the one that is preferentially prescribed to increase the basal levels of insulin.
| How it works | Stimulates glucose uptake by cell and reduces blood glucose level. |
| Effectiveness | Very effective - 1.5 to 3.5% point reduction in level of glucose bound to hemoglobin(A1C levels). |
| Convenience | Convenient. |
| Side effects | Hypoglycemia, lipodystrophy(abnormal mass of fat under the skin), allergic reaction. |
| Doses and timing | Dose needs to be individualized. Is usually given at bedtime or with breakfast, |
| Precaution( use cautiously or avoid) | Pregnancy and renal impairment. |
| Pregnancy category(FDA classification) | B |
| Cost | 3 ml penfill $4. |
- Long-acting insulins:
Insulin glargine, Insulin Degludec, and Insulin Detemir have a prolonged duration of action of 18-24 hours. Bovine Ultralente insulin also has a longer duration of action but its use is limited due to allergic reactions. This is injected only once or twice daily and therefore patients are much better at using this kind of insulin.
| How it works | Stimulates glucose uptake by cell and reduces blood glucose level. Has a long half-life and works for prolonged period. |
| Effectiveness | Very effective - 1.5 to 3.5% point reduction in level of glucose bound to hemoglobin(A1C levels). |
| Convenience | Very convenient. |
| Side effects | Hypoglycemia, lipodystrophy(abnormal mass of fat under the skin), allergic reaction. |
| Doses and timing | Dose need to be adjusted for the individual patient. Usually, 0.1-0.2 IU/kg subcutaneously at evening. |
| Precaution( use cautiously or avoid) | Renal and hepatic impairment. |
| Pregnancy category(FDA classification) | Insulin detemir and insulin glargine: B Insulin degludec: C |
| Cost | 3 ml catridge $13-$15
Insulin degludec $28-$30. |
- Rapid-acting insulin:
Insulin Lispro, Insulin Aspart, and Insulin Glulisine are termed as rapid acting because of their immediate onset of action. Their anti-glycemic action is observed within 30 minutes, reaches a peak in 0.5-2.5 hours and persists for 3-4.5 hours.These are generally prescribed to people with type 1 diabetes, but at times are also prescribed to people with type 2 diabetes in combination with other type of insulin. .
| How it works | Stimulates glucose uptake by cell and reduces blood glucose level. |
| Effectiveness | very effective - 1.5 to 3.5% point reduction in level of glucose bound to hemoglobin(A1C levels). |
| Convenience | Less convenient. |
| Side effects | Hypoglycemia, lipohypertrophy (abnormal mass of fat under the skin), hypersensitivity. |
| Doses and timing | Usual range is 0.5-1 IU/kg/day. Need to be given subcutaneously with a meal (just before or after a meal). |
| Precaution(use cautiously or avoid) | Kidney impairment, infection. |
| Pregnancy category(FDA classification) | B But for Insulin Glulisine: C |
| Cost | 3 ml penfill $8-$15. |
- Biphasic insulin or mixture preparations:
These are mixture of variable proportions of soluble insulin with NPH insulin, or of a rapid-acting insulin analog with NPH insulin. The most common preparation is 30/70 mixture of Regular insulin + Isophane insulin. Other popular formulations are Insulin Lispro +Protamine insulin mix, Insulin Degludec+ Insulin Aspart 70/30 premixed, Insulin Aspart biphasic etc.
| How it works | Stimulates glucose uptake by cell and reduces blood glucose level. |
| Effectiveness | Very effective -1.5 to 3.5% point reduction in level of glucose bound to hemoglobin(A1C levels). |
| Convenience | Very convenient. |
| Side effects | Hypoglycemia, weight gain, lipodystrophy(abnormal mass of fat under the skin), allergic reaction. |
| Doses and timing | Varies according to patients’ condition. Usually ⅔rd of daily dose at morning and ⅓rd at evening. |
| Precaution (use cautiously or avoid) | Kidney or liver impairment. |
| Pregnancy category(FDA classification) | Depends on the components of the combination. |
| Cost | Varies according to combination. |
Tier 2
- A. Thiazolidinediones (Glitazones):
Up to 1990, thiazolidinediones were widely prescribed. But nowadays only pioglitazone is used. However, this also has been linked with instances of bladder cancer although the evidence was deemed insufficient. However, if you are taking this medication, keep yourself aware of symptoms of bladder cancer. Glitazones increase insulin sensitivity and can be given with metformin. Due to the risk of developing cardiac failure, bone fracture etc. their use has declined.
