Can you avoid that antibiotic for your baby?

Adapted from Early life antibiotic exposure linked to asthma, obesity and coeliac disease by Heather Mason Univadis Medical News 24 Nov 2020.

Antibiotic exposure in the first two years of life increased the lifetime risk of developing various immunological, metabolic and neurodevelopmental conditions. This is thought to occur from the effect of the antibiotics on the gut microbiome.

Aversa Z et al published their findings in the Mayo Clinic Proceedings this year. They looked at over 14 thousand children. Half were boys and half were girls. 70% of the children had received an antibiotic during the first two years of life. These children were compared to the ones that had not had any antibiotics. The follow up was for the next 9 years.

All children were at increased risk of asthma and allergic rhinitis with a strong dose-response relationship. There was also an increased risk for attention deficit hyperactivity disorder. Girls were particularly susceptible to atopic dermatitis and coeliac disease and boys were more susceptible to obesity.

Aversa Z et al. Association of infant antibiotic exposure with childhood health outcomes. Mayo Clinic Proceedings. 2020 Nov6:S0025-6196(20)30785-0.

My comment: I wonder how much effect prematurity may have affected these results? It is well known that these babies have markedly less robust immune systems and their parents may also be more anxious about their health. I was premature and was given copious doses of penicillin for the tonsillitis that I got every 2 months. I remember that missing school and listening to the Jimmy Young show on the radio while my mum did the housework as being much better than going to school. As an adult I am very adversely affected by wheat. Whatever is going on, this article does lend credence to the fact that our gut bacteria have a lot more influence on our health than we have ever imagined. I easily recall the extreme pressure put on doctors to prescribe antibiotics for the most trivial of complaints. The younger the child, the more difficult it is to resist the “just in case” half plea-half threat from the parents.

Canagliflozin reduces onset of cardiac failure compared to other anti-diabetic drugs


Adapted from BMJ 10 Feb 18

A large population based cohort study showed that patients who started canagliflozin had a markedly reduced risk of being admitted to hospital with cardiac failure compared to three other types of anti-diabetes drugs.  There was no increase in heart attacks or stroke.

The study was based in the USA and the comparative drugs were DPP-4 inhibitors such as Victoza and Byetta, Gliptans such as Linagliptan and Sitagliptan, and sulphonylureas such as Gliclazide.   There was a 30-49% decrease in hospitalisations for cardiac failure.

None of the patients had a history of cardiac failure or cardiovascular disease at the start of the study and the patients were compared to others with the same HbA1C to ensure a fair comparison.

The reduction in cardiac failure could be a class effect of the Flozin drugs but further studies would be needed to find out. No other Flozins were used in the study as comparators.

Between 17,354 and 20,539 pairs of patients were matched for each comparison making this a very large study indeed.

Is there a new “magic bullet” for type two diabetes?

SLGT-2 Inhibitors Gaining Traction as a Class in Preventing Cardiovascular Consequences
April 15th, 2017 Diabetes in Control

Chest pain

Are we experiencing the next “magic bullet” in type 2 diabetes?
Cardiovascular mortality has long been established as the primary cause of death in patients with type 2 diabetes (T2D).

