Diabetes mellitus type 2 medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]Anahita Deylamsalehi, M.D.[3] Javaria Anwer M.D.[4]

Overview

The main goals of treatment are to eliminate hyperglycemic symptoms, control the long term complications and improve the patient's quality of life. Diabetes mellitus type 2 is initially treated by life style modification and weight loss, especially in obese patients. Metformin is the first line pharmacologic therapy that is usually started once the diagnosis is confirmed unless contraindications exist. Nevertheless, in patients presented with high HbA1C/fasting blood sugar levels or if glycemic goals are not achieved, a second agent must be added to metformin. A wide range of options are available to add as combination therapy based on the patient's condition and comorbidities.

Pharmacologic therapy

Inpatients

Main article: Diabetes Care in the Hospital Setting

Outpatients

A network meta-analysis summarizes the risks and benefits of available medications for diabetes mellitus type 2.

• Medical therapy starts with metformin monotherapy unless there is a contraindication for it. In the following conditions, treatment starts with dual therapy:
  • If HbA1C is greater than 9, start with dual oral blood glucose lowering agent.
  • If HbA1C is greater than 10 or blood glucose is more than 300 mg/dl or patient is markedly symptomatic, consider combination therapy with insulin.

• The most effective class of drugs for reducing death are probably sodium glucose transporter 2 (SGLT2) inhibitors or GLP-1 receptor agonists.

Metformin

• Metformin is effective, safe and inexpensive.
• It may reduce risk of cardiovascular events and death.
• Patients should be advised to stop the medication in cases of nausea, vomiting or dehydration.
• Metformin is capable of decreasing the body weight but it's effect on muscle mass is unclear.
• A systemic review, observing 34,000 patients in total concluded that Metformin is as safe as other anti-diabetic treatments in diabetic patients with heart failure.
• Some studies demonstrated lower risk of mortality in diabetic patients with concurrent COPD or Asthma who were taking Metformin compared to non-users.
• Metformin use in diabetic patients with sepsis, tuberculosis and Chronic obstructive pulmonary disease (COPD) were associated with lower mortality rate.
• One of the possible effects of Metformin is gut microbiota alteration, which results in Tauroursodeoxycholic acid (TUDCA) and Glycoursodeoxycholic Acid (GUDCA) elevation. Since both TUDCA and GUDCA act as intestinal farnesoid X receptor (FXR) antagonists, they can be effective in hyperglycemia treatment.

Contraindications

• As of June 2020, The US Food and Drug Administration (FDA) recalls extended-release metformin which is made by few pharma companies due to detection of high levels of N-Nitrosodimethylamine (NDMA).
• N-Nitrosodimethylamine (NDMA) is a carcinogenic agent when exposed in higher levels leads to cancer.
• The following are the pharma companies that the FDA recalls the extended-release metformin:
  • Lupin
  • Apotex Corp
  • Actavis
  • Time-Cap Labs, Inc
  • Amneal
• Contraindications to metformin include, heart failure, liver failure, GFR ≤30 and metabolic acidosis.

,Randomized controlled trial comparing initial doses for metformin.

Total duration was 14 weeks with at least 8 weeks on final dose.	Placebo	500 mg once daily	1000 mg (500 mg twice daily)	1500 mg (500 mg thrice daily)	2000 mg (1000 mg twice daily)	2500 mg (1000 am, 500 lunch, 1000 at supper daily
Any GI ADR	13%	16%	29%	24%	23%	29%
Diarrhea	5%	8%	21%	12%	19%	14%
HbA1c change	+ 1.2	+ 0.3	+ 0.1	- 0.5	- 0.8	- 0.04
Source: Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL (1997). "Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial". Am J Med. 103 (6): 491–7. doi:10.1016/s0002-9343(97)00254-4. PMID 9428832.CS1 maint: Multiple names: authors list (link)

Insulin

• The lack of inexpensive, generic insulin may lead to underuse of insulin and occurs for unusual reasons.
• The insulin analogues may not provide a meaningful advantage.
• Although Insulin increases the body weight, some data suggest that it is capable of increasing the muscle mass.
• A meta-analysis of randomized controlled trials by the Cochrane Collaboration found "only a minor clinical benefit of treatment with long-acting insulin analogues for patients with diabetes mellitus type 2" compared to human insulin More recent randomized controlled trials have found no differences with glargine and have found that although long acting insulins were less effective, they were associated with less hypoglycemia.
• Premixed combinations of insulin, human or analogue, have similar reductions in HbA1c. A cohort study likewise found similar rates of hypoglycemia.