| How it works | Acts on adipose tissue and decreases peripheral insulin resistance. |
| Effectiveness | Less effective – 0.5-1.4% point reduction in level of glucose bound to hemoglobin(A1C levels). |
| Convenience | Less convenient. |
| Side effects | Water retention, edema, weight gain, eyesight problems, reduced sense of touch, chest pain and infections, allergic skin reactions. Rare: macular edema (an eye complication), heart problems, liver failure anemia, bone fractures. |
| Doses and timing | Pioglitazone: 15-30mg once daily. |
| Precaution(use cautiously or avoid) | Heart failure, hypersensitivity. Increased risk of becoming pregnant if you are practicing birth-control. Very important to follow any instructions from your doctor about alcohol and other medicines if you are taking these. Make sure that you know what to do if you have fluid retention as fluid retention will increase or lead to heart problems. |
| Pregnancy category(FDA classification) | C (potential risk, better to avoid). |
| Cost | 90 tablets $22-$24. |
- B. GLP1 Agonists:
GLP1 (Glucagon like peptide -1) is a peptide produced by intestinal cells which makes the insulin production (in response to glucose) even more effective. However, this is a short-lived peptide. GLP1 agonists are drugs that mimic GLP1, but are long lived, and can therefore continue improving insulin secretion in response to glucose. These are a new class of injectable drugs prescribed to those who cannot control their diabetes with oral medication. The popular members are exenatide and liraglutide. As the action of this class of medications is only to promote the natural insulin secretion, it has the reduced risk of triggering hypoglycemia. These medications also induce weight loss – so is an appealing therapy for obese patients.
| How it works | Increases insulin secretion after eating even before the blood glucose starts to rise. As this response is related to carbohydrate in the gut, the chance of getting hypoglycemia is low. Delays the emptying of the stomach which slows glucose absorption into the bloodstream Decreases glucagon secretion by the pancreas which prevents the liver to release stored sugar into the bloodstream. |
| Effectiveness | Less effective – 0.5 to 1% point reduction in level of glucose bound to hemoglobin(A1C levels). |
| Convenience | Very convenient. |
| Side effects | Nausea, diarrhea, vomiting, headaches, dizziness, increased sweating, indigestion, constipation, loss of appetite. |
| Doses and timing | Liraglutide: 0.6-1.8 mg subcutaneously once daily Exenatide: 5mcg 12 hourly within 60 minutes of meal. |
| Precaution( use cautiously or avoid) | Avoid if personal or family history of medullary thyroid carcinoma. Pancreatitis Hypersensitivity. |
| Pregnancy category(FDA classification) | C |
| Cost | 1 vial $100. |
OTHER THERAPY
- A. Sulphonylurea-like drugs(Meglitinides/Glinides):
These are not members of sulphonylureas but have the same mechanism of action. Thesestart working very soon after they are taken but last for only a short time unlike sulphonylureas. . These are prescribed to limit the post-meal spikes in blood glucose.These are prescribed to people with type 2 diabetes who cannot control their blood glucose through tier 1, step 1 medication. These are suitable for people with non-routine lifestyles – they can thus take this medicine whenever they take food. Repaglinide and Nateglinide are important examples and they are meglitinide derivatives.