Cardiovascular effects of oral antidiabetic medications came to the forefront in 2007 with the landmark article in the New England Journal of Medicine, written by Dr. Steven Nissen.  In this publication, Dr. Nissen showed a strong association between use of rosiglitazone and increased incidence of cardiovascular complications and deaths.  In the years following, the FDA placed strong restrictions on the prescribing of rosiglitazone, sharply decreasing the market for Avandia.  Subsequent studies showed no correlation between the use of thiazolidinediones and adverse cardiovascular events, causing the FDA to reverse its stance on Avandia.  This class of agents was of particular interest because it was among the first of the oral agents that did not display the hypoglycemia seen with the sulfonylureas.  More importantly, this event caused the FDA to re-examine its approval process, and enforce that cardiovascular studies be done in all new drug presentation trials.
Until recently, there were no groundbreaking studies that suggested any class of oral hypoglycemic could significantly reduce CV risks associated with diabetes.  In January 2016, the European Heart Journal reported the results of EMPA-REG OUTCOME, a randomized placebo-controlled trial with over 7,000 subjects looked at empagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, which works by reducing glucose reabsorption at the renal tubule, thereby increasing glucose excretion. While a known effect is the reduction of hyperglycemia in T2D, there is also an increase in diuresis, weight loss, and reduction in blood pressure without associated tachycardia.  EMPA-REG OUTCOME showed that patients who received empagliflozin demonstrated significant declines in heart failure hospitalizations and cardiovascular deaths, without a rise in adverse effects, regardless of baseline heart failure state.  Based on these findings, Eli Lilly, the manufacturer of the Jardiance® brand of empagliflozin, saw a significant increase in their stock value, as their product was given preference over other available SGLT-2 inhibitors.
Earlier this month, the American College of Cardiology held the ACC.17, where the results of the CVD-REAL study were released .  CVD-REAL was a meta-analysis looking at over 364,000 patients from 6 different countries (United States, United Kingdom, Germany, Norway, Sweden, and Denmark), with T2D. Subjects were receiving either a SGLT-2 inhibitor or another glucose-lowering drug (oGLD) with even distribution across both arms in all six countries.  Of the patients studied, 3% had baseline heart failure, 13% had baseline cardiovascular disease, and 27% had baseline microvascular disease. The primary endpoint was hospitalization for heart failure, which showed a reduction strongly favoring the SGLT-2 inhibitors (hazard ratio [HR] 0.61; p < 0.001).  The secondary endpoints of all-cause mortality also favored the SGLT-2 inhibitors (HR, 0.49; p<0.001), as did heart failure hospitalizations and all-cause deaths in total (HR, 0.54; p<0.001).
Of important significance is the lack of population heterogeneity across the different countries, which suggests that the positive effects seen can be associated with the entire class of SGLT-2 inhibitors (which include dapagliflozin [Farxiga®] and canagliflozin [Invokana®]), and not just empagliflozin.

The investigators in CVD-REAL have come forth and stated that their findings do indeed line up with those from EMPA-REG OUTCOME.  The significance of this is there now exists an open market for SGLT-2 inhibitors, and that these once very costly medications may experience considerable cost reduction across the class, giving patients more affordable options.
As David Kliff, publisher of Diabetic Investor, recently stated, Dr. Nissen has received plenty of negative feedback from the community for his claims against rosiglitazone.  However, because of his initial findings and subsequent correction, the FDA has re-established its approach to the approval process for treatments of type 2 diabetes to include necessary studies of cardiovascular outcomes, much to the benefit of our patients, and that’s certainly a good thing.
Practice Pearls:
The significance of the fall and rise of rosiglitazone has had a tremendous impact on how type 2 diabetes treatments are evaluated.
EMPA-REG OUTCOME has demonstrated considerable positive effects on cardiovascular outcomes in T2D patients receiving empagliflozin, an SGLT-2 inhibitor.
The recent CVD-REAL study has strengthened the notion that all SGLT-2 inhibitors significantly reduce hospitalizations due to heart failure, as well as displaying a decline in cardiovascular deaths in the T2D population.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457-71.
FDA website. FDA significantly restricts access to the diabetes drug Avandia. Press release, September 23, 2010. NewsEvents/Newsroom/PressAnnouncements/ ucm226975.htm Accessed March 24, 2017.  
FDA website. FDA panel votes narrowly to modify Avandia restrictions, June 6, 2013.
American College of Cardiology Website. CVD-REAL Study: Lower Rates of Hospitalization For HF in New Users of SGLT-2 Inhibitors, March 19, 2017.

Mark T. Lawrence, RPh,PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTPD

Mayo Clinic Statin decision aid

Mayo clinic statin decision aid


The Mayo Clinic have a free online decision aid which will graphically represent the difference in heart attack risk that you face over the next ten years. You can choose three different calculation algorithms. Each varies a bit regarding factors that they consider important. The units section can transfer according to what system your lab uses for cholesterol results. In the UK they use the mmol/mol and in the US it is mg/dl.

Like other decision aids it has no facility to calculate the possible downside to statin use.

I put my measurements in and got a 3% risk on the AHA figures which would drop to a 2% risk on low dose statins. High dose statins would make no difference to this. Using the Framingham criteria my risk came in at 8% dropping to 6% on low dose statins. The Reynolds criteria uses high sensitivity CRP which we don’t measure in the UK. 



Double diabetes: watch out for ketoacidosis with some drug combinations


The use of adjuvant drugs for obese, insulin resistant type ones is increasing. What can you expect from therapy with some of the newer add on drugs? This article in Diabetes in Control tells you.

Type I Diabetes Mellitus: A Triple Therapy Approach

Diabetes management strategies have evolved since the discovery of newer oral agents that provide glycemic control through various pathways. Type 1 diabetes mellitus treatment has changed from traditional insulin regimens to incorporating other agents for improving glycemic control.