Bedtime insulin

For Diabetes mellitus type 2:

• Initially, a randomized controlled trial found that adding bedtime insulin to patients failed oral medications is more effective and with less weight gain than using multiple dose insulin. Nightly insulin combines better with metformin that with sulfonylureas.

• More recently, the Cochrane Collaboration concluded: "hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with insulin detemir instead of NPH insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted".

• Kaiser Permanente, in a large cohort study, found no benefit from long-acting insulin analogues compared to human NPH insulin.

Dosing

The initial dose of nightly insulin (measured in IU/d) should be equal to the fasting blood glucose level (measured in mmol/L). If the fasting glucose is reported in mg/dl, multiple by 0.05551 (or divided by 18) to convert to mmol/L.

Consider increasing by 3 units at a time.

Monitoring

In both trails above, dosing was adjusted by monitoring fasting sugars. In the second trial, the patient checked their "diurnal blood glucose level, measurements were taken before and 1.5 hours after breakfast, lunch and dinner; at 10 p.m.; and at 4 a.m." once a week for the first 3 months and then every other week.

Availability

Novo Nordisk’s Novolin ReliOn N is less expensive at Walmart and CVS pharmacies.

Combination therapy

• Any agent can be added as second drug based on patient condition. Nevertheless, the American Association of Clinical Endocrinologists recommends either incretin based therapy or sodium glucose transporter 2 (SGLT2) inhibition agents.

• The following table summarize the available FDA approved glucose lowering agents that may help to individualize treatment for each patient.

