Pills and More Pills – Which New Diabetes Medicine is Best?


More Pills.

Needles, too!  Sometimes…

It can be all too confusing to sort through the flood of information that is the new knowledge about diabetes.

But, in short, life for the diabetic is better than it was just 15 years ago.

Much better.

Still, getting a handle on the finer details so one can make an informed decision would go a long way towards knowing just how much better diabetes can be…for YOU.

diabetes-medicationThere have been tremendous advancements in diabetes mellitus medications

in the past few years, especially in type 2 diabetes the most prevalent.  Some are effective, and some are safe.  With a little research, the empowered individual can make an informed choice.

The American Diabetes Association (ADA) provides the standards for diabetic therapy using recommendations of diet, exercise, and available FDA-licensed medications.  This year’s annual revision describes the 2016 Standards of Medical Care in Diabetes to help individuals achieve the best quality of care currently available (Standards of Medical Care in Diabetes—2016, 2016).

An overview, available in the Annals of Internal Medicine, summarizes these standards.  In short, the recommendations focus on an individual’s need to monitor their diabetes, to focus on decreasing their risk for secondary complications, and to identify opportunities such as a fruit and vegetable diet for improved results (Chamberlain, Rhinehart, Shaefer & Neuman, 2016).

Type 1 diabetes is the classic diabetes, known for the pancreas and the Islets of Langerhans where its β cells insufficiently produce insulin (Chamberlain, Rhinehart, Shaefer & Neuman, 2016).  Type 2 diabetes is the more common, but different diabetes caused by the overweight condition, which reduces the cells’ ability to absorb fully available insulin and use it to metabolize ever-increasing stores of glucose.

Blood sugar levels have been established to identify prediabetes and then the diagnosis of diabetes.  A blood sugar of 126mg/dL or greater (7.0 mmol/L) is now considered the cutoff for diabetes when fasting without any food or liquid for at least eight hours.   However, according to the Standards of Medical Care in Diabetes—2016 (2016) 100-125 mg/dL (5.6-6.9 mmol/L) defines prediabetes and individuals between 40 and 70 years of age must begin treatment if their fasting glucose reads in this range.

The first line therapy for either type 1 or 2 diabetes is not diabetes medicine but a lifestyle modification.

Diet and exercise are the mainstays of a lifestyle modification.  If you have type 1 diabetes, you produce insufficient insulin and must reduce the “hit” or bolus of calories your body receives at one time, so you don’t trigger an output of Glucagon, which increases your own body’s glucose production (Chamberlain, Rhinehart, Shaefer & Neuman, 2016).   Frequent, mild calorie meals are suggested, for this reason, balanced with exercise to reduce the glucose production.

Type 2 diabetes lifestyle modification needs are similar for first line therapy, but for different reasons.  The overweight condition of type 2 diabetes prevents insulin absorption at the cells and glucose accumulates inside.  Reduced caloric intake at meals increases insulin absorption (AACE/ACE Consensus Statement, 2016).   Exercise reduces excess glucose production by the body.

The American Diabetes Association (ADA) recommends, after lifestyle modification, to control the body weight medically.  All of the agents in this group are well known, safe medications and include the selective serotonin (5-HT) receptor agonist, lorcaserin, the lipase inhibitor, orlistat, and the antiepileptic agent that creates dramatic weight loss, topiramate.  Liraglutide is a safe glucagon-like peptide (GLP-1) that lowers blood sugar levels, and naltrexone is the highly popular and much-used medication to pull opioids out of the body while creating weight loss (Standards of Medical Care in Diabetes—2016, 2016).

The first line agent for type 1 diabetes is insulin.  Type 1 diabetes is an insufficient supply of insulin, and this must be replaced using differing variations of injectable or implanted insulin.  Decreasing the need for insulin quantity becomes the next course of action and medications such as Pramlintide are available, which slows exiting rates from the stomach, and, in turn, reduces demand on the pancreas to release excessive quantities of Glucagon, the anti-insulin hormone (Chamberlain, Rhinehart, Shaefer & Neuman, 2016).

The first line agent for type 2 diabetes is metformin.  Metformin takes sucrose and converts it to galactose and glucose leaving glucose unusable by the body and thus allows it to be excreted harmlessly (Chamberlain, Rhinehart, Shaefer & Neuman, 2016).  As such, Metformin is now the safe, first agent for all type 2 diabetic individuals according to the ADA (Standards of Medical Care in Diabetes—2016, 2016).