Maintaining adequate glycemic control and preventing end-organ damage is of utmost importance when managing diabetes. Uncontrolled blood glucose levels can lead to retinopathy, neuropathy, and nephropathy, which affects overall quality of life in our patients.

Due to these effects and the increased rate of uncontrolled A1c levels in patients with type 1 diabetes, various researchers have devised various treatment approaches for these patients. Recent research efforts have looked into the benefits of SGLT-2 inhibitors and their effect on cardiovascular events and mortality.

Matteo Monami et al., have looked into the benefits of these agents in patients with type 2 diabetes in the EMPAREG OUTCOME study. The findings from this research study highlight the benefit from SGLT-2 inhibitor use.  Their use in T2DM was found to reduce the risk of all-cause mortality, cardiovascular mortality, and myocardial infarction, but there was no increase in the risk of stroke. These findings can also provide similar benefits in type 1 diabetes patients; however, more studies are needed to provide stronger evidence.

Previous studies with other SGLT-2 inhibitors (i.e. canagliflozin) showed an increased incidence of diabetic ketoacidosis (DKA) in T1D patients. The incidence of DKA is thought to be associated with an increase in glucagon and free fatty acids that induces insulin resistance, which can also predispose to renal complications.

Conversely, a recent study showed improvements in renal functions in patients taking dapagliflozin through reductions in ischemia and hypoperfusion. These findings are not seen in patients taking liraglutide due to suppression of ketogenesis.

Recently, Nitesh Kuhadiya and colleagues expanded on the use of SGLT-2 inhibitors in type 1 diabetes patients. In this randomized clinical trial, researchers looked at the reduction in glycemia and body weight when adding dapagliflozin to an insulin and liraglutide regimen. Researchers hypothesized that the addition of dapagliflozin to an insulin and liraglutide regimen would provide improvements in glycemia without leading to increased concentrations of glucagon and other ketosis mediators.

Eligible patients were enrolled based on the following characteristics: 18-75 years of age with type 1 diabetes, fasting C-peptide of <0.1nmol/L, on any insulin regimen for more than 12 months with or without history of DKA. All patients had an A1c of <9.2% and were knowledgeable on carbohydrate counting. Additionally, patients needed to be on liraglutide therapy for at least 6 months prior to the start of the trial. 30 patients were assigned in a 2:1 ratio to receive either dapagliflozin 10 mg or placebo for 12 weeks. Consistency of carbohydrate content was documented by a dietitian.

The primary end-point of the study was a change in mean A1c after 12 weeks of dapagliflozin. Each patient’s body weight, systolic blood pressure, carbohydrate intake, and ketosis mediators were measured throughout the study as secondary endpoints. 26 patients completed the study, out of which only 17 were part of the intervention group. Those in the intervention group received dapagliflozin 5 mg daily for one week followed by 10 mg daily for 11 weeks. All insulin doses were targeted to 3.8-8.8 mmol/L.

At the end of the study it was found that triple therapy with liraglutide, insulin, and dapagliflozin decreased A1c by 0.66% when compared to placebo (~0.1%) (p <0.01 vs placebo). No severe hypoglycemic episodes were reported even when weekly glucose concentrations fell by 0.83 + 0.33 mmol/L in patients receiving triple therapy; no significant changes observed in the placebo group (P< 0.05 vs baseline; P=0.07 vs placebo).

When looking at the effects of this regimen and body weight, it was observed that body weight fell by 1.9 + 0.54 kg in the triple therapy group (P<0.05 vs placebo). Furthermore, there was a significant increase in ketosis mediators. It was also seen that total cholesterol and LDL-C level increased by 6% and 8%, respectively. Blood pressure readings remained unchanged in both groups.

In conclusion, a significant decrease in A1c and weight can be obtained by incorporating dapagliflozin for type 1 into an insulin and liraglutide regimen. However, special consideration should be taken when utilizing this approach due to an increase in ketosis mediators that can predispose patients to develop DKA.

Practice Pearls:

  • Triple therapy with dapagliflozin, insulin, and liraglutide reduces blood glucose levels without increasing the risk of hypoglycemia.
  • Weight reduction and A1c reduction can be obtained in type 1 diabetes patients while providing cardiovascular and renal protection properties, however closer monitoring is warranted due to increases in cholesterol and LDL-C.
  • Frequent monitoring should be implemented when utilizing this triple therapy approach due to an increase in glucagon, free fatty acids, and other mediators of ketosis predisposing to DKA.