Class	Drug	Mechanism of action	Primary physiologic action	Advantages	Disadvantages	Cost
Biguanides	Metformin	Activates AMP-kinase	↓ Hepatic glucose production	Extensive experience Rare hypoglycemia ↓ CVD events Relatively higher A1C efficacy	Gastrointestinal side effects (diarrhea, abdominal cramping, nausea) Vitamin B12 deficiency Contraindications: eGFR ≤30 mL/min/1.73 m2, acidosis, hypoxia, dehydration. Lactic acidosis risk (rare)	Low
Sulfonylureas	2nd generation Glyburide Glipizide Glimepiride	Closes K-ATP channels on beta cell plasma membranes	↑ Insulin secretion	Extensive experience ↓ Microvascular risk Relatively higher A1C efficacy	Hypoglycemia ↑ Weight	Low
Meglitinides	Repaglinide Nateglinide	Closes K-ATP channels on beta cell plasma membranes	↑ Insulin secretion	↓ Postprandial glucose excursions Dosing flexibility	Hypoglycemia ↑ Weight Frequent dosing schedule	Moderate
Thiazolidinedione (TZDs)	Pioglitazone‡ Rosiglitazone§	Activates the nuclear transcription factor PPAR-gama	↑ Insulin sensitivity	Rare hypoglycemia Relatively higher A1C efficacy Durability ↓ Triglycerides (pioglitazone) ↓ CVD events (PROactive, pioglitazone) ↓ Risk of stroke and MI in patients without diabetes and with insulin resistance and history of recent stroke or TIA Pioglitazone use is associated with higher chance of pneumonia	↑ Weight Edema/heart failure Bone fractures ↑ LDL-C (rosiglitazone)	Low
α-Glucosidase inhibitors	Acarbose Miglitol	Inhibits intestinal α-glucosidase	Slows intestinal carbohydrate digestion/absorption	Rare hypoglycemia ↓ Postprandial glucose excursions ↓ CVD events in prediabetes Nonsystemic	Generally modest A1C efficacy Gastrointestinal side effects (flatulence, diarrhea) Frequent dosing schedule	Low to moderate
DPP-4 inhibitors	Sitagliptin Saxagliptin Linagliptin Alogliptin	Inhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentrations	↑ Insulin secretion (glucose dependent) ↓ Glucagon secretion (glucose dependent)	Rare hypoglycemia Well tolerated	Angioedema/urticaria and other immune-mediated dermatological effects Acute pancreatitis ↑ Heart failure hospitalizations (saxagliptin, alogliptin)	High
Bile acid sequestrants	Colesevelam	Binds bile acids in intestinal tract, increasing hepatic bile acid production	↓ Hepatic glucose production ↑ Incretin levels	Rare hypoglycemia ↓ LDL-C	Modest A1C efficacy Constipation ↑ Triglycerides May ↓ absorption of other medications	High
Dopamine-2 agonists	Bromocriptine (quick release)§	Activates dopaminergic receptors	Modulates hypothalamic regulation of metabolism ↑ Insulin sensitivity	Rare hypoglycemia ↓ CVD events	Modest A1C efficacy Dizziness/syncope Nausea Fatigue Rhinitis	High
SGLT2 inhibitors	Canagliflozin Dapagliflozin‡ Empagliflozin	Inhibits SGLT2 in the proximal nephron	Blocks glucose reabsorption by the kidney,increasing glucosuria	Rare hypoglycemia ↓ Weight ↓ Blood pressure ↓ The chance of kidney disease progression, including the macroalbuminuria. They are also capable of lowering the risk of worsening estimated glomerular filtration rate, end-stage kidney disease, or death due to renal failure. Research shows that SGLT-2 inhibitors and GLP-1 receptor agonists reduce cardiovascular and renal outcomes among patients with diabetes type 2. Empagliflozin is associated with lower CVD event rate and mortality in patients with CVD. It is also related to reduction of left ventricle mass after 6 months treatment. Dapagliflozin has minor effect on diastolic cardiac function of diabetic patients. Nevertheless, it is able to lower the risk of major adverse cardiovascular events in a diabetic patients with previous MI.	Genitourinary infections† Polyuria Volume depletion, hypotension, dizziness ↑ LDL-C ↑ Creatinine (transient) DKA, urinary tract infections leading to urosepsis, pyelonephritis	High
GLP-1 receptor agonists	Exenatide Exenatide extended release Liraglutide Albiglutide Lixisenatide Dulaglutide	Activates GLP-1 receptors	↑ Insulin secretion (glucose dependent) ↓ Glucagon secretion (glucose dependent) Slows gastric emptying ↑ Satiety	Rare hypoglycemia ↓ Weight ↓ Postprandial glucose excursions ↓ Some cardiovascular risk factors ↓ The chance of kidney disease progression, including the macroalbuminuria Liraglutide associated with lower CVD event rate and mortality in patients with CVD.	Gastrointestinal side effects (nausea/vomiting/diarrhea) ↑ Heart rate Acute pancreatitis C-cell hyperplasia/medullary thyroid tumors in animals Injectable Training requirements	High
Amylin mimetics	Pramlintide§	Activates amylin receptors	↓ Glucagon secretion Slows gastric emptying ↑ Satiety	Postprandial glucose excursions ↓ Weight	Modest A1C efficacy Gastrointestinal side effects (nausea/vomiting) Hypoglycemia unless insulin dose is simultaneously reduced Injectable Frequent dosing schedule Training requirements	High
Insulins	Rapid-acting analogs Lispro Aspart Glulisine Inhaled insulin	Activates insulin receptors	↑ Glucose disposal ↓ Hepatic glucose production Suppresses ketogenesis	Nearly universal response Theoretically unlimited efficacy ↓ Microvascular risk	Hypoglycemia Weight gain Training requirements Patient and provider reluctance Injectable (except inhaled insulin) Pulmonary toxicity (inhaled insulin)	High
	Short-acting Human Regular
	Intermediate-acting Human NPH
	Basal insulin analogs Glargine Detemir Degludec
	Premixed insulin products NPH/Regular 70/30 70/30 aspart mix 75/25 lispro mix 50/50 lispro mix

^‡ Initial concerns regarding bladder cancer risk are decreasing after subsequent study.

^§ Not licensed in Europe for type 2 diabetes.

^† One study demonstrates factors like previous genital infection history, concurrent estrogen therapy and younger age as risk factors that augment the chance of this side effect. This study also reports chronic kidney disease and baseline DPP4 inhibitor therapy as factors that lower the risk of genital infection development.