The difficulty is selecting the second line agent after metformin.  Safety becomes a primary issue.

One of the principle agents added to metformin at the second line is sulfonylureas class medications (glipizide, glyburide, glimepiride).  These agents are notorious for causing hypoglycemic events if the blood sugar level is not monitored closely (Standards of Medical Care in Diabetes—2016, 2016).

Canagliflozin, dapagliflozin, and empagliflozin are popular names for SGLT2 inhibitors.  These “gliflozin’s” are another second line medication but since they work directly at the nephron, the functional unit of the kidney, to inhibit glucose return back into the body they cause significant dehydration complications (Chamberlain, Rhinehart, Shaefer & Neuman, 2016).  Dehydration can include infection in the bladder and urinary tract, blood pressure loss, and increases in low density (bad) lipid cholesterol (Standards of Medical Care in Diabetes—2016, 2016).

Glucagon-like peptide-1 (GLP-1) receptor agonists and DPP-4 (Dipeptidyl peptidase-4) medications are considered incretin-based drugs.  The ADA has classified these as the best second line agents after metformin basing their findings on clinical results and safety studies (Standards of Medical Care in Diabetes—2016, 2016).  There reasoning is these agents reduce the HbA1c level (the glycated hemoglobin level), do not affect body weight or seriously lower blood sugar levels, and do not increase the cardiovascular risk (Lind et al., 2015; Li et al., 2016).

Exenatide, liraglutide, albiglutide and dulaglutide are examples of Glucagon-like peptide-1 receptor agonists.   Sitagliptin, vildagliptin, and linagliptin are DPP-4 class inhibitors.  The Merck Index, 13th Ed. (2001) mentions “gliptin(s)” in lupeol (mango and dandelion) and berberine (barberry plant).

There have been concerns about heart failure and cancer risks in these diabetes medications.  Li et al. (2016) reviewed 43 research and 12 observational trials with almost 1.8 million subjects and determined the quality of the evidence was considered low for DPP-4 inhibitors, but still reported an uncertain relative effect on the risk of heart failure in type 2 diabetes patients.

Both DPP-4 inhibitors and Glucagon-like peptide-1 (GLP-1) receptor agonists were evaluated in six observational studies after the FDA received 1221 complaints of pancreatic cancer.  Azoulay et al. (2016) studied almost one million patients from the USA, Canada, and the UK during a 5.5-year cycle starting from January 1, 2007.  They discovered when DPP-4 inhibitors and Glucagon-like peptide-1 (GLP-1) receptor agonists were compared to the previous medical standard for type 2 diabetes, sulfonylureas (class 1: tolbutamide. class 2: glipizide, glyburide. Class 3: glimepiride), incretin-based drugs had absolutely no risk for pancreatic cancer even when adjusted for the three sulfonylureas classes (Azoulay et al., 2016).

It should be noted that the vast majority of individuals who have diabetes also have an element of high blood pressure (Standards of Medical Care in Diabetes—2016, 2016).  Hypertension is the most frequent complication to diabetes and supersedes the next highest secondary risk, high cholesterol.  Still, there are other conditions that frequently receive a secondary diagnosis of diabetes, most notably pregnancy and cystic fibrosis (Standards of Medical Care in Diabetes—2016, 2016).

Brunström & Carlberg (2016) performed a meta-study reviewing 49 research trials, which included almost 74,000 study subjects and observed that systolic blood pressure (the high number) was frequently above 150 mm Hg.  The relative risk of mortality from all causes was reduced by 11 percent when the antihypertensive medication was added to the treatment regimen (Brunström & Carlberg, 2016).  Cardiovascular mortality and myocardial infarction relative risk were most improved by 25 and 26 percent, respectively, followed by stroke (23 percent improved) and end-stage renal disease improved 18 percent (Brunström & Carlberg, 2016).

The study continued to follow those individuals who received aggressive blood pressure therapy when their systolic blood pressure was below 140 mm Hg.  Benefit from antihypertensive medication continued for diabetic individuals who had top blood pressure numbers between 140 and 150 (Brunström & Carlberg, 2016).  However, the risk of cardiovascular mortality reversed when blood pressure was forced below 140 mm Hg; the relative risk increased by 15 percent (Brunström & Carlberg, 2016).

The SWIFT trial, which currently dominates the now aggressive “do not exceed 120 mm Hg” blood pressure mandate excluded all diabetic patients when factoring their guidelines (Landmark NIH study shows intensive blood pressure management may save lives, 2015; The SPRINT Research Group, 2015; Brunström & Carlberg, 2016).   The SWIFT trial exclusion followed ADA recommendations to target diabetes individuals at a systolic blood pressure of 140 mm Hg due to uniquely altered cellular membrane physiology (Standards of Medical Care in Diabetes—2016, 2016).