Researched and prepared by Pablo A. Marrero-Núñez – USF College of Pharmacy Student Delegate – Doctor of Pharmacy Candidate 2017, reviewed by Dave Joffe, BSPharm, CDE


Chang, Yoon-Kyung, Hyunsu Choi, Jin Young Jeong, Ki-Ryang Na, Kang Wook Lee, Beom Jin Lim, and Dae Eun Choi. “Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury.” PLOS ONE PLoS ONE 11.7 (2016). Web

Kuhadiya, Nitesh D., Husam Ghanim, Aditya Mehta, Manisha Garg, Salman Khan, Jeanne Hejna, Barrett Torre, Antoine Makdissi, Ajay Chaudhuri, Manav Batra, and Paresh Dandona. “Dapagliflozin as Additional Treatment to Liraglutide and Insulin in Patients With Type 1 Diabetes.” The Journal of Clinical Endocrinology & Metabolism (2016). Web.

Monami, Matteo, Ilaria Dicembrini, and Edoardo Mannucci. “Effects of SGLT-2 Inhibitors on Mortality and Cardiovascular Events: A Comprehensive Meta-analysis of Randomized Controlled Trials.” Acta Diabetol Acta Diabetologica (2016). Web.

Choosing medication in type two diabetes


Cardiovascular Mortality of Diabetes Medications from Diabetes in Control


What should be the proper treatment selection for patients with type 2 diabetes?

The incidence of diabetes has been growing and the complications arising from uncontrolled blood glucose has been increasing along with it. It is estimated that more than 80% of deaths in developing countries are associated with life-threatening complications associated with diabetes.

Various treatment approaches have been implemented to avoid these complications and deaths related to diabetes. The mainstay of therapy for diabetes has been diet and exercise in conjunction with glucose-lowering drugs. Each of these agents are implicated with a potential benefit in health outcomes and mortality.

Agents from metformin have proven to be the first-line treatment due to its long-term benefits and improved glycemic control, to thiazolidinediones, which were falling out of favor due to their effects on heart failure and now proves to be beneficial in stroke.

Ongoing research efforts have compared various treatment modalities in head-to-head trials in order to understand glycemic events in diabetes. In a recent meta-analysis conducted by Giovanni F.M. Strippoli, PhD at the University of Bari, it is explained that sometimes these trials fail to dive into the cardiovascular mortality of these medications due to its inability to compare all treatment modalities simultaneously.

Strippoli and colleagues wanted to estimate the relative efficacy and safety of glucose-lowering medications. They extracted data from 301 clinical trials, which took into account 1,417,367 patient-months. All of these trials were 24 weeks of duration or longer. They included biguanides, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 agonists, basal insulin, meglitinides, and alpha-glucosidase inhibitors.

All of those studies that looked at medication regimens no longer supported by treatment guidelines or that have been withdrawn from the market were excluded from the study.

The primary endpoint of the study was the association of drug treatments with cardiovascular mortality.

Secondary endpoints were stratified into two endpoints, individual safety and individual efficacy. Secondary efficacy endpoints included all-cause mortality, myocardial infarction, stroke, A1c levels, and treatment failure.

Secondary safety endpoints included serious adverse events, hypoglycemia, and body weight.(My comment: the  pros and cons that patients and doctors are most interested in)

After randomization, trials were separated into those where patients were given a monotherapy regimen, other drugs were added to metformin, or where other drugs added to metformin and sulfonylureas.

In those trials where drugs were used as monotherapy, there was no significant difference in the drugs used as monotherapy and the odds of death from cardiovascular complications. Nonetheless, these were associated with lower A1c levels. However, there was insufficient data to determine treatment rankings for these effects.

There was a greater risk of hypoglycemia with basal insulin (OR, 17.9 [95% CI, 1.97 to 162]; RD, 10% [95% CI, 0.08% to 20%]) or sulfonylureas (OR, 3.13 [95% CI, 2.39 to 4.12]; RD, 10% [95% CI, 7% to 13%]) as monotherapy. Furthermore, when analyzing those drugs added to metformin there was no significant association between any drug classes and the risk of death, despite 45 cardiovascular deaths reported in 26 trials. Similar findings were seen in all-cause mortality and myocardial infarction when adding other drugs to metformin therapy. However, there was lower risk of stroke in those regimens that included metformin and DPP-4 inhibitors when compared to metformin and sulfonylureas (OR, 0.47 [95% CI, 0.23 to 0.95]; RD, −0.2% [95% CI, −0.4% to −0.04%).

Treatment failure was noted less often in those patients receiving metformin and SGLT-2 inhibitors. In terms of weight and hypoglycemia, the use of metformin and sulfonylureas ranked worse when compared to all different treatment modalities. Furthermore, in the third set of trials that looked at drugs added to metformin and sulfonylureas, there was no association between any of drugs and the risk of cardiovascular death. This same trend was seen with all-cause mortality and serious adverse events; no significant association was observed.