| How it works | Promotes insulin secretion by acting on beta cells of pancreas. |
| Effectiveness | Less effective – 0.5 to 1.5% point reduction in level of glucose bound to hemoglobin(A1C levels). |
| Convenience | Convenient. |
| Side effects | Low blood glucose, indigestion, skin rashes, headache, nasal congestion, joint aches, back pain, liver problems, stomach pain, nausea, diarrhea, constipation |
| Doses and timing | Repaglinide: 0.5-16mg daily in 3 divided doses prior to meals Nateglinide:60-180mg daily in 3 divided doses prior to meals. |
| Precaution( use cautiously or avoid) | Liver or kidney impairment, elderly patients. Should be avoided in case of allergy to this. Before taking this medication, talk to your doctor if you are allergic to any other drug. Tell your doctor of any prescription/non-prescription medicine that you might be taking as these may interact with this medication causing dangerous side-effects. Tell your doctor about any surgery that you might undergo – including dental surgery, before taking this medication. Also talk to your doctor about taking alcohol along with this medicine. |
| Pregnancy category(FDA classification) | C |
| Cost | 90 tablet $28 – $63. |
- B. Gliptins (DPP-4 inhibitors):
Gliptins are newer antidiabetic drugs . These are prescribed to type 2 diabetics who do not respond to metformin and sulfonylureas. They promote insulin secretion but as the mechanism is different, they do not cause hypoglycemia. The popular members of this family are sitagliptin, vildagliptin, saxagliptin, and linagliptin. These may promote weight loss.
| How it works | DPP-4 is an enzyme that breaks down certain proteins (called incretins) produced by intestine that promote insulin production. This drug inhibits this enzyme and allows incretins to act longer.It reduces blood glucose spikes after meals and increases insulin secretion. This drug also decreases appetite and is helpful in reducing obesity. |
| Effectiveness | Low effective – 0.5-0.8% points reduction in level of glucose bound to hemoglobin(A1C levels). |
| Convenience | Very convenient. |
| Side effects | Headache,itchy skin, serious allergic reaction(rare). Stomach problems (nausea, diarrhea, and stomach pain), Flu-like symptoms (headache, runny nose, sore-throat). Increased risk of inflammation of pancreas (pancreatitis) – if you have a severe pain in upper abdomen along with nausea or vomiting, immediately call for medical help. |
| Doses and timing | Vildagliptin: 50mg orally once or twice daily Saxagliptin:2.5-5mg daily Sitagliptin:100mg orally once daily Linagliptin:5mg orally once daily. |
| Precaution( use cautiously or avoid) | Avoid if history of inflammation of pancreas (pancreatitis). |
| Pregnancy category(FDA classification) | N (Not classified). |
| Cost | 28 tablets $132 -$158. |
- C. α-glucosidase inhibitors:
These are also known as starch blockers. These are given post-meal to type 2 diabetics who have difficulty controlling their blood glucose levels with other medications following meals. Alpha-glucosidase are enzymes which digest carbohydrate, so stopping these from working leads to less glucose being produced. Acarbose and miglitol are available alpha-glucosidase inhibitors and may be prescribed with sulphonylureas..
| How it works | Delays carbohydrate absorption in the gut by reducing the rate of conversion of carbohydrates to glucose |
| Effectiveness | Less effective – 0.5-0.8% points reduction in level of glucose bound to hemoglobin(A1C levels). |
| Convenience | Convenient. |
| Side effects | Flatulence, abdominal bloating, diarrhea. |
| Doses and timing | Acarbose: 50-300mg daily at 3 divided doses Miglitol: 25-100 mg 3 times daily. |
| Precaution( use cautiously or avoid) | Abnormal liver function tests. |
| Pregnancy category(FDA classification) | B |
| Cost | 90 tablets $37-$54. |
- D. SGLT2 inhibitors:
SGLT2 stands for Sodium-glucose co-transporter-2. It is an protein that transports glucose back to the blood from the kidney. Anything that reduces this will lead to removal of glucose in the urine – this is what this class of drugs does. Dapagliflozin and canagliflozin are members of this group and this group is a newer addition to anti-diabetic medications and are prescribed to type 2 diabetics who do not respond to other medications like metformin and insulin. They reduce blood sugar level but increased incidence of UTI and genital tract infections has limited their use.