So, what are the “best” recommended medications for type 2 diabetes mellitus?  The current safety standard, according to the ADA, is to start with metformin even when screened as “prediabetic” and especially if the body mass index (BMI) is greater than 35 kg/m2 (Standards of Medical Care in Diabetes—2016, 2016).

Individuals who then need something more to reduce further blood sugar but do not yet require insulin injections are best served with the DPP-4 inhibitors like sitagliptin, vildagliptin, and linagliptin (Ou SM et al., 2015).  Ou et al. (2015) performed a three-year, head-to-head evaluation of the DPP-4 series medications against the sulfonylurea group, the former standard.  The “gliptin” DPP-4 group of medications had significantly lower incidences of death and stroke.



Azoulay, L., Filion, K.B., Platt, R.W., Dahl, M., Dormuth, C.R., Clemens, K.K., Durand, M., Juurlink, D.N., Targownik, L.E., Turin, T.C., Paterson, J.M., Ernst, P. (2016). Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study. BMJ. 352.  DOI: 10.1136/bmj.i581

Bennett, W. L., Maruthur, N. M., Singh, S., Segal, J. B., Wilson, L. M., Chatterjee, R., … & Nicholson, W. K. (2011). Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Annals of internal medicine, 154(9), 602-613. Retrieved March 14, 2016 from http://annals.org/data/Journals/AIM/20231/0000605-201105030-00005.pdf

Brunström, M. & Carlberg, B.  (2016). Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses. BMJ. 352:i717  DOI:10.1136/bmj.i717

Chamberlain JJ, Rhinehart AS, Shaefer CF & Neuman A. (2016). Diagnosis and Management of Diabetes: Synopsis of the 2016 American Diabetes Association Standards of Medical Care in Diabetes. Ann Intern Med. [Epub ahead of print 1 March 2016] doi:10.7326/M15-3016

Landmark NIH study shows intensive blood pressure management may save lives. (2015). Press Release. Embargoed for Release: September 11, 2015, 10:30 AM EDT. National Heart, Lung and Blood Institute. National Institutes of Health. U.S. Department of Health & Human Services. Retrieved March 15, 2016 from http://www.nhlbi.nih.gov/news/press-releases/2015/landmark-nih-study-shows-intensive-blood-pressure-management-may-save-lives

Li, L., Li, S., Deng, K., Liu, J., Vandvik, P.O., Zhao, P., Zhang, L., Shen, J., Bala, M.M., Sohani, Z.N., Wong, E., Busse, J.W., Ebrahim, S., Malaga, G., Rios, L.P., Wang, Y., Chen, Q., Guyatt, G.H., Sun, X. (2016). Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ; 352 doi: 10.1136/bmj.i610

Lind, M., Hirsch, I.B., Tuomilehto, J., Dahlqvist, S., Ahrén, B., Torffvit, O., Attvall, S., Ekelund, M., Filipsson, K., Tengmark, B-O., Sjöberg, S. (2015). Liraglutide in people treated for type 2 diabetes with multiple daily insulin injections: randomised clinical trial (MDI Liraglutide trial). BMJ. 351. doi: 10.1136/bmj.h5364

Ou SM et al. (2015). Effects on clinical outcomes of adding dipeptidyl peptidase-4 inhibitors versus sulfonylureas to metformin therapy in patients with type 2 diabetes mellitus. Ann Intern Med. [e-pub 13OCT2015].   DOI: 10.7326/M15-0308)

Siu, A.L. on behalf of the U.S. Preventive Services Task Force. (2015). Screening for Abnormal Blood Glucose and Type 2 Diabetes Mellitus: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 163(11):861-868.  doi:10.7326/M15-2345

Standards of Medical Care in Diabetes—2016. (2016). Supplement 1, American Diabetes Association.  ISSN 0149-5992.  Retrieved March 15, 2016 from http://care.diabetesjournals.org/content/suppl/2015/12/21/39.Supplement_1.DC2/2016-Standards-of-Care.pdf

The Merck Index, 13th Ed. (2001). Rahway: Merck & Co. ISBN-13: 978-0911910131

The SPRINT Research Group. (2015). A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med.  373:2103-2116 November 26, 2015.  DOI: 10.1056/NEJMoa1511939