Alpha-glucosidase inhibitors provided the least A1c reduction when added to metformin and sulfonylureas, when compared to the implementation of basal insulin or thiazolidinediones (SMD, 1.42 [95% CI, 0.57 to 2.26]). Treatment failure was more notable in patients receiving DPP-4 inhibitors when compared to those patients where basal insulin was added. Hypoglycemia was observed less in those patients receiving GLP-1 agonists than those receiving thiazolidinediones. All drug classes provided weight reductions except thiazolidinediones and basal insulin.

In conclusion, these findings highlight that the use of glucose lowering agents alone or in combination are not implicated with cardiovascular mortality, all-cause mortality, or serious adverse events. Significant reductions in A1c can be obtained with the use of individual glucose lowering) agents. When these agents are added to metformin, clinically significant reductions can be obtained.

Practice Pearls:

  • Sulfonylureas or basal insulin should be avoided in the setting where hypoglycemia is of great concern.
  • Weight reductions can be obtained with regimens utilizing SGLT-2 inhibitors and GLP-1 agonists.
  • There is no significant association between the use of various glucose-lowering medications (alone or in combination) and the risk of cardiovascular mortality.


Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis. JAMA. 2016;316(3):313-324. doi:10.1001/jama.2016.9400.

American Diabetes Association. Standards of medical care in diabetes: Summary of revisions-2016, 7: approaches to glycemic treatment. Diabetes Care. 2016;38(suppl):S4-S5

What do you do if you run out of insulin?

type 1 diabetes medical equipment

The predicament of having difficulty getting insulin if it runs out for any reason, shouldn’t be a disaster in the UK. We have the NHS and you can go to your regular Pharmacist, ANY Pharmacist, your own GP, ANY GP or ANY Accident and Emergency Department and get a prescription free of charge.  
This is NOT the situation in the USA and here is a “Disasters Averted” story published o  16 August 20016 which discusses the situation and possible options you can take if you live there or ever face problems in the country in which you live.
As always with diabetes it helps to know about your possible options before the worst happens. When travelling always carry double what you think you will need. Insulin MUST be taken on carry on luggage so it doesn’t freeze in the hold of a plane. Also split your medications and gear with a pal so that if one of you is robbed you have spares.
 Out  of Insulin, Too Early to Renew — What To Do?

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It is not unusual for people to have difficulty keeping insulin from freezing or getting overheated. A patient, with type 1 diabetes for 17 years, had glucose that did not respond to his rapid-acting insulin as it usually does. He had two new vials in the refrigerator. He took a new vial out of his refrigerator earlier in the day, and started using it a few hours after he took it out. Had high post prandials that did not respond as usual to correcting. He had enough experience to wonder if perhaps something was wrong with his new insulin, so he thought he’d try another vial. He saw it was frozen. He had put the two vials at the back, where for many refrigerators it is colder. He thought back and wondered if the first vial looked any different, but remembered, he did not look closely at it.

He then went to get a new prescription filled at his pharmacy, but was told insurance would not cover it at this date; it was too early. It was cost prohibitive for him to pay out of pocket ~$300.00/vial. He contacted a diabetes health care provider (hcp) who offered him two sample vials to cover him until his prescription would once again be covered. He corrected and his glucose lowered. Disaster averted!

Not everyone has the luxury of having a hcp who has samples available in such a timely manner. If their hcp even had them, what if it were a weekend, or another time that the hcp did not have access to the samples? I reached out to certified diabetes educator, Laurie Klipfel, RN, MSN, BC-ANP, CDE, to see if she could offer any pearls of wisdom:

“This was a recent discussion on an AADE list serve with many good suggestions. The best suggestion was asking the healthcare provider if samples were available.  My next option would be to see if the insurance would make an exception under the circumstances (but this may take time). Someone with type 1 needs their insulin and cannot wait a day or two. The next option is to see if a diabetes educator could contact a rep for samples (their prescribing healthcare provider would also need to be involved). My next option would be to see if there were coupons available online from websites like:, or other websites. As a last resort (but may be the fastest option in a pinch), if a patient was not able to afford the analog insulins such as Novolog, Humalog, or Apidra, I might suggest discussing with the healthcare provider if using regular insulin instead would be an option. Though the analogs match insulin need to insulin much better than regular insulin, taking regular insulin (especially when using a generic brand such as Walmart’s ReliOn brand) can be a much cheaper option and would be much better than not taking any meal dose insulin at all.  It would be beneficial to explain the differences in action times and suggest taking regular insulin 15-30 min. before the meal and beware of potential hypoglycemia 3-5 hours after injection due to longer action of regular. Of note, you do not need a prescription for regular, NPH or 70/30 insulin.