| How it works | Inhibits SGLT2 and promotes excretion of glucose via urine. |
| Effectiveness | Less effective – 0.5 to 1% point reduction in level of glucose bound to hemoglobin (A1C levels). |
| Convenience | Convenient. |
| Side effects | Hypoglycemia, UTI, genital infection, dysuria. |
| Doses and timing | Dapagliflozin: 5-10mg once daily before breakfast Canagliflozin: 100-300mg once daily before breakfast. |
| Precaution( use cautiously or avoid) | Severe renal impairment, frequent ketones in blood or urine, elderly patients. If you are taking this medication, your urine will show glucose in urine almost all the time when you check with urine glucose strips – this is a normal happening with this medication. |
| Pregnancy category(FDA classification) | C |
| Cost | 28 tablets $158 -$269. |
Combined oral anti-diabetic preparations:
Oral anti-diabetic drugs can be used in combinations which potentiate their efficacy. Several popular combinations are available in the market. These are the following:
Metformin + glipizide combination:
This is a popular combination, usually used when metformin alone or sulfonylureas alone fails to control hyperglycemia.
| How it works | Glipizide stimulates insulin secretion while metformin slows sugar absorption, stops conversion of stored sugar into blood sugar by the liver and helps body use the natural insulin more efficiently. This way the combination reduces blood glucose level together. |
| Effectiveness | Moderately effective. |
| Convenience | Very convenient. |
| Side effects | Allergic reaction, diarrhea, hypoglycemia, lactic acidosis (needs emergency medical attention). |
| Doses and timing | Should start with 1 tablet containing 2.5mg glipizide and 250mg metformin. |
| Precaution(use cautiously or avoid) | Renal impairment. Drinking alcohol or taking other medications. |
| Pregnancy category(FDA classification) | C |
| Cost | 100 tablets $79. |
Metformin+vildagliptin/sitagliptin combination:
It is an effective combination and very effective in type-2 DM if β-cells are not destroyed. This combination is more effective than metformin alone – in improving blood sugar control as well as improving beta cell function. It is also prescribed if and when sulphonylurea is not tolerated or is contraindicated, or to patients for whom low-blood sugar (hypoglycemia) could be very risky.
| How it works | Increases insulin release Decreases endogenous glucose production. |
| Effectiveness | Moderately effective. |
| Convenience | Very Convenient. |
| Side effects | Mild: Headache, stomach upset, nausea, vomiting, diarrhea, dermatitis, dizziness (worse with alcohol intake) is common on starting the treatment. Severe: Lactic acidosis (which needs emergency attention) can develop later during treatment. Severe inflammation of pancreas can occur which can be fatal. Discuss with your doctor immediately if you develop severe or persistent stomach or back pains which may be accompanied by nausea and vomiting. |
| Doses and timing | Dose need to be individualized. Usually administered twice daily with meal. |
| Precaution( use cautiously or avoid) | Liver disease, renal impairment, older than 80 years, stroke or heart attack, surgery or lab procedures. |
| Pregnancy category(FDA classification) | B |
| Cost | 60 tablet $144-$177. |
Glimepride + pioglitazone combination:
Tablet containing glimepride 2/4 mg + pioglitazone 15/30 mg are available. Can be effective for many patients but not so popular due to side effects of pioglitazone
| How it works | Increases insulin secretion Decreases peripheral insulin resistance. |
| Effectiveness | Moderately effective. |
| Convenience | Convenient. |
| Side effects | Hypoglycemia, edema, bone fracture, drowsiness, dizziness, blurred vision, or light-headedness, increased risk for heart disease and bladder cancer, severe skin reaction (Steven-Johnson syndrome/toxic epidermal necrolysis) which can be serious and cause death, serious and sometimes fatal liver problems. |
| Doses and timing | Initially, 1 tablet once daily and then titrate gradually. |
| Precaution (use cautiously or avoid) | Heart failure, bone disease, elderly, children, bladder cancer, high blood acid levels (ketoacidosis), type 1 diabetes. |
| Pregnancy category(FDA classification) | C |
| Cost | 15 tablets $4-$5. |
*FDA Pregnancy Categories
The FDA has established five categories to indicate the potential of a drug to cause birth defects if used during pregnancy. These categories are determined by the reliability of documentation and the risk to benefit ratio (whether benefits are more than the risk or vice-versa). They do not take into account any risks from pharmaceutical agents or their metabolites in breast milk. The pregnancy categories are:
Category A
Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).
Category B
Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.
Category C
Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
Category D
There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
Category X
Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.
Category N
FDA has not classified the drug.