“I would also agree with suggestions made on the list serve for keeping the insulin in the door of the refrigerator and using a thermometer in the refrigerator. If the temperature in the refrigerator is not stable, it may be helpful to have the thermostat of the refrigerator checked.“

Lessons Learned:


    • People who have diabetes, especially type 1 diabetes, need to have and take insulin that is effective.
    • If you have type 1 diabetes, you are in danger of DKA. Know what it is, how to prevent, recognize, and get help for DKA.
    • A back-up plan for insulin gone bad or not available.
    • To double check insulin when taken out of the refrigerator for the “feel of the temperature” of the insulin. Do not use if hot, warm, or frozen.
    • To know what their insulin should look like, clear or cloudy. Avoid it if crystals, clumps or anything unusual is noted.
    • The onset, peak, and length of action of insulins they are taking, as well as replacements if needed.
    • If insulin is not available and can’t get insulin within hours, to visit the nearest ED or urgent care center.

Influenza vaccine reduces total mortality in diabetics



From Diabetes in Control

Could Influenza Vaccination Prevent More Than Just the Flu?


Currently, only low-quality evidence exists to support efficacy of influenza vaccination to prevent seasonal influenza in patients with diabetes. There is even less information regarding the impact of influenza vaccination on cardiovascular events or all-cause mortality in this population. A recent study published in the Canadian Medical Association Journal was designed to evaluate the impact of seasonal influenza vaccination on admission to the hospital for acute myocardial infarction, stroke, heart failure, or pneumonia, and all-cause mortality in patients with type 2 diabetes.

Conducted over a 7-year time period from 2003 – 2009, the study analyzed retrospective patient data from the Clinical Practice Research Datalink in England. The analysis included 124,503 adult patients diagnosed with type 2 diabetes. At baseline, characteristics such as age, sex, smoking status, BMI, cholesterol labs, HbA1c, blood pressure, medications, and comorbidities were compared between patient groups. Vaccination rates of the included participants ranged from 63.1% to 69.0% per year. In general, unvaccinated participants were younger, had lower rates of pre-existing comorbidities, and were taking fewer medications.

The baseline characteristics of subjects enrolled in this retrospective analysis showed that sicker subjects received the flu vaccination more frequently. Given this observation, and seasonal confounding of flu outbreaks, data adjustments favored fewer cardiovascular events and lower rates of all-cause mortality during the influenza season spanning 7 years of data.  While other studies have shown that influenza vaccination can reduce the risk of cardiovascular events in high-risk patients, this study is the first to demonstrate a reduction in cardiovascular events associated with influenza vaccination in patients with diabetes. This study is notable for its large sample size and long duration. However, given the retrospective nature of the study, further trials are warranted to offer conclusive evidence about the benefits of influenza vaccination in patients with diabetes.

Practice Pearls:

  • Previous clinical trials aimed at studying the effectiveness of the flu vaccine in patients with diabetes are often small, inconclusive, and have not investigated cardiovascular outcomes.
  • When data was adjusted for baseline covariates and seasonal residual confounding, patients who received the influenza vaccination had significantly reduced rates of hospital admissions for stroke, heart failure, pneumonia or influenza, and all-cause mortality.
  • Large experimental or quasi-experimental trials are needed to establish a causal link between influenza vaccination and clinical endpoints in patients with diabetes.


Vamos EP, Pape UJ, Curcin V, Harris DPhil MJ, Valabhji J, Majeed A, et al.  Effectiveness of the Influenza vaccine in preventing admission to hospital and death in people with type 2 diabetes.  CMAJ. 2016 July 25.

Remschmidt C, Wichmann O, Harder T. Vaccines for the prevention of seasonal influenza in patients with diabetes: systematic review and meta-analysis. BMC Med 2015;13:53.

Researched and prepared by Alysa Redlich, Pharm.D. Candidate, University of Rhode Island, reviewed by Michelle Caetano, Pharm.D., BCPS, BCACP, CDOE, CVDOE

Ghost pills: has it happened to you?


Metformin_500mg_TabletsFrom Diabetes in Control: Disasters averted series
August 2nd, 2016


When it comes to metformin, when appropriate, I recommend the extended release version.

Last week my patient, female, 56 years of age, type 2 diabetes, visited. A1C was elevated, and she gained 5 pounds.  She had been on metformin ER for the last 6 months and doing well. She said she recently noticed a bean-looking/pill-looking thing in her stools that seemed to be related to her metformin. (She hadn’t looked before this).

She stopped her metformin and said she didn’t see it after that. “If it was coming out of me, it must not have been working, so I stopped it.” She refuses to check her glucose or weigh herself, therefore she did not notice the increase in her glucose levels. She did mention noticing her pants being tighter around her waist.
I informed her that the bean-looking/pill-looking thing in her stool was the metformin, but that did not mean it wasn’t working, it was. It was just a different method of delivery to be a slower release than other medications she takes or has taken. Some call the remains…ghost pills.
She resumed her metformin. Sure enough, she saw them again, but she did not stop taking her metformin.  Three months later, her A1C and weight returned to the levels before stopping.
Lessons Learned:
Understand that some controlled or extended release medications may look like they haven’t been “digested,” but that’s the formulation of the medication. The active ingredient has been released.
When starting your patients on medications that seem to not be “digested” such as extended release metformin, teach they may see this.
Learn more at: and


My comment:  As a GP I have come across this. At least I know what to say about it  now.

Forthcoming Drug Recommendations for Type 2 Diabetics from NICE

NICE have some drug recommendations to make for diabetics in their forthcoming guidelines later this year. It can be seen that NICE are heavily influenced by drug costs. So what could these new guidelines mean for you?

The blood pressure recommendations have scarcely changed but the use of Repaglinide first or second line for blood sugar control is a change from previously. Blood sugar targets have tightened up a bit and structured education is expected for insulin users. Cheaper, older insulins are favoured. Blood sugar testing is being rationed considerably. Aspirin is out of favour but drugs for erectile dysfunction are in. Erythromycin is being adopted for the very difficult to manage problem of gastroparesis.

The medications you will need to take to improve your life with diabetes will depend on many factors. Primarily, what do you want a medication to do for you?

The answer to this will depend on how well you are managing lifestyle changes, how long you have had the condition, the presence of any complications, and how tight you want glycaemic control, blood pressure and lipids to be. The targets need to be individualised to you, and this can be done by becoming more informed about your condition and discussing it with other health care providers and people with diabetes. We discuss these factors in our book, the Diabetes Diet, and I will be updating you on some of the new recommendations in further articles.

This article covers the changes to blood pressure medications, glycaemic targets and drugs to control blood sugar, self-monitoring of blood sugar, insulin initiation and the management of complications.

Blood pressure

For diabetics the BP target is 140/80 if there are no blood vessel complications such as kidney, eye or cerebrovascular disorders. If these are present the target is 130/80. BP lowering can improve peripheral neuropathy as well as stroke, MI, blindness and renal failure. 25% of those with type 2 diabetes develop nephropathy within 20 years of diagnosis.

Because ACE inhibitors and sartans reduce progression to renal disease better than other classes of anti-hypertensive agent they should be used first in diabetics unless they are a woman who could get pregnant as this class of drug is teratogenic. First line for women in this situation is a Calcium channel blocker CCB instead.

For Afro-Caribbean use ACE + diuretic or ACE + Calcium channel blocker. This is because this group respond less well to ACEs and sartans so should have add on drugs right from the start.

For those who can’t tolerate an ACE use a sartan unless there is renal deterioration or hyperkalaemia.

If BP is still not controlled add a CCB or thiazide diuretic.

If still not controlled use any of an alpha blocker e.g. Doxasozin or a beta blocker e.g. Bisoprolol or potassium sparing diuretic e.g. Spironolactone.

If someone has already had a heart attack or heart failure they will probably be on a beta blocker anyway. Carvedilol was superior to metoprolol in metabolic terms for renal protection in one study.

Use spironolactone with caution if someone is already on a sartan or ACE because they all can raise potassium.

Glycaemic control


All-cause mortality rises as hbaic rises and decreases as hbaic reduces. The risk of microvascular complications increase over hba1c of 6.5% (48 mmol/mol) or 7% (53) for macrovascular complications. Fasting blood glucose levels influence MI but not stroke or angina.  Amputation rates rise over the age of 60 for any given hbaic. Therefore it can be seen that to improve life expectancy and the quality of life that in general the tighter the blood sugar control the better.  At the same time doctors are asked to adopt an individualised approach to blood sugar targets and consider life expectancy, personal preferences, co-morbidities, risks of polypharmacy and they should consider stopping ineffective drugs.


NICE felt they could not comment on hba1c under 6% because only one study they looked at achieved this. Hba1cs in the 4s or 5s are not uncommon in low carbing diabetics however so don’t let this put you off your stride. NICE do say that if adults reach a lower blood sugar target than they were expecting and are not having hypoglycaemia the doctor should encourage them to maintain it.

They suggest:

6.5% for non-drug using diabetics or on drugs that don’t cause hypos e.g. metformin, pioglitazone, gliptins, victoza.

7% for the rest e.g. repaglinide, sulphonylureas, insulin.

7.5% intensify treatment, but individual circumstances e.g. life expectancy, co-morbidities, hypos need to be taken into account.

Drug step-laddering:

The first step for most diabetics is to offer metformin as the initial drug treatment.  But don’t give or stop metformin if the kidney test, the egfr is below 30 and use with caution if under 45. Regular metformin can give diarrhoea and if this is a problem the long acting version can be used.

If there is symptomatic hyperglycaemia, such as thirst and weight loss consider a sulphonylurea or insulin first. Other drugs may be considered once the blood sugars have stabilised. .

Next they suggest Repaglinide on its own or with metformin. Repaglinide is not licenced with other drugs. For people who could not tolerate metformin and repaglinide are the most cost effective treatment option.

If repaglinide was not suitable or is not achieving the desired blood sugar target any of pioglitazone, a sulphonylurea or a gliptin can be used.  The choice can be tailored to the patient.

Sulphonylureas had the most hypos and gliptins the least. Metformin had the best weight loss. Sulphonylurea and Pioglitazone had the most weight gain. NICE prefer doctors to use the lowest cost gliptin because they are relatively expensive.

Reducing hypoglycaemia should be a particular aim for those on insulin or a sulphonylurea. As blood sugar monitoring is necessary for these drugs, this factor can increase the cost considerably over and above the costs of the medication.

Consider GLP1 mimetic i.e. Byetta or Victoza if the BMI is over 35.  Only continue it if hba1c goes down by 1% and weight goes down by 3% over six months.

Insulin is considered to be the “last option”. There is currently research being carried out on the effects of early use of insulin in type two diabetes and this may change practice in the future.

Only offer insulin + Victoza in specialist care setting.

Insulin initiation

When starting insulin use support from an appropriately trained health professional and give:

Structured education

Telephone support

Frequent self monitoring

Dose titration to target

Dietary understanding

Hypoglycaemia management

Management of acute rises in blood sugar

Continue metformin

The usual first choice insulin is NPH insulin at bedtime or twice daily.

The more expensive Lantus or Levemir may be considered if a carer would be able to cut to once daily injections or if hypoglycaemia is a problem or otherwise the patient would need twice daily NPH and oral drugs or they can’t use the NPH device.

If hbaic is 9% (75) consider twice daily pre-mixed bi-phasic insulin.

Blood sugar testing

NICE recommends that self- monitoring of blood sugars is to be avoided unless a person is on insulin, has symptomatic hypoglycaemia, or oral medication that causes hypos or driving or operating machinery, pregnant or trying for a baby.  It may be worth considering if a patient is on oral or intravenous steroids.

Doctors or nurses should reassess the need for self monitoring annually to see if it remains worthwhile.

Self monitoring produced only a 0.22% reduction in hbaic. It was considered by NICE to be not helpful for most people with type two diabetes though more hypos were detected with it.


Anti-platelet therapy for cardiovascular protection

There is no overall benefit to taking aspirin or clopidogrel in type 2 diabetes unless they already have cardiovascular disease.

Managing complications

Autonomic neuropathy symptoms are: gastroparesis, diarrhoea, faecal incontinence, erectile dysfunction, bladder disturbance, orthostatic hypotension, gustatory and other sweating disorders, dry feet and ankle oedema.

Treatments for gastroparesis are metoclopramide, domperidone and erythromycin.

Refer to a specialist if severe or persistent vomiting occurs or the diagnosis is in doubt.

Nocturnal diarrhoea may indicate autonomic neuropathy.

Tricyclics are often given for neuropathic pain but can increase postural hypotension.

Erectile dysfunction

Offer men the chance to speak about this at their annual review. Offer Viagra, Cialis and similar and refer if these don’t work.

Eye damage

Diabetic eye damage is the single largest cause of blindness before old age.

Refer to the emergency ophthalmologist if:

Sudden loss of vision

Rubeus’s Iridis

Pre-retinal or vitreous haemorrhage

Retinal detachment

Send for rapid review if there is new vessel formation.

So what do you think of the new NICE recommendations?  Do you think these changes will affect your medications?